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Introduction: Due to the increasing use of dynamic breast MRI and the limited availability of MR-guided interventions, MRI-detected lesions usually undergo a second-look ultrasound (SLUS). We investigated the safety of a negative SLUS and a benign SLUS correlate in excluding malignant and high-risk lesions (B3) and evaluated criteria for the rate of detection on SLUS., Methods: In the retrospective analysis, all breast MRIs performed between 2011 and 2013 were screened for newly detected lesions. We analyzed the SLUS detection rate dependent on breast density, mass character, lesion size, and histology. We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a negative and benign SLUS for malignant lesions (B5) and lesions requiring surgical excision (including high-risk and B5 lesions)., Results: We successfully correlated 110 of 397 lesions. The detection rate was significantly higher for mass than for non-mass lesions and correlated with lesion size for mass lesions only. Lesions without/with a benign SLUS correlate were more frequently benign (including B3) or required no further procedure (B2). The sensitivity of SLUS in the detection of B3 and B5 lesions was 58%, and 73% in the detection of B5 lesions. The NPV of a negative or benign SLUS for B3 and B5 lesions was 89%, and 96% for B5 lesions., Discussion: SLUS is a safe diagnostic tool for the management of MRI-detected lesions and can spare patients from undergoing invasive procedures., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Background: Prediction of histological tumor size by post-neoadjuvant therapy (NAT) ultrasound and magnetic resonance imaging (MRI) was evaluated in different breast cancer subtypes., Methods: Imaging was performed after 12-week NAT in patients enrolled into three neoadjuvant WSG ADAPT subtrials. Imaging performance was analyzed for prediction of residual tumor measuring ≤10 mm and summarized using positive (PPV) and negative (NPV) predictive values., Results: A total of 248 and 588 patients had MRI and ultrasound, respectively. Tumor size was over- or underestimated by < 10 mm in 4.4% and 21.8% of patients by MRI and in 10.2% and 15.8% by ultrasound. Overall, NPV (proportion of correctly predicted tumor size ≤10 mm) of MRI and ultrasound was 0.92 and 0.83; PPV (correctly predicted tumor size > 10 mm) was 0.52 and 0.61. MRI demonstrated a higher NPV and lower PPV than ultrasound in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-positive and in HR-/HER2+ tumors. Both methods had a comparable NPV and PPV in HR-/HER2- tumors., Conclusions: In HR+/HER2+ and HR-/HER2+ breast cancer, MRI is less likely than ultrasound to underestimate while ultrasound is associated with a lower risk to overestimate tumor size. These findings may help to select the most optimal imaging approach for planning surgery after NAT., Trial Registration: Clinicaltrials.gov , NCT01815242 (registered on March 21, 2013), NCT01817452 (registered on March 25, 2013), and NCT01779206 (registered on January 30, 2013).

Purpose: To report on 10 years of high-risk service screening with annual MRI in the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC)., Methods: A cohort of 4,573 high-risk, previously unaffected women (954 BRCA1 carriers, 598 BRCA2 carriers, 3021 BRCA1/2 non-carriers) participating in the GC-HBOC surveillance program was prospectively followed. Screening outcomes for 14,142 screening rounds with MRI between 2006 and 2015 were analyzed and stratified by risk group, type of screening round, and age., Results: A total of 221 primary breast cancers (185 invasive, 36 in situ) were diagnosed within 12 months of an annual screening round with MRI. Of all cancers, 84.5% (174/206, 15 unknown) were stage 0 or I. In BRCA1 carriers, 16.9% (10/59, 5 unknown) of all incident cancers (screen-detected and interval cancers combined) and in BRCA2 carriers 12.5% (3/24, 4 unknown) were stage IIA or higher, compared to only 4.8% (2/42, 2 unknown) in high-risk BRCA1/2 non-carriers. Program sensitivity was 89.6% (95% CI 84.9-93.0) with no significant differences in sensitivity between risk groups or by age. Specificity was significantly lower in the first screening round (84.6%, 95% CI 83.6-85.7) than in subsequent screening rounds (91.1%, 95% CI 90.6-91.7), p < 0.001. Cancer detection rates (CDRs) and as a result positive predictive values were strongly dependent on type of screening round, risk group and patient age. CDRs ranged from 43.5‰ (95% CI 29.8-62.9) for the first screening round in BRCA2 carriers to 2.9‰ (95% CI 1.3-6.3) for subsequent screening rounds in high-risk non-carriers in the age group 30 to 39 years., Conclusions: High-risk screening with MRI was successfully implemented in the GC-HBOC with high sensitivity and specificity. Risk prediction and inclusion criteria in high-risk non-carriers need to be adjusted to improve CDRs and thus screening efficacy in these patients.

Background: Cancer-related cognitive dysfunction has mostly been attributed to chemotherapy; this explanation, however, fails to account for cognitive dysfunction observed in chemotherapy-naïve patients. In a controlled, longitudinal, multisite study, we tested the hypothesis that cognitive function in breast cancer patients is affected by cancer-related post-traumatic stress., Methods: Newly diagnosed breast cancer patients and healthy control subjects, age 65 or younger, underwent three assessments within one year, including paper-and-pencil and computerized neuropsychological tests, clinical diagnostics of post-traumatic stress disorder (PTSD), and self-reported cognitive function. Analysis of variance was used to compare three groups of participants-patients who did or did not receive chemotherapy and healthy control subjects-on age- and education-corrected cognitive performance and cognitive change. Differences that were statistically significant after correction for false discovery rate were investigated with linear mixed-effects models and mediation models. All statistical tests were two-sided., Results: Of 226 participants (166 patients and 60 control subjects), 206 completed all assessment sessions (attrition: 8.8%). Patients demonstrated overall cognitive decline (group*time effect on composite z -score: -0.13, P = .04) and scored consistently worse on Go/Nogo errors. The latter effect was mediated by PTSD symptoms (mediation effect: B = 0.15, 95% confidence interval = 0.02 to 0.38). Only chemotherapy patients showed declined reaction time on a computerized alertness test. Overall cognitive performance correlated with self-reported cognitive problems at one year ( T = -0.11, P = .02)., Conclusions: Largely irrespective of chemotherapy, breast cancer patients may encounter very subtle cognitive dysfunction, part of which is mediated by cancer-related post-traumatic stress. Further factors other than treatment side effects remain to be investigated., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Clinical Issue: In the daily clinical routine characterization of focal lesions using native B‑mode classical ultrasound and color Doppler can be difficult or insufficient; therefore, additional diagnostic information must be taken into consideration., Standard Radiological Methods: Standard radiological methods in the daily clinical routine include native B‑mode ultrasound and color Doppler ultrasound., Methodical Innovations: Using sonoelastography it is possible to evaluate and characterize tissue properties and focal lesions regarding their stiffness to acquire additional information on a noninvasive basis., Performance: Sonoelastography enables the differentiation between benign and malignant lesions especially in organs that can be easily evaluated using ultrasound. This particularly includes the liver, the thyroid gland, the breasts and the testicles. Regarding the liver, sonoelastography techniques can also be used for evaluation of the tissue flexibility in the diagnostics of fibrosis and cirrhosis., Achievements: Nowadays, elastography is implemented into every modern ultrasound system and has been established as a supplementary examination technique to the conventional ultrasound techniques., Practical Recommendations: Sonoelastography should be used in cases with unclear findings as an additional noninvasive tool for the differentiation between benign and malignant lesions.

