Objective
Metaplastic breast cancer (MetaBC) is a rare breast cancer subtype poorly responsive to systemic therapy in the metastatic setting with high recurrence rates in the adjuvant setting. ...However, limited data exist regarding response to neoadjuvant chemotherapy (NAC). We performed a single institutional study to assess the clinical and pathological complete response rates (pCR) of MetaBC to NAC.
Methods
Mayo Clinic Rochester patients with MetaBC treated with NAC were identified using the institutional medical index. Patient demographics, tumor characteristics, chemotherapy treatment, clinical and pathological response, and long-term outcomes were reviewed. Pathologic response was assessed by direct pathology review (
n
= 14) or review of outside surgical and pathology reports (
n
= 4).
Results
Women with MetaBC (
n
= 18) received NAC from January 1991 to June 2014. The mean age was 50 years (range 33–79) with a mean tumor size of 5.1 cm (range 2.3–11 cm) and 6/18 had pathologically confirmed lymph nodes prior to surgery. The majority (13/18; 72%) were estrogen receptor (ER), progesterone receptor (PR) and HER-2 negative (TNBC), and 1/18 (5.5%) was HER-2 positive. Five had BRCA testing and 2/5 were BRCA-2 positive. The chemotherapy regimens included anthracycline/cyclophosphamide (AC) (
n
= 1), AC/taxane (
n
= 3), AC/taxane/platinum (
n
= 8), taxane/platinum-based regimens (
n
= 4), taxane/cyclophosphamide (
n
= 1) and taxane/trastuzumab (
n
= 1). Five of 18 (28%) progressed on initial treatment including two who developed metastatic disease during NAC. The overall pCR rate was 2/18 (11%).
Conclusion
MetaBC is poorly responsive to NAC, with a pCR rate (11%), that is lower than expected in a predominantly TNBC cohort. MetaBC patients should be considered for clinical trials testing new NAC regimens and in the absence of clinical trial enrollment, MetaBC patients with resectable disease should proceed directly to definitive operative management.
Solid cancers are a leading cause of death worldwide, primarily due to the failure of effective clinical detection and treatment of metastatic disease in distant sites. There is growing evidence that ...the presence of circulating tumor cells (CTCs) in the blood of cancer patients may be an important indicator of the potential for metastatic disease and poor prognosis. Technological advances have now facilitated the enumeration and characterization of CTCs using methods such as PCR, flow cytometry, image-based immunologic approaches, immunomagnetic techniques, and microchip technology. However, the rare nature of these cells requires that very sensitive and robust detection/enumeration methods be developed and validated in order to implement CTC analysis for widespread use in the clinic. This review will focus on the important technical and statistical considerations that must be taken into account when designing and implementing CTC assays, as well as the subsequent interpretation of these results for the purposes of clinical decision making.
The osteochondral junction is the interface between bone and cartilage. Chondroid bone forms the intermediate between the two tissue types. Damage to the cartilage surface often results in ...degeneration of the subchondral region. This region is comprised of different cell types and varied composition of extracellular matrix. Hence, dual regeneration strategies have been investigated to simultaneously regenerate both tissue types. Bi-phasic constructs have been developed to deliver the necessary cells, growth factors, and mechanical support to facilitate regeneration. This review discusses the use of biphasic scaffolds to promote the repair, development, and function of the osteochondral junction.
To identify factors predicting positive margins at lumpectomy prompting intraoperative reexcision in patients with breast cancer treated at a large referral center.
We reviewed all breast cancer ...lumpectomy cases managed at our institution from January 1, 2012, through December 31, 2013. Associations between rates of positive margin and patient and tumor factors were assessed using χ
tests and univariate and adjusted multivariate logistic regression, stratified by ductal carcinoma in situ (DCIS) or invasive cancer.
We identified 382 patients who underwent lumpectomy for definitive surgical resection of breast cancer, 102 for DCIS and 280 for invasive cancer. Overall, 234 patients (61.3%) required intraoperative reexcision for positive margins. The reexcision rate was higher in patients with DCIS than in those with invasive disease (78.4% 80 of 102 vs 56.4% 158 of 280; univariate odds ratio, 2.80; 95% CI, 1.66-4.76; P<.001). Positive margin rates did not vary by patient age, surgeon, estrogen receptor, progesterone receptor, or ERBB2 status of the tumor. Among the 280 cases of invasive breast cancer, the only factor independently associated with lower odds of margin positivity was seed localization vs no localization (P=.03).
Ductal carcinoma in situ was associated with a higher rate of positive margins at lumpectomy than invasive breast cancer on univariate analysis. Within invasive disease, seed localization was associated with lower rates of margin positivity.
Summary High-risk human papillomavirus (hrHPV) is an etiologic agent in squamous cell carcinoma (SqCC) arising in the oropharynx and cervix, and a proven prognostic factor in oropharyngeal SqCC. Many ...studies have found HPV in non–small cell lung carcinoma (NSCLC). Recent studies advocate the detection of messenger RNA transcripts of E6/E7 as more reliable evidence of transcriptively active HPV in tumor cells. The clinical significance of finding HPV remains unclear in NSCLC. This study sought to determine the prevalence of biologically active HPV infection in NSCLC comparing different methodologies. Surgical pathology material from resected primary lung adenocarcinoma (ADC; n = 100) and SqCC (n = 96) were retrieved to construct tissue microarrays. In situ hybridization (ISH) for hrHPV DNA (DNA-ISH), hrHPV E6/E7 RNA (RNA-ISH), and p16 immunohistochemistry were performed. Cases of oropharyngeal SqCC with known HPV infection were used as positive controls. Expression of p16 was scored as positive if at least 70% of tumor cells showed diffuse and strong nuclear and cytoplasmic staining. Punctate nuclear hybridization signals by DNA-ISH in the malignant cells defined an HPV-positive carcinoma. Of the 196 patients (range, 33-87 years; 108 men), p16 was positive in 19 ADCs and 9 SqCCs, but HPV DNA-ISH and RNA-ISH were negative in all cases. Our study did not detect HPV infection by DNA-ISH or RNA-ISH in any cases of primary NSCLC despite positive p16 expression in a portion of ADC and SqCC. p16 should therefore not be used as a surrogate marker for HPV infection in NSCLC.
