Histologic changes associated with false‐negative sentinel lymph nodes after preoperative chemotherapy in patients with confirmed lymph node‐positive breast cancer before treatment

BACKGROUND:

A wide range of false‐negative rates has been reported for sentinel lymph node (SLN) biopsy after preoperative chemotherapy. The purpose of this study was to determine whether histologic findings in negative SLNs after preoperative chemotherapy are helpful in assessing the accuracy of SLN biopsy in patients with confirmed lymph node‐positive disease before treatment.

METHODS:

Eighty‐six patients with confirmed lymph node‐positive disease at presentation underwent successful SLN biopsy and axillary dissection after preoperative chemotherapy at a single institution between 1994 and 2007. Available hematoxylin and eosin‐stained sections from patients with negative SLNs were reviewed, and associations between histologic findings in the negative SLNs and SLN status (true negative vs false negative) were evaluated.

RESULTS:

Forty‐seven (55%) patients had at least 1 positive SLN, and 39 (45%) patients had negative SLNs. The false‐negative rate was 22%, and the negative predictive value was 67%. The negative SLNs from 17 of 34 patients with available slides had focal areas of fibrosis, some with associated foamy parenchymal histiocytes, fat necrosis, or calcification. These histologic findings occurred in 15 (65%) of 23 patients with true‐negative SLNs and in only 2 (18%) of 11 patients with false‐negative SLNs (P = .03, Fisher exact test, 2‐tailed). The lack of these histologic changes had a sensitivity and specificity for identifying a false‐negative SLN of 82% and 65%, respectively.

CONCLUSIONS:

Absence of treatment effect in SLNs after chemotherapy in patients with lymph node‐positive disease at initial presentation has good sensitivity but low specificity for identifying a false‐negative SLN. Cancer 2010. © 2010 American Cancer Society.     

Proliferative and inflammatory factors in the vitreous of patients with proliferative diabetic retinopathy

Purpose:

The purpose was to measure the concentrations of various cytokines and growth factors (including vascular endothelial growth factor [VEGF] and pigment epithelium-derived factor [PEDF]) in the vitreous of patients with proliferative diabetic retinopathy (PDR) and to investigate interaction between inflammatory and proliferative factors in the genesis of PDR.

Materials and Methods:

Vitreous samples from 32 eyes with PDR and 25 eyes without diabetes mellitus and signs of DR (control) were collected. Vitreous concentrations of VEGF, PEDF, monocyte chemotactic protein-1 (MCP-1), interleukin-4 (IL-4), IL-6, IL-8, IL-10, IL-17A, and secretory immunoglobulin A (sIgA) were simultaneously measured using enzyme-linked immunoassay.

Results:

Vitreous levels of VEGF, PEDF, IL-17A, IL-6, IL-8, IL-4, and sIgA were significantly (Π < 0.05) higher in eyes with PDR compared to control. The concentration of VEGF was more than 17-times higher than in control, and the concentration of PEDF was not changed oppositely and was also higher (1.45-times) compared to control, that may indicate disturbances of compensatory mechanisms in angiogenesis regulation in PDR. Significant (P < 0.05) positive correlations were observed between vitreous concentrations of VEGF and IL-17A (r = 0.45), VEGF and IL-8 (r = 0.48), VEGF and IL-4 (r = 0.51), PEDF and IL-17A (r = 0.48), PEDF and IL-8 (r = 0.59), MCP-1 and PEDF (r = 0.72), MCP-1 and IL-8 (r = 0.45), IL-4 and IL-17A (r = 0.65), IL-4 and IL-8 (r = 0.71), IL-8 and IL-17A (r = 0.59).

Conclusions:

Significantly raised levels of inflammatory and proliferative factors and numerous positive correlations between them may demonstrate a significant role of activation of vascular proliferation and local inflammation in the pathogenesis of PDR.     