Purpose: To evaluate the value of contrast-enhanced ultrasound (CEUS) using a high-end ultrasound system in the characterization of endoleaks after endovascular aortic repair (EVAR)., Material and Methods: In this mono-center study, 41 patients were retrospectively analyzed after being examined using a modern high-end ultrasound system (RS80A with Prestige, Samsung Medison Co., Ltd., Seoul, Korea). The maximum diameters of the aneurysms were measured in two planes (right-left and ventral-dorsal). The performance of Color Doppler in comparison to CEUS was evaluated and CEUS was considered as the gold standard in endoleaks detection., Results: 41 patients were included in the study. Between June and December 2016, mostly male patients (n = 38; 92,7%) were examined, corresponding to the incidence of abdominal aortic aneurysms in the population. Average age was 75±8 years (range 58-100 years). Average diameter of the treated aneurysm-sacs was 5,04±1.5 cm (range 2.7-10.5 cm) in the right-left plane and 4,75±1.36 cm (range 2.8-8.9 cm) in the ventral-dorsal plane. Using CEUS as the gold standard endoleaks could be detected in 28 patients (68,3%) with 13 patients not showing an endoleak after EVAR. Color Doppler showed a sensitivity of 32.1%, a specificity of 92.3%, a positive predictive value (PPV) of 90.0% and a negative predictive value (NPV) of 38,7% compared to CEUS being the gold standard., Conclusion: CEUS after EVAR using a modern high-end ultrasound system is a fast and cost-effective imaging modality for the detection and follow-up of endoleaks with superior benefits compared to Color Doppler. CEUS remains the initial standard-of-care examination for follow-up.

Purpose: To analyse the diagnostic performance of contrast-enhanced ultrasound (CEUS) in patients with vascular complications and transplant rejection compared to histopathological results., Materials and Methods: Our study consisted of 45 retrospectively analysed patients that underwent liver transplantations between January 1993 and December 2015 and developed post-transplant vascular complications with transplant rejection. CEUS examinations took place between September 2006 and December 2015. CEUS findings were correlated with histopathological results., Results: CEUS showed a sensitivity of 61.5%, a specificity of 100.0%, a positive predictive value (PPV) of 100.0% and a negative predictive value (NPV) of 86,5% in the detection of vascular complications with post-transplant rejection. 5 examinations were reported as normal whereas the histopathological result showed a transplant rejection (false-negative)., Conclusion: CEUS might be a useful additional non-invasive technique for the assessment of vascular complications with post-transplant rejection in patients after liver transplantation.

Purpose: To compare the value of a portable ultrasound system and a high end ultrasound system in detection of endoleaks after EVAR., Material and Methods: In this retrospective study, a cohort of 25 patients underwent both standard examination using a portable ultrasound system (Philips VISIQ) and a second examination using a high end ultrasound system (Philips EPIQ 7). The examination included B-mode and color Doppler in detection of endoleaks. Additional the maximum diameter of the aneurysm was measured in two planes (right-left and ventral-dorsal). The gold standard was contrast-enhanced ultrasound (CEUS) in detection of endoleaks., Results: 25 patients were included in the study. Patients were predominantly male (n = 23) with an average age of 73,30±7.82 years (range 54-85). Diameters of the treated aneurysms were in the right-left plane 5,32±1.88 cm and ventral-dorsal 4,99±1.78 cm using the high end system. Diameters of the treated aneurysms were in the right-left plane 5,30±1.82 cm and ventral-dorsal 4,87±1.74 cm using portable ultrasound system. In 80% of the cases CEUS could detect an endoleak. Whereas the high end system could detect in B-mode 40% and color Doppler 45% of the cases an endoleak. The portable system could detect in B-mode 30% and in color Doppler 35% of the cases an endoleak. On both systems in B-mode a false positive endoleak was found on the same patient. All high flow endoleaks, which needed intervention, could be detected on all systems., Conclusion: The high end ultrasound system does not seem to have an additional advantage in the measurement of the aneurysm diameter. Due to a higher resolution, more endoleaks could be detected in B-mode and color Doppler by using the high end system. The presence of small endoleaks could only be detected by using contrast enhanced ultrasound on an high end ultrasound system. High flow endoleaks could be reliable seen on both systems.

Cowpox viruses are orthopoxviruses that may survive in the environment for years. Rodents are regarded as the primary hosts, but transmission to other species has been reported. This report describes a cowpox virus infection in a cat with subsequent transmission to its owner leading to protracted, atypical and severe clinical signs. A young cat presented with multiple crusts and plaques on the neck, muzzle and tail base. The owner developed an erythematous lesion with elevated margins, central necrosis and crust formation below the left breast, a neurogenic inflammation, enlarged regional lymph nodes, a colliquative lymphadenitis and concomitant flu-like symptoms. Cultures were taken at the first visit from the cat's lesional skin and the patient's skin, and polymerase chain reaction with sequencing of the haemagglutinin region of both were positive for cowpox virus. The patient was treated with various antibiotics and methylprednisolone and was in clinical remission after 7 months., (© 2015 British Association of Dermatologists.)

