We present a case, considered to be a form of the Koebner phenomenon, of bullous pemphigoid that was exacerbated mainly within the irradiated field after breast conservative radiotherapy. In May ...2009, a 60-year-old woman was diagnosed with bullous pemphigoid, which was treated with steroid therapy. The following month, she was diagnosed with breast cancer (invasive ductal carcinoma, pT1cN0M0). After breast conservative surgery in December 2009, conservative radiotherapy to the right breast was performed (50 Gy in 25 fractions). Portal skin showed no serious change (up to grade 1 skin erythema) and no bullous neogenesis during conservative radiotherapy. However, 2 months after conservative radiotherapy, new blisters became exacerbated mainly within the irradiated field but also in the area outside the irradiated field. Increasing the dosage of oral steroid and minocycline resulted in relief of bullous pemphigoid, although patchy skin pigmentation remained especially in the irradiated skin.
The capillary wall is the chief barrier to tissue entry of therapeutic nanoparticles, thereby dictating their efficacy. Collagen fibers are an important component of capillary walls, affecting ...leakiness in healthy or tumor vasculature. Using a computational model along with in vivo systems, we compared how collagen structure affects the diffusion flux of a 1-nm chemotherapeutic molecule doxorubicin (DOX) and an 80-nm chemotherapy-loaded pegylated liposome (DOX-PLD) in tumor vasculature. We found a direct correlation between the collagen content around a tumor vessel to the permeability of that vessel permeability to DOX-PLD, indicating that collagen content may offer a biophysical marker of extravasation potential of liposomal drug formulations. Our results also suggested that while pharmacokinetics determined the delivery of DOX and DOX-PLD to the same tumor phenotype, collagen content determined the extravasation of DOX-PLD to different tumor phenotypes. Transport physics may provide a deeper view into how nanotherapeutics cross biological barriers, possibly helping explain the balance between biological and physical aspects of drug delivery.
Current treatments for liver metastases arising from primary breast and lung cancers are minimally effective. One reason for this unfavorable outcome is that liver metastases are poorly vascularized, ...limiting the ability to deliver therapeutics from the systemic circulation to lesions. Seeking to enhance transport of agents into the tumor microenvironment, we designed a system in which nanoparticle albumin-bound paclitaxel (nAb-PTX) is loaded into a nanoporous solid multistage nanovector (MSV) to enable the passage of the drug through the tumor vessel wall and enhance its interaction with liver macrophages. MSV enablement increased nAb-PTX efficacy and survival in mouse models of breast and lung liver metastasis. MSV-nAb-PTX also augmented the accumulation of paclitaxel and MSV in the liver, specifically in macrophages, whereas paclitaxel levels in the blood were unchanged after administering MSV-nAb-PTX or nAb-PTX. In vitro studies demonstrated that macrophages treated with MSV-nAb-PTX remained viable and were able to internalize, retain, and release significantly higher quantities of paclitaxel compared with treatment with nAb-PTX. The cytotoxic potency of the released paclitaxel was also confirmed in tumor cells cultured with the supernatants of macrophage treated with MSV-nAB-PTX. Collectively, our findings showed how redirecting nAb-PTX to liver macrophages within the tumor microenvironment can elicit a greater therapeutic response in patients with metastatic liver cancer, without increasing systemic side effects.
Contrast-enhanced ultrasonography with Sonazoid (SNZ) enables real-time visualization, resulting in more precise identification of lymphatic flow to sentinel lymph nodes (SLNs). This study aimed to ...classify lymphatic drainage patterns to SLNs. Patients (n = 75) with T1-2 N0 M0 breast cancer received a periareolar injection of SNZ to identify SNZ-enhanced SLNs (SNZ-SLNs), followed by SLN biopsy with blue dye. The lymphatic drainage patterns were classified into four types: type A, single lymphatic route/single SLN; type B, multiple lymphatic routes/single SLN; type C, single lymphatic route/multiple SLNs; and type D, multiple lymphatic routes/multiple SLNs. SLNs were successfully identified in all patients using both blue dye and SNZ. The drainage lymphatic pathways identified were as follows: type A in 53 cases (70.7%), type B in seven (9.3%), type C in eight cases (10.7%) and type D in seven (9.3%). SNZ-SLN biopsy is a technically simple method with a 100% identification rate, enabling the real-time visualization of lymphatic flow to SNZ-SLNs.