Improving the detection of patients with inherited predispositions to hematologic malignancies using next‐generation sequencing‐based leukemia prognostication panels

Recognizing and referring patients with possible inherited cancer predisposition syndromes for appropriate genetic evaluation and testing provides insights into optimal patient treatment approaches and also can provide education and testing opportunities for family members. Next‐generation sequencing (NGS)‐based, targeted genotyping for somatic mutations is increasingly used in the diagnosis, prognostication, and treatment selection for patients with hematologic malignancies. However, certain mutations that may be somatically acquired can also be present as germline mutations in some individuals and families. Whether the results of NGS‐based leukemia panels can be used to inform decisions and subsequent evaluation of patients with possible inherited cancer predispositions has not been described previously. Because a normal control often is not available when using NGS panels in patients with hematologic malignancies, NGS panel results offer both an opportunity and a challenge to determine the origin and pathogenicity of identified mutations. In the absence of a matched germline control, variant allele frequency (VAF) estimation and data from publically available data sets provide important clues to the possible germline origin of a variant. Careful annotation and review of NGS panels in patients with hematologic malignancies can provide a useful screening tool to systematically improve upon the detection of potentially pathogenic germline variants. Cancer 2018;124:2704‐2713 . © 2018 American Cancer Society     

Measuring social support for weight loss in an internet weight loss community

Although overweight and obese individuals are turning to Internet communities for social support for weight loss, there is no validated online instrument for measuring the subjective social support experiences of participants in these communities. The authors' objective was to determine whether an online version of a validated paper questionnaire, the Weight Management Support Inventory, is appropriate for measuring social support among members of Internet weight loss communities. The authors administered the paper and online versions of the questionnaire in random, counterbalanced fashion to 199 members of a large Internet weight loss community. Scores for the paper and online versions were comparable in between-subjects and within-subjects comparisons. Convergent validity is suggested by the finding that participants who posted messages on Internet forums several times per day reported more social support than those who posted less frequently. However, the instrumental (tangible) support items did not load significantly on the instrumental support factor, suggesting that instrumental support is not relevant to the social support exchanged among participants in these communities. The authors conclude that the online, modified Weight Management Support Inventory, without items for instrumental support, is an appropriate instrument for measuring social support for weight loss among members of Internet weight loss communities.     

The SMART Platform: early experience enabling substitutable applications for electronic health records

Objective

The Substitutable Medical Applications, Reusable Technologies (SMART) Platforms project seeks to develop a health information technology platform with substitutable applications (apps) constructed around core services. The authors believe this is a promising approach to driving down healthcare costs, supporting standards evolution, accommodating differences in care workflow, fostering competition in the market, and accelerating innovation.

Materials and methods

The Office of the National Coordinator for Health Information Technology, through the Strategic Health IT Advanced Research Projects (SHARP) Program, funds the project. The SMART team has focused on enabling the property of substitutability through an app programming interface leveraging web standards, presenting predictable data payloads, and abstracting away many details of enterprise health information technology systems. Containers—health information technology systems, such as electronic health records (EHR), personally controlled health records, and health information exchanges that use the SMART app programming interface or a portion of it—marshal data sources and present data simply, reliably, and consistently to apps.

Results

The SMART team has completed the first phase of the project (a) defining an app programming interface, (b) developing containers, and (c) producing a set of charter apps that showcase the system capabilities. A focal point of this phase was the SMART Apps Challenge, publicized by the White House, using http://www.challenge.gov website, and generating 15 app submissions with diverse functionality.

Conclusion

Key strategic decisions must be made about the most effective market for further disseminating SMART: existing market-leading EHR vendors, new entrants into the EHR market, or other stakeholders such as health information exchanges.     

Locoregional Interaction of Ixabepilone (Ixempra) After Breast Cancer Radiation

Background.