Background: Pretreatment cognitive impairment in cancer patients is well established but unexplained. Similar cognitive compromise has been observed in post-traumatic stress disorder (PTSD) patients, and PTSD symptoms are a frequent concomitant of cancer diagnosis. We tested the hypothesis that pretreatment cognitive impairment is attributable to cancer-related post-traumatic stress., Methods: Women aged 65 years or younger who were diagnosed with breast cancer (case patients) or had undergone negative routine breast imaging (control patients) at one of six participating breast centers underwent traditional and computerized neuropsychological testing, clinician-administered diagnostic assessment of stress disorders, and self-report assessments of cognitive function and depression. To minimize confounding, case patients were evaluated prior to any local or systemic treatment. Cognitive indices of case patients, control patients, and normative samples were compared. The patients' risk of overall cognitive impairment was determined. Linear regression and a mediation model were used to test the study hypothesis. All statistical tests were two-sided., Results: The 166 case patients and 60 well-matched control patients showed near-identical deviations from population norms. Case patients scored worse than control patients on two of 20 cognitive indices (Go/Nogo commission errors, Go/Nogo omission errors). Self-reported cognitive problems were associated with Go/Nogo omission errors and more pronounced in case patients. Only PTSD symptoms (Beta = 0.27, P = .004) and age (Beta = 0.22, P = .04) statistically significantly predicted Go/Nogo errors. The effect of having cancer on Go/Nogo errors was mediated by PTSD symptoms. Case patients did not have an increased risk of overall cognitive impairment., Conclusion: Prior to any treatment, breast cancer patients may show limited cognitive impairment that is apparently largely caused by cancer-related post-traumatic stress., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

In recent years the use of elastography in addition to sonography has become a routine clinical tool for the characterization of breast masses. Whereas free hand compression elastography results in qualitative imaging of tissue stiffness due to induced compression, shear wave elastography displays quantitative information of tissue displacement. Recent studies have investigated the use of elastography in addition to sonography and improvement of specificity in differentiating benign from malignant breast masses could be shown. Therefore, additional use of elastography could help to reduce the number of unnecessary biopsies in benign breast lesions especially in category IV lesions of the ultrasound breast imaging reporting data system (US-BI-RADS).

Purpose: To compare the value of high-resolution contrast-enhanced ultrasound in the detection and characterisation of endoleaks after EVAR., Material and Methods: In this retrospective study, a cohort of 80 patients underwent both standard examination using a curved array 5 MHz transducer and a second examination using a curved array 9 MHz transducer. The examination included B-mode, color Doppler and contrast-enhanced ultrasound using the Philips EPIQ 7 scanner., Results: 80 patients were included in the study. CEUS was used as the preferred examination in determining the presence of an endoleak. The sensitivity and specificity for the detection of endoleak using the 5 MHz transducer was: CEUS (96.8%, 100%), Color Doppler (47.6%, 94.1%), B-mode (15.8%, 94.1%), while for the 9 MHz transducer: CEUS (100%, 100%), Color Doppler (39.7%, 94.1%), B-mode (23.8%, 24.1%)., Conclusion: High resolution ultrasound (9 MHz) in detection and characterization of endoleaks after EVAR has some minor advantages in comparison to lower resolution ultrasound (5 MHz).

Purpose: To evaluate the use of color Doppler sonography and free hand sonoelastography in the assessment of breast fibroadenomas according to their size and shape., Materials and Methods: From December 2012 to March 2013 women with 16 solid breast masses, classified as BI-RADS category 3 or 4 were examined with B-mode ultrasound, sonoelastography and color Doppler sonography. Lesions were subdivided according to their shape in round, ovoid or macrolobulated and according to their size (<2.0 cm or ≥2.0 cm). Two readers assessed sonoelastographic findings at 12.5 MHz using the tsukuba elasticity score and results of Doppler sonography using a score of 0, 1 or 2, depending on the degree of perfusion., Results: Among the 16 examined lesions 3 showed a round shape, 9 were ovoid and in 4 cases a macrolobulated appearance could be seen. No significant differences concerning Tsukuba-score depending on various shapes of fibroadenomas in B-mode sonography could be shown (p = 0.91) and also comparison of Tsukuba-scores and size of masses revealed no significant differences (p = 1.0). Sizes of fibroadenomas ≥2 cm were significantly associated with an increased vascularization of the lesions (p = 0.04) and a macrolobulated appearance in B-mode sonography (p = 0.04)., Conclusion: The combination of color Doppler sonography and sonoelastography in addition to B-mode sonography leads to an increased accuracy in distinguishing benign from malignant breast masses and to an improvement in characterization of fibroadenomas independent of their shape or size.

Purpose: To compare compression elastography and contrast enhanced ultrasound in the follow-up after endovascular aortic aneurysm repair., Material and Methods: In this retrospective study a cohort of 33 patients with both CEUS and elastography follow-up examinations after EVAR were included. The examinations were done with a Siemens S 2000 with curved array 4 MHz multi-frequency transducer., Results: Regarding our inclusion and exclusion criteria we obtained 33 patients. CEUS was used as the preferred examination in determining the presence of an endoleak. The true positive rate for the detection of Endoleaks with compression elastography was 42.4% (14/33), the false positive rate was 12.1% (4/33), the true negative rate was 15.2% (5/33) and the false negative rate was 30.3% (10/33). The sensitivity of compression elastography was therefore 58.3% and the specifity was 55.6%. Kappa coefficient was 0.115., Conclusion: Compression elastography does not seem to have any additional advantages in the detection and classification of endoleaks in comparison to CEUS.

Purpose: To evaluate the additional effect of higher frequent linear probes than 12.5 MHz in color Doppler sonography and free hand sonoelastography of benign and malignant breast masses and to compare different color encodings in sonoelastography., Materials and Methods: From December 2012 to March 2013, 37 patients with benign or malignant breast masses were prospectively included in this study. All solid masses have been histologically proven. Two readers assessed sonoelastographic findings at 12.5 MHz vs. 17 MHz according to the tsukuba elasticity score and additionally different color encodings were compared. Results of Doppler sonography using a score of 0, 1 or 2, depending on the degree of perfusion, also were assessed at 12.5 MHz vs. 17 MHz., Results: Among the 37 examined breast masses there were 10 cysts, 16 fibroadenomas and 11 carcinomas. Median participant age was 49.0 years. Use of color Doppler sonography enabled to distinguish cysts from solid breast masses (p < 0.001), without an improvement at 17 MHz. Additional sonoelastography significantly improved the specificity in solid breast masses (p < 0.001). No changes could be seen using different colors in sonoelastography., Conclusion: Combination of color Doppler sonography and sonoelastography can increase the accuracy in distinguishing benign from malignant breast masses. The use of linear probes with a higher frequency than 12.5 MHz does not show any benefit, neither in color Doppler sonography nor in sonoelastography.

