ScipionTomo: Towards cryo-electron tomography software integration, reproducibility, and validation.

Image processing in cryogenic electron tomography (cryoET) is currently at a similar state as Single Particle Analysis (SPA) in cryogenic electron microscopy (cryoEM) was a few years ago. Its data processing workflows are far from being well defined and the user experience is still not smooth. Moreover, file formats of different software packages and their associated metadata are not standardized, mainly since different packages are developed by different groups, focusing on different steps of the data processing pipeline. The Scipion framework, originally developed for SPA (de la Rosa-Trevín et al., 2016), has a generic python workflow engine that gives it the versatility to be extended to other fields, as demonstrated for model building (Martínez et al., 2020). In this article, we provide an extension of Scipion based on a set of tomography plugins (referred to as ScipionTomo hereafter), with a similar purpose: to allow users to be focused on the data processing and analysis instead of having to deal with multiple software installation issues and the inconvenience of switching from one to another, converting metadata files, managing possible incompatibilities, scripting (writing a simple program in a language that the computer must convert to machine language each time the program is run), etcetera. Additionally, having all the software available in an integrated platform allows comparing the results of different algorithms trying to solve the same problem. In this way, the commonalities and differences between estimated parameters shed light on which results can be more trusted than others. ScipionTomo is developed by a collaborative multidisciplinary team composed of Scipion team engineers, structural biologists, and in some cases, the developers whose software packages have been integrated. It is open to anyone in the field willing to contribute to this project. The result is a framework extension that combines the acquired knowledge of Scipion developers in close collaboration with third-party developers, and the on-demand design of functionalities requested by beta testers applying this solution to actual biological problems.

Physical fatigability and muscle pain in patients with Hashimoto thyroiditis.

INTRODUCTION: Hashimoto thyroiditis (HT) may lead to muscle weakness due to hypothyroid dysfunction. However, clinical experience treating patients with HT suggests that neuromuscular symptoms may develop in these patients despite long-standing euthyroidism. METHODS: In 24 euthyroid patients with HT and 25 healthy controls, physical fatigability was assessed using the arm movement test (AMT) and 6-min walk test (6MWT). Fatigability was based on calculation of linear trend (LT) reflecting dynamic performance within subsequent constant time intervals. Perception of physical fatigue and muscle pain was analyzed using fatigue (FSMC) and pain questionnaires. Obtained results were correlated with clinical, neurophysiological and lab findings. RESULTS: HT patients showed a negative LT in 6MWT significantly differing from stable performance in controls. LT in AMT did not differ between HT and controls. FSMC scores and pain perception revealed significantly higher levels in HT patients than in controls. Physical FSMC score was primarily influenced by pain perception (standardized regression coefficient, beta = 0.633, p = 0.002). Neither pain score nor physical fatigue score showed a correlation with LT in 6MWT nor did mood, or anti-TPO antibody titer. CONCLUSION: A significant physical fatigability could be shown in euthyroid HT patients despite missing obvious neuromuscular deficits in routine testing. Further, elevated pain and fatigue perception in HT patients seem to contribute to nonspecific muscle complaints in these patients. A possible pathogenic role of thyroid autoimmunity in hidden neuromuscular involvement may be suggested.

TRIP12 as a mediator of human papillomavirus/p16-related radiation enhancement effects.

Patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) have better responses to radiotherapy and higher overall survival rates than do patients with HPV-negative HNSCC, but the mechanisms underlying this phenomenon are unknown. p16 is used as a surrogate marker for HPV infection. Our goal was to examine the role of p16 in HPV-related favorable treatment outcomes and to investigate the mechanisms by which p16 may regulate radiosensitivity. HNSCC cells and xenografts (HPV/p16-positive and -negative) were used. p16-overexpressing and small hairpin RNA-knockdown cells were generated, and the effect of p16 on radiosensitivity was determined by clonogenic cell survival and tumor growth delay assays. DNA double-strand breaks (DSBs) were assessed by immunofluorescence analysis of 53BP1 foci; DSB levels were determined by neutral comet assay; western blotting was used to evaluate protein changes; changes in protein half-life were tested with a cycloheximide assay; gene expression was examined by real-time polymerase chain reaction; and data from The Cancer Genome Atlas HNSCC project were analyzed. p16 overexpression led to downregulation of TRIP12, which in turn led to increased RNF168 levels, repressed DNA damage repair (DDR), increased 53BP1 foci and enhanced radioresponsiveness. Inhibition of TRIP12 expression further led to radiosensitization, and overexpression of TRIP12 was associated with poor survival in patients with HPV-positive HNSCC. These findings reveal that p16 participates in radiosensitization through influencing DDR and support the rationale of blocking TRIP12 to improve radiotherapy outcomes.