Radiation recall is an acute inflammatory reaction within a previously irradiated field triggered by chemotherapy administration. We observed a series of patients with unexpectedly severe reactions that included radiation recall and delayed healing when patients received the microtubule stabilizer ixabepilone (Ixempra; Bristol-Myers Squibb, Princeton, NJ) after radiation. We therefore decided to evaluate our experience in patients receiving ixabepilone following radiotherapy.

Methods.

We performed a retrospective chart review of all patients treated with curative intent in the Department of Radiation Oncology at the MD Anderson Cancer Center from 2008–2011 who received any ixabepilone after completion of external-beam radiation therapy. These patients received adjuvant ixabepilone on one of two protocols, either for locally advanced breast cancer or for metastatic breast cancer. In total, 19 patients were identified and their charts were subsequently reviewed for evidence of ixabepilone-related toxicity.

Results.

Of the 19 patients identified who received ixabepilone following radiation therapy, three (15.8%) had unexpectedly serious reactions in the months following radiation therapy. Complications included delayed wound closure and drain placement into the seroma, intense erythema, and delayed wound closure and grade 4 chest wall necrosis requiring latissimus flap and skin grafting. The average number of days between the end of radiation therapy and documentation of reaction was 99.

Conclusions.

Ixabepilone chemotherapy may induce radiation recall and delayed wound healing when used shortly after the completion of external-beam radiotherapy. Significant clinical interactions have not been previously reported and merit further evaluation.     

Cytologically proven axillary lymph node metastases are eradicated in patients receiving preoperative chemotherapy with concurrent trastuzumab for HER2‐positive breast cancer

BACKGROUND:

The axillary pathologic complete response rate (pCR) and the effect of axillary pCR on disease‐free survival (DFS) was determined in patients with HER2‐positive breast cancer and biopsy‐proven axillary lymph node metastases who were receiving concurrent trastuzumab and neoadjuvant chemotherapy. The use of neoadjuvant chemotherapy is reported to result in pCR in the breast and axilla in up to 25% of patients. Patients achieving a pCR have improved DFS and overall survival. To the authors' knowledge, the rate of eradication of biopsy‐proven axillary lymph node metastases with trastuzumab‐containing neoadjuvant chemotherapy regimens has not been previously reported.

METHODS:

Records were reviewed of 109 consecutive patients with HER2‐positive breast cancer and axillary metastases confirmed by ultrasound‐guided fine‐needle aspiration biopsy who received trastuzumab‐containing neoadjuvant chemotherapy followed by breast surgery with complete axillary lymph node dissection. Survival was evaluated by the Kaplan‐Meier method. Clinicopathologic factors and DFS were compared between patients with and without axillary pCR.

RESULTS:

Eighty‐one patients (74%) achieved a pCR in the axilla. Axillary pCR was not associated with age, estrogen receptor status, grade, tumor size, initial N classification, or median number of lymph nodes removed. More patients with an axillary pCR also achieved a pCR in the breast (78% vs 25%; P < .001). At a median follow‐up of 29.1 months, DFS was significantly greater in the axillary pCR group (P = .02).

CONCLUSIONS:

Trastuzumab‐containing neoadjuvant chemotherapy appears to be effective in eradicating axillary lymph node metastases in the majority of patients treated. Patients who achieve an axillary pCR are reported to have improved DFS. The success of pCR with concurrent trastuzumab and chemotherapy in eradicating lymph node metastases has implications for surgical management of the axilla in these patients. Cancer 2010. © 2010 American Cancer Society.     

Frequency of mesenchymal‐epithelial transition factor gene (MET) and the catalytic subunit of phosphoinositide‐3‐kinase (PIK3CA) copy number elevation and correlation with outcome in patients with early stage breast cancer

BACKGROUND:

The current study was conducted to determine the frequency and association between recurrence‐free survival (RFS) and MET and catalytic subunit of phosphoinositide‐3‐kinase (PIK3CA) copy number elevations in patients with early stage breast cancer.