Objective: The evaluation of breast implants for rupture is currently the domain of ultrasound and MRI, while mammography is of very limited diagnostic value. Recently, specific visualisation of silicone has become feasible using dual-energy CT. Our objective was to evaluate whether it is feasible to identify silicone in breast implants by dual-energy CT and to reliably diagnose or rule out ruptures., Methods: Seven silicone breast implant specimens were examined on dual-source CT at 100- and 140-kV tube potential with a 0.8-mm tin filter (collimation 128 × 0.6 mm, current-time products 165 and 140 mAsref with modulation, rotation time 0.28 s, pitch 0.55). Two patients scheduled for implant removal or replacement were examined with identical parameters., Results: The silicone of the implant specimens showed a strong dual-energy signal. In one patient, both implants were intact, while a rupture was identified in the other patient. Ultrasound, MRI, surgical findings and histology confirmed the dual-energy CT diagnosis., Conclusion: Dual-energy CT may serve as an alternative technique for speedy evaluation of silicone breast implants. Specific clinical studies are required to determine the diagnostic accuracy and define indications for this technique.

Objective: We used an algorithm for quantitative image processing to classify breast tissue into the categories fibrosis, involution atrophy, and normal. The algorithm entailed use of Minkowski functionals in topologic analysis of x-ray attenuation patterns on digital mammograms. The results were compared with those of techniques based on evaluation of gray-level histograms., Materials and Methods: One hundred digital mammograms were classified by consensus of two experienced readers. A topologic parameter extracted from the Minkowski functional spectra was obtained for retromammilar image sections (512 x 512 pixels). From the gray-level histogram of each of these samples, the 20th percentile, median, and mean were determined. Discriminant analysis was used to assess the predictive value of the methods with respect to correct categorization., Results: The mean gray-level intensity of normal breast tissue was 90 +/- 9, and the 20th percentile was 68 +/- 18. The mean gray-level intensity was 84 +/- 7 for involution and 90 +/- 8 for fibrosis; the 20th percentile was 75 +/- 6 for involution and 73 +/- 10 for fibrosis. The results of discriminant analysis showed that use of the gray-level histogram parameters led to correct classification in 66% of cases. Use of topologic analysis with Minkowski functionals increased the rate of correct classification to 83%. When a combined model of histogram-derived parameters and Minkowski functionals was used, 89% of cases were categorized correctly., Conclusion: Topologic analysis of x-ray attenuation patterns on digital mammograms obtained with Minkowski functionals is simple and robust, and the results agree with radiologists' ratings. Because correct classification is significantly higher than with use of density features, our technique may be an objective and quantitative alternative in the evaluation of the parenchymal structure of the breast.

Background: Galactooligosaccharides (GOS) and long-chain fructooligosaccharides (lcFOS) proliferate bifidobacteria in infant gut microbiota. However, it is not known how GOS and FOS influence the microbiota of pregnant women and whether a potential prebiotic effect is transferred to the offspring., Objectives: We aimed to test how supplementation with GOS and lcFOS (GOS/lcFOS) in the last trimester of pregnancy affects maternal and neonatal gut microbiota. Variables of fetal immunity were assessed as a secondary outcome., Design: In a randomized, double-blind, placebo-controlled pilot study, 48 pregnant women were supplemented 3 times/d with 3 g GOS/lcFOS (at a ratio of 9:1) or maltodextrin (placebo) from week 25 of gestation until delivery. Percentages of bifidobacteria and lactobacilli within total bacterial counts were detected by fluorescent in situ hybridization and quantitative polymerase chain reaction in maternal and neonatal (days 5, 20, and approximately 182) stool samples. Variables of fetal immunity were assessed in cord blood by using flow cytometry and cytokine multiplex-array analysis., Results: The proportions of bifidobacteria in the maternal gut were significantly higher in the supplemented group than in the placebo group (21.0% and 12.4%, respectively; P = 0.026); the proportion of lactobacilli did not differ between the groups. In neonates, bifidobacteria and lactobacilli percentages, diversity and similarity indexes, and fetal immune parameters did not differ significantly between the 2 groups. Mother-neonate similarity indexes of bifidobacteria decreased over time., Conclusions: GOS/lcFOS supplementation has a bifidogenic effect on maternal gut microbiota that is not transferred to neonates. The increased maternal bifidobacteria did not affect fetal immunity as measured by a comprehensive examination of cord blood immunity variables.

Examination of tumor biological factors for prognostic and predictive indicators is not part of routine testing in ovarian cancer. As in other tumors, the detection of hematogenous tumor spread could help to estimate the risk of metastatic disease. We examined the expression of p53, KI67, topoisomerase IIalpha (Top IIa), epidermal growth factor receptor (EGFR), human epithelial growth factor receptor 2 (HER2) and nm23 in tumor tissues from 90 patients with ovarian cancer. All underwent bone marrow (BM) aspiration and screening for disseminated tumor cells in the bone marrow (DTC-BM) at primary diagnosis. BM aspiration, cytospin preparation, and immunocytochemical staining with the anticytokeratin antibody (A45-B/B3) were done following a standardized protocol. The expression of p53, KI67, Top IIa, EGFR, HER2, and nm23 was evaluated by immunohistochemistry on paraffin-embedded tissue samples and classified by percentage of stained cells or immunoreactive score (IRS). The prognostic impact of the individual factors together with standard histologic parameters was calculated by univariate and multivariate analyses. Expression rates for HER2 (2+/3+: 34.5%), KI67 (median 30%), p53 (median IRS 5), and Top IIa (median IRS 4) were relatively high, whereas nm23 (median IRS 2) and EGFR (IRS 0: 61%) showed weak staining. In 21/90 patients (23.3%), DTC-BM (>/=1/2 x 10(6) cells) could be detected. The presence of DTC-BM was inversely related to nodal status (P = .015) but not to the other factors examined. Tumor stage (P = .02), lymph node involvement (P = .003), grade (P = .046), postoperative tumor residue (P < .001), peritoneal seeding (P = .02), and KI67 (P = .046) significantly correlated with overall survival (OS) after a median observation time of 28 months (2-105). The finding of ascites was borderline significant (P = .050). The presence of DTC-BM (P = .04) and KI67 positivity (P = .02) predicted reduced distant disease-free survival. By multivariate analysis, postoperative tumor residue remained an independent factor for OS (P = .02, relative risk = 4.6). As a primarily locoregional disease, tumor stage and postoperative tumor residue are the main determinants of prognosis in patients with ovarian cancer. However, even in advanced stages, examination of tumor biological factors could help to stratify subgroups of patients and establish targeted therapies.