Survival of women with inflammatory breast cancer: a large population-based study.

BACKGROUND: Our group has previously reported that women with inflammatory breast cancer (IBC) continue to have worse outcome compared with those with non-IBC. We undertook this population-based study to see if there have been improvements in survival among women with stage III IBC, over time. PATIENT AND METHODS: We searched the Surveillance, Epidemiology and End Results Registry to identify female patients diagnosed with stage III IBC between 1990 and 2010. Patients were divided into four groups according to year of diagnosis: 1990-1995, 1996-2000, 2001-2005, and 2006-2010. Breast cancer-specific survival (BCSS) was estimated using the Kaplan-Meier method and compared across groups using the log-rank test. Cox models were then fit to determine the association of year of diagnosis and BCSS after adjusting for patient and tumor characteristics. RESULTS: A total of 7679 patients with IBC were identified of whom 1084 patients (14.1%) were diagnosed between 1990 and 1995, 1614 patients (21.0%) between 1996 and 2000, 2683 patients (34.9%) between 2001 and 2005, and 2298 patients (29.9%) between 2006 and 2010. The 2-year BCSS for the whole cohort was 71%. Two-year BCSS were 62%, 67%, 72%, and 76% for patients diagnosed between 1990-1995, 1996-2000, 2001-2005, and 2006-2010, respectively (P < 0.0001). In the multivariable analysis, increasing year of diagnosis (modeled as a continuous variable) was associated with decreasing risks of death from breast cancer (HR = 0.98, 95% confidence interval 0.97-0.99, P < 0.0001). CONCLUSION: There has been a significant improvement in survival of patients diagnosed with IBC over a two-decade time span in this large population-based study. This suggests that therapeutic strategies researched and evolved in the context of non-IBC have also had a positive impact in women with IBC.

Accelerated partial-breast irradiation using intensity-modulated proton radiotherapy: do uncertainties outweigh potential benefits?

OBJECTIVE: Passive scattering proton beam (PSPB) radiotherapy for accelerated partial-breast irradiation (APBI) provides superior dosimetry for APBI three-dimensional conformal photon radiotherapy (3DCRT). Here we examine the potential incremental benefit of intensity-modulated proton radiotherapy (IMPT) for APBI and compare its dosimetry with PSPB and 3DCRT. METHODS: Two theoretical IMPT plans, TANGENT_PAIR and TANGENT_ENFACE, were created for 11 patients previously treated with 3DCRT APBI and were compared with PSPB and 3DCRT plans for the same CT data sets. The impact of range, motion and set-up uncertainties as well as scanned spot mismatching between fields of IMPT plans was evaluated. RESULTS: IMPT plans for APBI were significantly better regarding breast skin sparing (p<0.005) and other normal tissue sparing than 3DCRT plans (p<0.01) with comparable target coverage (p=ns). IMPT plans were statistically better than PSPB plans regarding breast skin (p<0.002) and non-target breast (p<0.007) in higher dose regions but worse or comparable in lower dose regions. IMPT plans using TANGENT_ENFACE were superior to that using TANGENT_PAIR in terms of target coverage (p<0.003) and normal tissue sparing (p<0.05) in low-dose regions. IMPT uncertainties were demonstrated for multiple causes. Qualitative comparison of dose-volume histogram confidence intervals for IMPT suggests that numeric gains may be offset by IMPT uncertainties. CONCLUSION: Using current clinical dosimetry, PSPB provides excellent dosimetry compared with 3DCRT with fewer uncertainties compared with IMPT. ADVANCES IN KNOWLEDGE: As currently delivered in the clinic, PSPB planning for APBI provides as good or better dosimetry than IMPT with less uncertainty.