Stem cell-based bone tissue engineering with adipose-derived stromal cells (ASCs) has shown great promise for revolutionizing treatment of large bone deficits. However, there is still a lack of ...consensus on cell surface markers identifying osteoprogenitors. Fluorescence-activated cell sorting has identified a subpopulation of CD105(low) cells with enhanced osteogenic differentiation. The purpose of the present study was to compare the ability of CD90 (Thy-1) to identify osteoprogenitors relative to CD(105).
Unsorted cells, CD90(+), CD90(-), CD105(high), and CD105(low) cells were treated with an osteogenic differentiation medium. For evaluation of in vitro osteogenesis, alkaline phosphatase (ALP) staining and alizarin red staining were performed at 7 days and 14 days, respectively. RNA was harvested after 7 and 14 days of differentiation, and osteogenic gene expression was examined by quantitative real-time polymerase chain reaction. For evaluation of in vivo osteogenesis, critical-sized (4-mm) calvarial defects in nude mice were treated with the hydroxyapatite-poly(lactic-co-glycolic acid) scaffold seeded with the above-mentioned subpopulations. Healing was followed using micro-CT scans for 8 weeks. Calvaria were harvested at 8 weeks postoperatively, and sections were stained with Movat's Pentachrome.
Transcriptional analysis revealed that the CD90(+) subpopulation was enriched for a more osteogenic subtype relative to the CD105(low) subpopulation. Staining at day 7 for ALP was greatest in the CD90(+) cells, followed by the CD105(low) cells. Staining at day 14 for alizarin red demonstrated the greatest amount of mineralized extracellular matrix in the CD90(+) cells, again followed by the CD105(low) cells. Quantification of in vivo healing at 2, 4, 6, and 8weeks postoperatively demonstrated increased bone formation in defects treated with CD90(+) ASCs relative to all other groups. On Movat's Pentachrome-stained sections, defects treated with CD90(+) cells showed the most robust bony regeneration. Defects treated with CD90(-) cells, CD105(high) cells, and CD105(low) cells demonstrated some bone formation, but to a lesser degree when compared with the CD90(+) group.
While CD105(low) cells have previously been shown to possess an enhanced osteogenic potential, we found that CD90(+) cells are more capable of forming bone both in vitro and in vivo. These data therefore suggest that CD90 may be a more effective marker than CD105 to isolate a highly osteogenic subpopulation for bone tissue engineering.
Background
Approximately 8–56% of patients with a core needle biopsy (CNB) diagnosis of ductal carcinoma in situ (DCIS) will be upstaged to invasive disease at the time of excision. Patients with ...invasive disease are recommended to undergo axillary nodal staging, most often requiring a second operation. We developed and validated a nomogram to preoperatively predict percentage of risk for upstaging to invasive cancer.
Methods
We reviewed 834 cases of DCIS on CNB between January 2004 and October 2014. Multivariable analysis was used to evaluate CNB and imaging factors to develop a nomogram to predict the risk of upstaging from DCIS to invasive cancer. This nomogram was validated with an external dataset of 579 similar patients between November 1998 and September 2016. An area under the receiver operating characteristic curve was constructed to evaluate nomogram discrimination.
Results
The rate of upstaging to invasive disease was 118/834 (14.1%). On multivariable analysis, grade on CNB and imaging factors, including mass lesion, multicentric disease, and largest linear dimension, were associated with upstage to invasive disease, and was used to develop a nomogram (c-statistic 0.71). In the external validation dataset, 62/579 (10.7%) patients were upstaged to invasive disease. Our nomogram was validated in this dataset with a c-statistic of 0.71.
Conclusion
For patients with a CNB diagnosis of DCIS, our validated nomogram using DCIS grade on biopsy, and imaging factors of mass lesion, multicentric disease, and largest linear dimension, may be used for preoperative assessment of risk of upstaging to invasive disease, allowing patient counseling regarding axillary staging at the time of definitive surgery.
Antidiabetic treatments aiming to reduce body weight are currently gaining increased interest. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist administered twice daily via s.c. ...injection, improves glycemic control, often with associated weight reduction. To further improve the therapeutic efficacy of exendin-4, we have developed a novel peptide engineering strategy that incorporates a serum protein binding motif onto a covalent side-chain staple and applied to the peptide to enhance its helicity and, as a consequence, its potency and serum half-life. We demonstrated that one of the resulting peptides, E6, has significantly improved half-life and glucose tolerance in an oral glucose tolerance test in rodents. Chronic treatment of E6 significantly decreased body weight and fasting blood glucose, improved lipid metabolism, and also reduced hepatic steatosis in diet-induced obese mice. Moreover, the high potency of E6 allowed us to administer this peptide using a dissolvable microstructure- based transdermal delivery system. Pharmacokinetic and pharmacodynamic studies in guinea pigs showed that a single 5-min application of a microstructure system containing E6 significantly improved glucose tolerance for 96 h. This delivery strategy may offer an effective and patient-friendly alternative to currently marketed GLP-1 injectables and can likely be extended to other peptide hormones.
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