Purpose: The presence of isolated tumor cells in the bone marrow (ITC-BM) is an independent prognostic factor in all stages of breast cancer. Both the expression/amplification of human epithelial growth factor receptor 2 (HER2) and Topoisomerase IIalpha (TOP IIa), a key enzyme of DNA replication and main target of anthracyclins, in breast cancer tissue seem to have predictive value regarding the effectiveness of systemic therapies., Methods: To investigate the correlation between these factors and their influence on clinical outcome, tumor tissue of 54 patients who were screened for ITC-BM before and after anthracyclin-based chemotherapy (abCTX) was examined for HER2 and TOP IIa by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH)., Results: By IHC, 31% of the tumors showed positive for HER2 (2+/3+), 14.6% were amplified in FISH. TOP IIa expression (>50%) was found in 13/53 patients (25%), FISH was positive in 5/47 cases (11%). TOP IIa amplification was not seen in cases without HER2 amplification, five of the seven HER2 amplified cases also were amplified for TOP IIa (71% co-amplification). Forty-three patients had adjuvant, seven neo-adjuvant, four palliative abCTX. ITC-BM were present in 24% of patients before and 31% after CTX. Patients with HER2 (IHC, P = 0.29) and TOP IIa (FISH, P = 0.16) positive tumors tended to stay or become negative in BM status after abCTX and vice versa. After a median follow-up of 44 months (6-127), none of the factors reached significance for overall survival. Yet, patients with HER2 (P = 0.16) and TOP IIa (P = 0.09) positive tumors showed a trend towards prolonged disease-free survival. Remarkably, none of the TOP IIa FISH-positive patients developed distant metastases (P = 0.099) or died (P = 0.19) after CTX so far., Conclusions: HER2- and TOP IIa positivity seem to improve the effect of abCTX. The combination of the prognostic value of ITC-BM and the predictive capacity of HER2 and TOP IIa could help to stratify patients for certain therapies. The direct examination of those factors on ITC-BM is the focus of ongoing studies.

Background: The prognostic significance of isolated tumor cells (ITCs) in bone marrow (BM) from patients with breast carcinoma at the time of their primary diagnosis recently was been confirmed by a large pooled analysis. If the persistence of ITCs after adjuvant therapy confers a similar risk for recurrence, then it would be an indication to consider secondary adjuvant therapy., Methods: The authors analyzed BM aspirates from 228 patients during recurrence-free follow-up at a median interval +/- standard deviation (SD) of 21.3 +/- 29.1 months after a primary diagnosis of breast carcinoma (pathologic T1 [pT1]-pT2, pN0-pN3, pM0). Carcinoma cells were detected using a standardized immunoassay with monoclonal antibody A45-B/B3 directed against cytokeratin (CK). Patients were followed for a median +/- SD of 49.8 +/- 32.1 months after their primary diagnosis., Results: Persistent ITCs in BM were detected in 12.7% of patients (n=29 patients). Positive BM status was more frequent (15.7%) within the first 21 months after primary diagnosis than after a follow-up > 21 months (9.7%). The Kaplan-Meier estimate for mean recurrence-free survival was 149.7 months (95% confidence interval [95% CI], 139.6-159.8 months) in patients with negative BM status and 86.5 months (95% CI, 65.7-107.4 months; P=0.0003) in patients with positive BM status at the time patients underwent follow-up BM aspiration. Patients who were without evidence of persistent ITCs had a significantly longer overall survival (162.1 months; 95% CI, 152.1-172.0 months) compared with patients who had positive BM status (overall survival, 98.7 months; 95% CI, 79.7-117.9 months; P=0.0008). In multivariate Cox regression analysis that included BM status, tumor size, lymph node status, and histopathologic grade, evidence of ITCs was an independent significant predictor for reduced disease-free survival (relative risk [RR], 4.57; P <0.0001) and overall survival (RR, 5.57; P=0.002). Persistent ITCs had the greatest prognostic relevance when they were detected between 25 months and 42 months after primary diagnosis (RR, 7.68)., Conclusions: Evidence of persistent ITCs in BM from patients with breast carcinoma indicated an increased risk for subsequent recurrence. Prospective trials should investigate the benefit of secondary adjuvant treatment on the basis of BM marrow status., (2005 American Cancer Society.)

Background: The number of axillary lymph-node metastases is not only a function of disease progression in primary breast cancer, but is also influenced by the intra-mammary location of the tumor. Nevertheless, the prognostic role of the tumor site is discussed controversially. The objective of this study was to analyze the impact of primary-tumor location on axillary lymph-node involvement, relapse, and mortality risk by univariate and multivariate analysis, in patients both with and without systemic and loco-regional treatment., Method: Retrospective analysis was conducted on 2,414 patients at the I. Frauenklinik, Ludwig-Maximilians University, Munich and Berlin-Charlottenburg, who underwent R(0) resection of the primary tumor and systematic axillary lymph-node dissection (at least five lymph nodes resected) for UICC I-III-stage breast cancer. Patients with unknown tumor site, multifocal tumor spread, central tumor location, or tumor location within 15 degrees of the border between outer and inner quadrants were excluded from the study. Median observation time was 6.7 years., Results: The primary tumor site was within or between the medial quadrants of the breast in 33.6% of the patients ( n=810) and in the lateral hemisphere of the breast in 66.4% ( n=1,604). Tumor size, histopathological grading, and estrogen receptor status were balanced between patients with lateral and medial tumor location. Metastatic axillary lymph-node involvement was significantly associated with a lateral tumor location ( P<0.0001). The mean number of axillary lymph-node metastases was increased by 29% in cases with lateral tumor location (2.2 vs 1.7, P=0.003). In a multivariate logistic regression analysis allowing for tumor location, estrogen receptor status, grading and tumor size, tumor location was confirmed as a significant risk factor ( P=0.02) for axillary lymph-node involvement. Tumor location, however, did not correlate with either disease-free survival (DFS) or overall survival (OS), by univariate (DFS: P=0.41; OS: P=0.57) or by multivariate analysis (DFS: P=0.16; OS: P=0.98)., Conclusion: We conclude that there is no sufficient evidence to support any independent prognostic significance of intra-mammary tumor location in early breast cancer. However, medial tumor location may lead to the underestimation of axillary lymph-node involvement.