Pathologic complete response to neoadjuvant chemotherapy with trastuzumab predicts for improved survival in women with HER2-overexpressing breast cancer.

BACKGROUND: We sought to determine the prognostic value of pathologic response to neoadjuvant chemotherapy with concurrent trastuzumab. PATIENTS AND METHODS: Two hundred and twenty-nine women with HER2/neu (HER2)-overexpressing breast cancer were treated with neoadjuvant chemotherapy plus trastuzumab between 2001 and 2008. Patients were grouped based on pathologic complete response (pCR, n = 114) or less than pCR (

Multifocality and multicentricity in breast cancer and survival outcomes.

BACKGROUND: The clinicopathological characteristics and the prognostic significance of multifocal (MF) and multicentric (MC) breast cancers are not well established. PATIENTS AND METHODS: MF and MC were defined as more than one lesion in the same quadrant or in separate quadrants, respectively. The Kaplan-Meier product limit was used to calculate recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS). Cox proportional hazards models were fit to determine independent associations of MF/MC disease with survival outcomes. RESULTS: Of 3924 patients, 942 (24%) had MF (n = 695) or MC (n = 247) disease. MF/MC disease was associated with higher T stages (T2: 26% versus 21.6%; T3: 7.4% versus 2.3%, P < 0.001), grade 3 disease (44% versus 38.2%, P < 0.001), lymphovascular invasion (26.2% versus 19.3%, P < 0.001), and lymph node metastases (43.1% versus 27.3%, P < 0.001). MC, but not MF, breast cancers were associated with a worse 5-year RFS (90% versus 95%, P = 0.02) and BCSS (95% versus 97%, P = 0.01). Multivariate analysis shows that MF or MC did not have an independent impact on RFS, BCSS, or OS. CONCLUSIONS: MF/MC breast cancers were associated with poor prognostic factors, but were not independent predictors of worse survival outcomes. Our findings support the current TNM staging system of using the diameter of the largest lesion to assign T stage.

Identifying factors that impact survival among women with inflammatory breast cancer.

BACKGROUND: The objective of this retrospective study was to determine factors impacting survival among women with inflammatory breast cancer (IBC). METHODS: The Surveillance, Epidemiology and End Results Registry (SEER) was searched to identify women with stage III/IV IBC diagnosed between 2004 and 2007. IBC was identified within SEER as T4d disease as defined by the sixth edition of the American Joint Committee on Cancer. The Kaplan-Meier product-limit method was used to describe inflammatory breast cancer-specific survival (IBCS). Cox models were fitted to assess the multivariable relationship of various patient and tumor characteristics and IBCS. RESULTS: Two thousand three hundred and eighty-four women with stage IIIB/C and IV IBC were identified. Two-year IBCS among women with stage IIIB, IIIC and IV disease was 81%, 67% and 42%, respectively (P < 0.0001). In the multivariable model, patients with stage IIIB disease and those with stage IIIC disease had a 63% [hazard ratio (HR) 0.373, 95% confidence interval (CI) 0.296-0.470, P < 0.001] and 31% (HR 0.691, 95% CI 0.512-0.933, P = 0.016) decreased risk of death from IBC, respectively, compared with women with stage IV disease. Other factors significantly associated with decreased risk of death from IBC included low-grade tumors, being of white/other race, undergoing surgery, receiving radiation therapy and hormone receptor-positive disease. Among women with stage IV disease, those who underwent surgery of their primary had a 51% decreased risk of death compared with those who did not undergo surgery (HR = 0.489, 95% CI 0.339-0.704, P < 0.0001). CONCLUSIONS: Although IBC is an aggressive subtype of locally advanced breast cancer, it is heterogeneous with various factors affecting survival. Furthermore, our results indicate that a subgroup of women with stage IV IBC may benefit from aggressive combined modality management.

Risk factors and incidence of thromboembolic events (TEEs) in older men and women with breast cancer.