METHODS:

Tumor DNA was extracted from 971 formalin‐fixed, paraffin‐embedded early breast cancers for molecular inversion probes arrays. Data were segmented using the single‐nucleotide polymorphism (SNP)‐FASST2 segmentation algorithm. Copy number gains were called when the copy number of each segment was greater than 2.3 or 1.7, respectively. RFS was estimated by the Kaplan‐Meier method. Cox proportional hazards models were fit to determine independent associations between copy number and RFS.

RESULTS:

Of the 971 tumors studied, 82 (8.44%) and 134 (13.8%) had an elevation of the MET or PIK3CA copy number, respectively, and 25.6% of tumors with a MET copy number elevation had a PIK3CA copy number elevation. Patients with either a MET or PI3KCA high copy number tended to have poorer prognostic features (larger tumor size, higher tumor grade, and hormone receptor negativity). Both MET and PIK3CA high copy numbers were more likely to occur in patients with triple receptor‐negative disease (P = .019 and P < .001, respectively). At a median follow‐up of 7.4 years, there were 252 cases of disease recurrence. The 5‐year RFS rates were 63.5% and 83.1% for MET high copy number and MET normal/low copy number, respectively (P = .06) and 73.1%, and 82.3% for PIK3CA high copy number and PIK3CA normal/low copy number, respectively (P = .15). A high copy number for either gene was not found to be an independent predictor of RFS.

CONCLUSIONS:

A high copy number of MET or PIK3CA was found to be associated with poorer prognostic features and triple receptor‐negative disease. Coamplification was frequent. Patients with tumors with high MET copy numbers tended to have a worse RFS. Cancer 2013. © 2012 American Cancer Society.     

Magnetic resonance imaging as a predictor of pathologic response in patients treated with neoadjuvant systemic treatment for operable breast cancer

BACKGROUND:

Increased pathologic complete response (pCR) rates observed with neoadjuvant chemotherapy (NCT) for some subsets of patients with invasive breast cancer have prompted interest in whether patients who achieved a pCR can be identified preoperatively and potentially spared the morbidity of surgery. The objective of this multicenter, retrospective study was to estimate the accuracy of preoperative magnetic resonance imaging (MRI) in predicting a pCR in the breast.

METHODS:

MRI studies at baseline and after the completion of NCT plus data regarding pathologic response were collected retrospectively from 746 women who received treatment at 8 institutions between 2002 and 2011. Tumors were characterized by immunohistochemical phenotype into 4 categories based on receptor expression: hormone (estrogen and progesterone) receptor (HR)‐positive/human epidermal growth factor receptor 2 (HER2)‐negative (n = 327), HR‐positive/HER2‐positive, (n = 148), HR‐negative/HER2‐positive, (n = 101), and triple‐negative (HR‐negative/HER2 negative; n = 155). In all, 194 of 249 patients (78%) with HER2‐positive tumors received trastuzumab. Univariate and multivariate analyses of factors associated with radiographic complete response (rCR) and pCR were performed.

RESULT:

For the total group, the rCR and pCR rates were 182 of 746 patients (24%) and 179 of 746 patients (24%), respectively, and the highest pCR rate was observed for the triple‐negative subtype (57 of 155 patients; 37%) and the HER2‐positive subtype (38 of 101 patients; 38%). The overall accuracy of MRI for predicting pCR was 74%. The variables sensitivity, negative predictive value, positive predictive value, and accuracy differed significantly among tumor subtypes, and the greatest negative predictive value was observed in the triple‐negative (60%) and HER2‐positive (62%) subtypes.

CONCLUSIONS:

The overall accuracy of MRI for predicting pCR in invasive breast cancer patients who were receiving NCT was 74%. The performance of MRI differed between subtypes, possibly influenced by differences in pCR rates between groups. Future studies will determine whether MRI in combination with directed core biopsy improves the predictive value of MRI for pathologic response. Cancer 2013. © 2013 American Cancer Society.