Background: The presence of isolated tumor cells (ITC) in the bone marrow at the time of primary diagnosis indicates an increased risk for subsequent development of distant metastases in various solid tumors. This study evaluates the prevalence and prognostic significance of ITC in patients with primary carcinoma of the cervix uteri., Method: We immunocytochemically analyzed bone marrow aspirates of 130 patients with newly diagnosed carcinoma of the cervix uteri for the presence of cytokeratin(CK)-positive cells from May 1994 to January 2001. We used a quantitative immunoassay with the monoclonal anti-CK antibody A45-B/B3 and evaluated 2 x 10(6) bone marrow cells per patient. Patients were followed prospectively for a median of 43 (range, 1-85) months., Results: Isolated tumor cells were found in the bone marrow of 38 patients (29%). The presence of ITC did not correlate with the International Federation of Gynecology and Obstetrics (FIGO) tumor stage (P = 0.61), pelvic and paraaortal lymph node involvement (P = 0.41), histopathologic grading (P = 0.67), the histologic type of the carcinoma (P = 0.93), invasion of lymph nodes (P = 0.93) and blood vessels (P = 0.92), or with menopausal status (P = 0.17). The bone marrow status at the time of primary diagnosis did not correlate with the overall survival as estimated by Kaplan-Meier analysis (P = 0.30). However, distant metastases occurred in 5% of the patients (n = 5) with negative bone marrow status and in 15% of the patients (n = 6) with positive bone marrow status (P = 0.054). The median distant disease-free survival period was 78 months (95% confidence interval 73-82) in patients with negative bone marrow status and 72 months (95% CI 61-82) in patients with positive bone marrow status (P = 0.051). Multivariate analysis revealed the presence of ITC as a significant, independent risk factor for the subsequent development of distant metastases (relative risk 3.6, P = 0.046)., Conclusion: Despite the locoregional predominance of cervical carcinoma at the time of primary diagnosis, the presence of ITC in the bone marrow indicates an increased risk for the development of distant metastases. This information may prove useful to stratify patients for systemic treatment., (Copyright 2003 American Cancer Society)

Background and Objective: In the last few years special attention has been paid to the serum concentration of haemoglobin in patients with cancer. It was the aim of this study to ascertain whether at the time of the initial diagnosis low haemoglobin levels in patients with breast cancer denote a higher risk of primary haematogenous dissemination of tumour cells in bone marrow than that in those with higher levels., Patients and Methods: Between March 1994 and March 2000 bone marrow aspirates were performed and serum haemoglobin concentrations (g/dl) measured before primary surgical treatment in 360 consecutive patients (mean age 57.5 years) with primary breast cancer. Evidence of isolated tumour cells in bone marrow was obtained with the pancytokeratin antibody A45-B/B3. The cohort was divided into two groups on the basis of mean haemoglobin values, and the patients underwent follow-up examination a mean of 30.7 months after the initial diagnosis. Patients with metastases at first diagnosis or those who had received nonsurgical treatment at that time were excluded., Results: The mean pre-treatment haemoglobin concentration of the cohort was 13.8 g/dl (median 13.9 g/dl, S.D.1.2). There was no statistically significant difference in the frequency of cytokeratin-positive bone marrow findings between the two groups. While disseminated tumour cells were demonstrated in the bone marrow of 48 (28%) patients with a pre-treatment haemoglobin of 13.9 g/dl. There was also no difference between the two groups regarding median survival time (67.9 vs. 65.8 months; p = 0.46). However, there was a significant difference in probability of survival between patients with or without isolated tumour cells in the bone-marrow (59.7 vs. 69.2 months; p < 0.0001)., Conclusion: There is no evidence at present that the preoperative haemoglobin concentration is of prognostic value regarding the haematogenous dissemination of tumour cells and the survival time of patients with primary breast cancer.

Background: Breast-conserving therapy has been demonstrated to be just as safe and a less disruptive experience compared with mastectomy for surgically manageable breast cancer. There is, however, no agreement in the literature about the impact of these procedures on several important aspects of quality of life (QOL). The purpose of the present study is to compare the long-term impact of these two surgical approaches on QOL in patients with identical tumor stages and to suggest possible shortcomings of the standard QOL questionnaires., Method: Between August 1999 and May 2000, QOL questionnaires were answered by 152 pair-matched patients at the I. Frauenklinik, Ludwig-Maximilians University Munich, as part of routine follow-up examinations. The pairs of patients, each consisting of one patient after mastectomy and one after breast conservation, were selected according to the highest degree of equivalence in tumor stage. All patients had been initially treated for stage I-III breast cancer without evidence of distant metastases. The QOL was evaluated by using the QLQ-C30 questionnaire version 2.0 of the EORTC Study Group on Quality of Life. We formulated seven additional questions about the patients' satisfaction with the primary surgical treatment modality as viewed from their current perspective. The QOL questionnaires were answered after a median interval of 46 months following primary treatment., Results: Tumor stage, prognostic factors, and adjuvant systemic treatment were well balanced between the two groups. No differences between the two groups were observed in terms of all QOL items measured by the QLQ-C30. Our additional questions, however, revealed that patients in the mastectomy group were less satisfied with the cosmetic result of their primary operation (P < .0001), were more likely to feel basic changes in their appearance (P < .0001), and were more likely to be emotionally stressed by these facts (P < .0001). From their perspective at the time of completing the questionnaires, 11 patients in the mastectomy group (15%) would decide differently about the surgical treatment modality, compared with only 3 patients (4%) in the breast conservation group (P = .025)., Conclusion: While the primary surgical treatment modality seems to have no long-term impact on general QOL, certain body-image-related problems may be caused by mastectomy. Standard measuring instruments for QOL may fail to detect differences in satisfaction and adaptation with the primary surgical treatment modality.