BACKGROUND: The purpose of this study is to evaluate the risk factors and the prevalence of thromboembolic events (TEEs) in breast cancer patients. PATIENTS AND METHODS: This is a retrospective cohort study using the Surveillance, Epidemiology, and End Results-Medicare database. Breast cancer patients diagnosed from 1992 to 2005 ≥66 years old were identified. International Classification of Diseases, Ninth Revision, and Healthcare Common Procedure Coding System codes were used to identify TEEs within 1 year of the breast cancer diagnosis. Analyses were conducted using descriptive statistics and logistic regression. RESULTS: A total of 89 841 patients were included, of them 2658 (2.96%) developed a TEE. In the multivariable analysis, males had higher risk of a TEE than women [odd ratio (OR) = 1.57; confidence interval (CI) 1.10-2.25] and blacks had higher risk than whites (OR = 1.20; CI 1.04-1.40). Compared with stage I patients, patients with stage II, III and IV had 22%, 39% and 98% increase, respectively, in risk. Placement of central catheters (OR = 2.71; CI 2.43-3.02), chemotherapy treatment (OR = 1.66; CI 1.48-1.86) or treatment with erythropoiesis-stimulating agents (ESAs) (OR = 1.33; CI 1.33-1.52) increase the risk. Other significant predictors included comorbidities, age, receptor status, marital status and year of diagnosis. Similar estimates were seen for pulmonary embolism, deep vein thromboembolism and other TEEs. CONCLUSIONS: In total, 2.96% of patients in this cohort developed a TEE within 1 year from breast cancer diagnosis. Stage, gender, race, use of chemotherapy and ESAs, comorbidities, receptor status and catheter placement were associated with the development of TEEs.

International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment.

BACKGROUND: Inflammatory breast cancer (IBC) represents the most aggressive presentation of breast cancer. Women diagnosed with IBC typically have a poorer prognosis compared with those diagnosed with non-IBC tumors. Recommendations and guidelines published to date on the diagnosis, management, and follow-up of women with breast cancer have focused primarily on non-IBC tumors. Establishing a minimum standard for clinical diagnosis and treatment of IBC is needed. METHODS: Recognizing IBC to be a distinct entity, a group of international experts met in December 2008 at the First International Conference on Inflammatory Breast Cancer to develop guidelines for the management of IBC. RESULTS: The panel of leading IBC experts formed a consensus on the minimum requirements to accurately diagnose IBC, supported by pathological confirmation. In addition, the panel emphasized a multimodality approach of systemic chemotherapy, surgery, and radiation therapy. CONCLUSIONS: The goal of these guidelines, based on an expert consensus after careful review of published data, is to help the clinical diagnosis of this rare disease and to standardize management of IBC among treating physicians in both the academic and community settings.

Incidence of and survival following brain metastases among women with inflammatory breast cancer.

BACKGROUND: The purpose of this study was to determine the incidence of and survival following brain metastases among women with inflammatory breast cancer (IBC). PATIENTS AND METHODS: Two hundred and three women with newly diagnosed stage III/IV IBC diagnosed from 2003 to 2008, with known Human epidermal growth factor receptor 2 (HER2) and hormone receptor status, were identified. Cumulative incidence of brain metastases was computed. Survival estimates were computed using the Kaplan-Meier product limit method. Multivariable Cox proportional hazards models were fitted to explore the relationship between breast tumor subtype and time to brain metastases. RESULTS: Median follow-up was 20 months. Thirty-two (15.8%) patients developed brain metastases with a cumulative incidence at 1 and 2 years of 2.7% and 18.7%, respectively. Eleven (5.3%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 1 and 2 years of 1.6% and 5.7%, respectively. Compared with women with triple receptor-negative IBC, those with hormone receptor-positive/HER2-negative disease [hazard ratio (HR) = 0.55, 95% confidence interval (CI) 0.19-1.51, P = 0.24] had a decreased risk of developing brain metastases, and those with HER2-positive disease (HR = 1.02, 95% CI 0.43-2.40, P = 0.97) had an increased risk of developing brain metastases, although these associations were not statistically significant. Median survival following a diagnosis of brain metastases was 6 months. CONCLUSION: Women with newly diagnosed IBC have a high early incidence of brain metastases associated with poor survival and may be an ideal cohort to target for site-specific screening.

Inclusion of taxanes, particularly weekly paclitaxel, in preoperative chemotherapy improves pathologic complete response rate in estrogen receptor-positive breast cancers.