Background: The current study examines the fate of occult metastatic cells detected in bone marrow (BM) at primary diagnosis and evaluates whether persistently positive findings support the prognostic influence of these cells in patients with Stage I--III (International Union Against Cancer) breast carcinoma., Methods: The authors analyzed BM aspirates, at the time of primary diagnosis and after a median interval of 19 months (range, 7--67 months), from 89 patients who were free of recurrence. The presence of cytokeratin (CK) positive cells was assessed with the monoclonal anti-CK antibody A45-B/B3. Patients were observed prospectively for a median of 41 (range, 12--78) months after the first aspiration., Results: At the time of primary diagnosis, 24 of 89 patients (27%) presented with occult metastatic cells in the BM. Of the same 89 patients, 25 (28%) had a positive BM finding at the time of the second BM analysis. Among those patients with an initially negative BM finding, 15 patients (17%) had occult metastatic cells at time of the second BM aspiration, whereas 10 patients (11%) had a persistently positive BM finding. Patients with a persistently negative BM status (n = 50) had a significantly better overall survival than patients with a positive BM status at the time of the second BM aspiration (n = 25), both by univariate analysis (P = 0.045, log-rank) and multivariate analysis (P = 0.034, Cox regression)., Conclusions: In many patients with primary breast carcinoma, minimal residual disease can be detected by follow-up examination of the BM. This finding is prognostically relevant and provides reason to include BM monitoring in future clinical trials., (Copyright 2001 American Cancer Society.)

Background: Local recurrence remains a major concern after primary treatment of breast cancer and has a major impact on subsequent survival. While most studies report a poorer survival rate in patients with a local recurrence after mastectomy than after breast conservation, it remains controversial whether different risk profiles at the time of primary diagnosis may account for this difference., Method: Matched pair analysis of 134 patients with newly diagnosed locoregional recurrence of breast cancer without evidence of systemic disease. Matching criteria included the primary surgical treatment, tumor size, nodal status, and age. The significance of various prognostic parameters at the time of primary diagnosis and at the time of recurrence were evaluated, by univariate and multivariate analyses, with respect to survival after recurrence. The median follow-up was 8.4 years., Results: Risk factors at the time of presentation, such as tumor size and lymph node status, were comparable between both groups. Local recurrence occurred on an average 9 months earlier in patients after mastectomy (P = 0.08). Univariate analysis showed that lymph node status (P = 0.0001) and disease-free interval from primary treatment to local recurrence (P = 0.0002) were the most significant single prognostic factors for subsequent survival after local recurrence. The primary surgical treatment modality was shown to be of marginal statistical influence (only P = 0.05)., Conclusion: Local recurrence after mastectomy seems to be associated with worse survival than after breast-conserving therapy. Early onset of chest-wall recurrence, moreover, represents the highest independent risk for cancer-associated death.

Purpose: In node-negative patients, of whom up to 30% will recur within 5 years after diagnosis, markers are still needed that identify patients at high enough risk to warrant further adjuvant treatment. In the present study we analyzed whether a correlation exists between microscopic tumor cell spread to bone marrow and to lymph nodes and attempted to determine which route is clinically more important., Patients and Methods: According to a prospective design, bone marrow aspirates and axillary lymph nodes of level I (n = 1,590) from 150 node-negative patients with stage I or II breast cancer were analyzed immunocytochemically with monoclonal anticytokeratin (CK) antibodies. We investigated associations with prognostic factors and the effect of micrometastasis on patients' prognosis., Results: CK-positive cells in bone marrow aspirates were present in 44 (29%) of 150 breast cancer patients, whereas only 13 patients (9%) had such positive findings in lymph nodes; simultaneous microdissemination to bone marrow and lymph nodes was seen in merely two patients. No correlation of bone marrow micrometastases with other risk factors was assessed. Reduced 4-year distant disease-free and overall survival were each associated with a positive bone marrow finding (P =.032 and P =.014, respectively) but not with lymph node micrometastasis. Multivariate analysis revealed an independent prognostic effect of bone marrow micrometastasis on survival, with a hazards ratio of 6.1 (95% confidence interval, 1.2 to 31.3) for cancer-related death (P =.031) in our series., Conclusion: Immunocytochemical detection of micrometastatic cells in bone marrow but not in lymph nodes is an independent prognostic risk factor in node-negative breast cancer that may have implications for surgery and stratification into adjuvant therapy trials.

Introduction: In several studies, low-molecular-weight-heparins (LMWH) have been shown to be as effective in the prevention of deep vein thrombosis (DVT) as unfractionated heparin. However, different LMWHs vary significantly in their pharmacokinetic profile and bioavailability pattern. It remains unknown, whether these pharmacological differences result in a clinically divergent behavior., Methods: Safety and antithrombotic efficacy of three LMWHs, certoparin (18 mg), dalteparin (30 mg) and enoxaparin (24 mg), were compared in a prospective, randomized controlled trial involving 188 patients undergoing knee or hip replacement or spinal surgery. Efficacy was assessed by changes in venous flow patterns between pre- and postoperative Doppler sonography. The clinical endpoint for the assessment of safety were intra- and postoperative bleeding, changes in activated partial thromboplastin time (APTT) and thrombin clotting time (TCT), local hematoma and local infections., Results: Two verified DVTs (1.1%) were observed in the study, leading to no statistical difference in the antithrombotic efficacy of the used LMWHs. In 21 patients (11.2%) local hematoma or local infections complicated the postoperative course. Of these 21 patients, 13 belonged to the certoparin group, compared to 4 patients each in the other groups (p < 0.01). An allergic reaction occurred in only one case treated with dalteparin. No differences between the groups were observed in terms of intra- and postoperative bleeding, APTT, TCT and blood count., Conclusion: The results of this study suggest, that all three LMWHs are equally efficacious in the prophylaxis of DVT in high risk patients after orthopedic surgery. Larger randomized controlled trials are necessary to confirm this conclusion and to evaluate the clinical relevance of the observed differences in postoperative complications.