BACKGROUND: We examined if inclusion of a taxane and more prolonged preoperative chemotherapy improves pathologic complete response (pCR) rate in estrogen receptor (ER)-positive breast cancer compared with three to four courses of 5-fluorouracil, doxorubicin, cyclophosphamide (FAC). PATIENTS AND METHODS: Pooled analysis of results from seven consecutive neo-adjuvant chemotherapy trials including 1079 patients was carried out. These studies were conducted at MD Anderson Cancer Center from 1974 to 2001. Four hundred and twenty-six (39.5%) patients received taxane-based neo-adjuvant therapy. pCR rates and survival times were analyzed as a function of chemotherapy regimen and ER status. Multivariate logistic and Cox regression analysis were carried out to identify variables associated with pCR and survival. RESULTS: Patients with ER-negative cancer had higher overall pCR rate than patients with ER-positive tumors (20.1% versus 4.9%, P < 0.001). In ER-negative patients, the pCR rates were 29% and 15% with and without a taxane (P < 0.001). In ER-positive patients, the pCR rates were 8.8% and 2.0% with and without a taxane (P < 0.001). In multivariate analysis, clinical tumor size (P < 0.001), ER-negative status (P < 0.001) and inclusion of a taxane (P = 0.01) were independently associated with pCR. For patients with pCR, survival was similar regardless of ER status or the type of regimen that induced pCR. CONCLUSION: pCR rates increased for patients with both ER-positive and ER-negative tumors as regimens started to include a taxane and became longer. This indicates that a subset of patients with ER-positive breast cancer benefits from more aggressive chemotherapy, similarly to patients with ER-negative tumors.

High-dose chemotherapy and autologous peripheral blood stem cell transplantation for primary breast cancer refractory to neoadjuvant chemotherapy.

The role of high-dose chemotherapy (HDCT) in patients with refractory breast cancer is not well established. Forty-two female patients (median age of 46 years) with breast cancer refractory to neoadjuvant chemotherapy received HDCT (cyclophosphamide, carmustine and thiotepa) supported by an autologous peripheral blood stem cells transplant. Their disease had been refractory (defined as less than partial response) to one (18 patients) or two (24 patients) regimens of neoadjuvant chemotherapy. Twenty-nine patients had surgery before HDCT. The best response after surgery, HDCT, and radiation therapy was assessed 60 days after transplantation. Thirty patients had complete remission, eight had a PR, one had a minor response, and three had progressive disease. In seven of 13 patients whose disease was inoperable before HDCT, it became operable. After a median follow-up of 42 months, 21 patients were alive, and 15 remained disease free. Five-year overall survival (OS) was 57% (CI, 50-64%), and the estimated 5-year progression-free survival was 40% (CI, 32-48%). Both OS and PFS were better in patients whose disease became operable after chemotherapy than in those whose disease remained inoperable. A randomized study is warranted in this patient population.

Biphasic metaplastic sarcomatoid carcinoma of the breast.

BACKGROUND: Breast biphasic metaplastic sarcomatoid carcinoma (MSC) is rare and aggressive. We analyzed 100 patients treated at M. D. Anderson Cancer Center (MDACC) with 213 MSC and 98 carcinosarcoma patients identified through the Surveillance, Epidemiology and End-Results (SEER) database to describe clinical and pathologic characteristics. PATIENTS AND METHODS: We searched the MDACC (1985-2001) and SEER databases (1988-2001) for breast MSC and carcinosarcoma patients. RESULTS: We identified 100 MDACC MSC patients: 66% had node-negative disease and 6% distant metastases at presentation. Median recurrence-free survival (RFS) of 94 patients with stages I-III disease was 74 months (range 3-74), with 52% 5-year RFS [95% confidence interval (CI) 0.42-0.63]. Median overall survival in these patients was not reached, with 64% 5-year survival (95% CI 0.54-0.75). The initial stage of the tumor, but not use of adjuvant chemo- or radiotherapy, had a strong association with outcome. The pathologic complete response rate to neoadjuvant chemotherapy was 10%. Median survival from the time of recurrent disease was 14 months (range 1-55). Tumors were usually hormone receptor- and HER2/neu-negative. SEER data were consistent with MDACC findings. CONCLUSIONS: Breast MSC and carcinosarcoma are aggressive, treatment-refractory tumors with shared clinical features and outcome similar to poorly differentiated receptor-negative adenocarcinomas. New therapeutic agents are needed.