Introduction and Objective: A clinically important myelosuppression due to adjuvant chemotherapy is seen more frequently as dosage is intensified and new drugs are used. The assessment of the cytopenia expected is frequently hampered by a lack of directly comparable data. The aim of this study was to compare - in our own patient population - the chemotherapy-associated myelosuppression of four chemotherapeutic regimens used in gynecological oncology., Methods: 79 patients with primary breast cancer and 26 patients with epithelial ovarian carcinoma underwent cytostatic treatment, and the associated myelosuppression was evaluated by the determination of cytopenia and the need for supportive therapy. The chemotherapy regimens investigated were CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), 5-fluorouracil 600 mg/m(2), 6xq3w), EC/CMF (epirubicin 90 mg/m(2), cyclophosphamide 600 mg/m(2), 4xq3w, followed by CMF, 3xq3w), DE (docetaxel 75 mg/m(2), epirubicin 90 mg/m(2), 6xq3w) and CC (cyclophosphamide 600 mg/m(2), carboplatin AUC 6, 6xq3w)., Results: The EC/CMF and DE regimens were used significantly more frequently for more advanced tumor stages, but there were no differences concerning tumor-dependent prechemotherapeutic myelosuppression. Hemopoiesis was most impaired in the CC group with a mean drop of serum hemoglobin of 1.5 g/dl to the end of the cytostatic treatment; correspondingly, most transfusions of concentrated erythrocytes were needed in this group. The strongest suppression of leukopoiesis was found in the DE group, with a mean drop in leukocyte counts of 6.2 x 10(3)/microliter per cycle; in this group, a mean of 7.6 ready-made syringes with 263 microgram Lenogastrim was used to stimulate leukopoiesis. The severest drop in the mean thrombocyte count, i.e. 171.7 x 10(3)/microliter, was found in the CC group., Conclusions: The CC regimen impairs thrombo- and erythropoiesis most, whereas the DE regimen causes marked leukopenia. The regimen with the smallest myelosuppression was CMF. No severe cytopenia-associated complications were detected in any of the cases investigated.

Introduction: Recent studies have renewed an old controversy about the efficacy of adjuvant radiotherapy following mastectomy for breast cancer. Radiotherapy is usually recommended for advanced disease, but whether or not to use it in pT1-T2 pN0 situations is still being debated. This study was designed to clarify whether or not routine radiotherapy of the chest wall following mastectomy reduces the risk of local recurrence and if it influences the overall survival rate., Methods: Retrospective analysis of patients treated with mastectomy for pT1-T2 pN0 tumors and no systemic treatment. Patients treated with radiotherapy of the chest wall following mastectomy (Group A) are compared with those treated with mastectomy alone (Group B)., Results: A total of 918 patients underwent mastectomy. Patients who received adjuvant radiotherapy after mastectomy (n = 114) had a significantly lower risk for local recurrence. Ten years after the primary diagnosis, 98.1% of the patients with radiotherapy were disease free compared to 86.4% of the patients without radiotherapy. The average time interval from primary diagnosis until local recurrence was 8.9 years in Group A and 2.8 years in Group B. The Cox regression analysis including radiotherapy, tumor size and tumor grading found the highest risk for local recurrence for patients without radiotherapy (p < 0.0004). In terms of overall survival however, the Kaplan-Meier analysis showed no difference between the two groups (p = 0.8787) and the Cox regression analysis failed to show any impact on overall survival., Conclusion: With observation spanning over 35 years, this study shows that adjuvant radiotherapy of the chest wall following mastectomy reduces the risk for local recurrence in node-negative patients with pT1-T2 tumors but has no impact on the overall survival rate.

Data are emerging about the prognostic relevance of occult metastatic cells in the bone marrow of patients with various solid tumors. Discrepancies among different studies on the prognostic relevance of isolated tumor cells may be caused by tumor cell heterogeneity and the use of different immunoassays. There is increasing evidence that validated anticytokeratin antibodies (e.g., A45-B/B3) represent the present standard for the detection of isolated tumor cells. This immunocytochemical assay allows the identification of patients with occult tumor cell dissemination that cannot be identified by conventional screening methods in tumor staging. According to recent studies, these patients are at higher risk for subsequent development of distant metastases and might therefore benefit from early systemic therapy. At advanced stages of the disease, the micrometastatic tumor load after adjuvant therapy, or at the time of emerging recurrences, appears to reflect the tumor's ability to progress. Therapeutic monitoring and cell-cycle independent antibody-based therapy are among possible implications of this new, promising diagnostic tool. The present review also focuses on state of the art, reliable detection methods of occult metastatic cells in the bone marrow of breast cancer patients and on the prognostic relevance of these cells at different stages of the disease.

Background: Using cytokeratin (CK) as a histogenetic marker of epithelial tumor cells in the bone marrow of patients with primary breast carcinoma, a subgroup of patients with decreased survival can be identified. This study was designed to evaluate the frequency and prognostic relevance of such cells in patients with recurrent breast carcinoma., Methods: Bone marrow aspirates from 65 patients were analyzed immunocytochemically for the presence of CK positive cells. A quantitative immunoassay with monoclonal anti-CK antibody A45-B/B3 was used and 2 x 10(6) bone marrow cells per patient were evaluated. For prognostic evaluation the authors calculated a cutoff value of micrometastatic tumor cells by analogy to classification and regression tree (CART) analysis. Patients were monitored prospectively for a median of 37 months (range, 11-63 months)., Results: Bone marrow micrometastases were present in 5 of 32 patients (16%) with locoregional recurrence and in 24 of 33 patients (73%) with distant recurrence. The bone marrow status yielded no prognostic indication for patients with locoregional recurrence. In contrast, a cutoff value of 2.5 tumor cells per 1 million bone marrow cells analyzed (2.5 x 10(-6) tumor cells) correlated with a significantly different prognosis for women with distant disease. Patients with metastatic disease and a micrometastatic tumor load of > 2.5 x 10(-6) tumor cells survived for a mean of 6 months (95% confidence interval [95% CI], 2.0-9.1) compared with 17 months (95% CI, 11.6-22.0) for patients with < or = 2.5 x 10(-6) tumor cells (P < 0.0001). Multivariate analysis, allowing for hormone receptor status, disease free interval prior to recurrence, manifestation site of metastases, age, and micrometastases in bone marrow, revealed that bone marrow involvement was an independent risk factor, with a hazard ratio of 7.4 (95% CI, 1.6-13.3) for disease-related death., Conclusions: An increased number of micrometastases identified in the bone marrow of patients with metastatic breast carcinoma represents an independent prognostic factor that may influence future therapeutic strategies for patients with metastatic breast carcinoma.