Polymorphisms in the ACE and PAI-1 genes are associated with recurrent spontaneous miscarriages.

BACKGROUND: Successful pregnancies require fine tuning of fibrinolytic activities in order to secure fibrin polymerization and stabilization of the placental basal plate as well as to prevent excess fibrin deposition in placental vessels and intervillous spaces. Fibrinolysis is tightly regulated by plasminogen activator inhibitor-1 (PAI-1). Endothelial PAI-1 synthesis is induced by angiotensin II, which is generated by angiotensin I-converting enzyme (ACE). METHODS: We studied the ACE deletion (D)/insertion (I) polymorphism and the PAI-1 4G/5G polymorphism in women with recurrent spontaneous miscarriages (RM). Both polymorphisms have been shown to be associated with ACE and PAI-1 expression levels respectively. A study group of 184 patients with a history of two or more consecutive unexplained spontaneous miscarriages was compared with a control group of 127 patients with uneventful term deliveries and no history of miscarriages. RESULTS: Our findings show: (i) homozygosity for the D allele of the ACE gene, which results in elevated PAI-1 concentrations and hypofibrinolysis, is associated with an elevated risk of RM; (ii) the combination of the D/D genotype with two 4G alleles of the PAI-1 promoter, which further increases PAI-1 plasma levels, is significantly more frequent in RM patients compared with controls. CONCLUSIONS: Based on these results, we recommend the incorporation of these two polymorphisms into the spectrum of thrombophilic mutations which should be analysed in individuals with recurrent spontaneous miscarriages. Patients homozygous for both the ACE D and PAI-1 4G alleles may benefit from the application of low molecular weight heparin as early as possible in the pregnancy in order to prevent uteroplacental microthromboses.

Noncontact, laser-mediated extraction of polar bodies for prefertilization genetic diagnosis.

PURPOSE: We tested an entirely noncontact polar body-extraction method using an ultraviolet laser beam for laser zona drilling and a near infrared laser beam for polar body (PB) trapping and extraction. METHODS: A hole was drilled into the zona pellucida of an oocyte. Then, the PB was trapped with optical tweezers and dragged through the drilled hole. RESULTS: Bovine first PBs could be extracted in 49 out of 63 oocytes (78%) using this method. In human oocytes, PB extraction was successfully demonstrated, which however was more time consuming. A number of extracted PBs were dried on a special membrane, circumcised with the laser microbeam, and successfully catapulted into the lid of a microfuge tube (laser pressure catapulting). CONCLUSIONS: This solely laser-mediated extraction method allows convenient procurement of PBs without the danger of contamination and is a promising approach that might replace standard micromanipulation methods in the future.

A custom three-dimensional electron bolus technique for optimization of postmastectomy irradiation.

PURPOSE: Postmastectomy irradiation (PMI) is a technically complex treatment requiring consideration of the primary tumor location, possible risk of internal mammary node involvement, varying chest wall thicknesses secondary to surgical defects or body habitus, and risk of damaging normal underlying structures. In this report, we describe the application of a customized three-dimensional (3D) electron bolus technique for delivering PMI. METHODS AND MATERIALS: A customized electron bolus was designed using a 3D planning system. Computed tomography (CT) images of each patient were obtained in treatment position and the volume to be treated was identified. The distal surface of the wax bolus matched the skin surface, and the proximal surface was designed to conform to the 90% isodose surface to the distal surface of the planning target volume (PTV). Dose was calculated with a pencil-beam algorithm correcting for patient heterogeneity. The bolus was then fabricated from modeling wax using a computer-controlled milling device. To aid in quality assurance, CT images with the bolus in place were generated and the dose distribution was computed using these images. RESULTS: This technique optimized the dose distribution while minimizing irradiation of normal tissues. The use of a single anterior field eliminated field junction sites. Two patients who benefited from this option are described: one with altered chest wall geometry (congenital pectus excavatum), and one with recurrent disease in the medial chest wall and internal mammary chain (IMC) area. CONCLUSION: The use of custom 3D electron bolus for PMI is an effective method for optimizing dose delivery. The radiation dose distribution is highly conformal, dose heterogeneity is reduced compared to standard techniques in certain suboptimal settings, and excellent immediate outcome is obtained.

Factors predictive of outcome in patients with breast cancer refractory to neoadjuvant chemotherapy.

PURPOSE: The purpose of this study was to determine the clinical, pathological, and treatment factors that are predictive of local-regional recurrence and overall survival for patients with breast cancer that is refractory to neoadjuvant chemotherapy. PATIENTS AND METHODS: This study analyzed the data of the 177 breast cancer patients treated on our institutional protocols who had less than a partial response to neoadjuvant chemotherapy. The initial clinical stage of disease was II in 27%, III in 69%, and IV (supraclavicular lymph node involvement) in 4%. Surgery was performed in 94% of the patients, and 77% of these patients also received adjuvant chemotherapy. RESULTS: After a median follow-up of 5.2 years, 106 patients experienced disease recurrence, with 98 of these having distant metastases and 45 having local-regional recurrence. The 5- and 10-year overall survivals for the entire group were 56% and 33%, respectively. The factors that were independently associated with a statistically significant poorer overall survival in a Cox regression analysis were pathologically involved lymph nodes after surgery, estrogen receptor-negative disease, and progressive disease during neoadjuvant chemotherapy. The 5-year overall survival for patients with pathologically negative lymph nodes ranged from 84% (estrogen receptor-positive disease) to 75% (estrogen re-ceptor-negative disease), compared with rates for patients with pathologically positive lymph nodes of 66% (estrogen receptor-positive disease) and 40% (estrogen receptor-negative disease). The 5-year survival of patients with progressive disease was only 19%. The 5- and 10-year local-regional recurrence rates for the 177 patients were 27% and 34%, respectively. Significant factors on Cox analysis that predicted for local-regional recurrence were four or more pathologically involved lymph nodes and estrogen receptor-negative disease. For the 105 patients treated with surgery and postoperative radiation therapy, the 10-year local-regional recurrence rates for the subgroups with 0, 1, or 2 of these factors were 12%, 25%, and 44%, respectively. CONCLUSIONS: For patients with a poor response to neoadjuvant chemotherapy, conventional treatments achieve reasonable outcomes in those with lymph node-negative disease or estrogen receptor-positive disease. However, more active systemic and local therapies are needed for patients with estrogen receptor-negative disease and positive lymph nodes and for those with clinical evidence of progressive disease during neoadjuvant chemotherapy.

Relationship of sentinel and axillary level I-II lymph nodes to tangential fields used in breast irradiation.

PURPOSE: To evaluate the volume of nodal irradiation associated with breast-conserving therapy, we defined the anatomic relationship of sentinel lymph nodes and axillary level I and II lymph nodes in patients receiving tangential breast irradiation. METHODS AND MATERIALS: A retrospective analysis of 65 simulation fields in women with breast cancer treated with sentinel lymph node surgery and 39 women in whom radiopaque clips demarcated the extent of axillary lymph node dissection was performed. We measured the relationship of the surgical clips to the anatomic landmarks and calculated the percentage of prescribed dose delivered to the sentinel lymph node region. RESULTS: A cranial field edge 2.0 cm below the humeral head the sentinel lymph node region was included or at the field edge in 95% of the cases and the entire extent of axillary I and II dissection in 43% of the axillary dissection cases. In the remaining 57%, this field border encompassed an average of 80% of cranial/caudal extent of axillary level I and II dissection. In 98.5% of the cases, all sentinel lymph nodes were anterior to the deep field edge and 71% were anterior to the chest wall-interface, whereas 61% of the axillary dissection cohort had extension deep to the chest wall-lung interface. If the deep field edge had been set 2 cm below the chest wall-lung interface, the entire axillary dissection would have been included in 82% of the cases, and the entire sentinel lymph node would have been covered with a 0.5-cm margin. The median dose to the sentinel lymph node region was 98% of the prescribed dose. CONCLUSIONS: By extending the cranial border to 2 cm below the humeral head and 2 cm deep to the chest wall-lung interface, the radiotherapy fields used to treat the breast can include the sentinel lymph node region and most of axillary levels I and II.