Although nanotherapeutics can be advantageous over free chemotherapy, the benefits of drug vectors can vary from patient to patient based on differences in tumor microenvironments. Although systemic ...pharmacokinetics (PK) of drugs is considered as the major determinant of its efficacy in clinics, recent clinical and basic research indicates that tumor-based PK can provide better representation of therapeutic efficacy. Here, we have studied the role of the tumor extravascular tissue in the extravasation kinetics of doxorubicin (DOX), delivered by pegylated liposomes (PLD), to murine lung (3LL) and breast (4T1) tumors. We found that phenotypically different 3LL and 4T1 tumors shared the similar systemic PK, but DOX extravasation in the tumor extravascular tissue was substantially different. Liquid chromatography–mass spectrometry (LC–MS) measurements showed that DOX fluorescence imaged by fluorescence microscopy could be used as a marker to study tumor microenvironment PK, providing an excellent match to DOX kinetics in tumor tissues. Our results also suggest that therapeutic responses can be closely related to the interplay of concentration levels and exposure times in extravascular tissue of tumors. Finally, the computational model of capillary drug transport showed that internalization of drug vectors was critical and could lead to 2–3 orders of magnitude more efficient drug delivery into the extravascular tissue, compared to non-internalized localization of drug vectors, and explaining the differences in therapeutic efficacy between the 3LL and 4T1 tumors. These results show that drug transport and partitioning characteristics can be phenotype- and microenvironment-dependent and are highly important in drug delivery and therapeutic efficacy.
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Purpose
There is an urgent need for the development of a predictor of response to chemotherapy for ER-positive breast cancer which is less chemosensitive than for ER-negative breast cancer in order ...to avoid unnecessary chemotherapy. In the present study, intrinsic subtyping by PAM50 was evaluated for its ability to predict a response to chemotherapy.
Patients and Methods
For this study, 124 patients with ER-positive breast cancer treated with neoadjuvant sequential paclitaxel and FEC (NAC) were evaluated. Tumor biopsy specimens obtained before NAC were subjected to intrinsic subtyping (IS) by gene expression (GE) using PAM50 (PAM50-IS) or immunohistochemistry (IHC-IS).
Results
Of the PAM50-ISs (Luminal A, Luminal B, HER2-enriched, and Basal-like), GE-Luminal A showed the lowest pCR rate (1.9%), and multivariate analysis revealed that GE-Luminal A was a significant (
P
= 0.031) predictor of non-pCR independently of other clinicopathological parameters, including Ki67, and tumor-infiltrating lymphocytes. Of the IHC-ISs, on the other hand, IHC-Luminal A was not significantly associated with pCR. We also found that breast tumors with low ER levels (1–9%), like ER-negative tumors, were mostly GE-HER2-enriched and GE-Basal-like, and more sensitive to NAC than those with high ER levels (≥ 10%).
Conclusions
GE-Luminal A intrinsically subtyped by PAM50 was the least sensitive to NAC and very unlikely to attain pCR. IHC-Luminal A identified by IHC, on the other hand, was not significantly predictive of pCR. In addition, PAM50 revealed that tumors with low ER (1–9%) were more like ER-negative tumors than ER-positive tumors, and most such cases should therefore would better be treated with chemotherapy.
Abstract Purpose Circulating tumor DNA (ctDNA) is known to harbor tumor-specific genetic or epigenetic alterations. In the present study, the correlation of ctDNA with tumor response to neoadjuvant ...chemotherapy (NAC) was evaluated in primary breast cancer patients. Materials and Methods Plasma samples were obtained from 87 primary breast cancer patients (stage II-III) before and after NAC, as well as one year after surgery. Methylated ctDNA (met-ctDNA) was determined by one-step methylation specific PCR (OS-MSP) for the promoter region of RASSF1A. Results The positivity (23.0%, 20/87) of met-ctDNA before NAC was significantly ( P <0.05) higher than that of CEA (8.6%) and CA15-3 (7.4%). In the patients with positive met-ctDNA before NAC, met-ctDNA significantly decreased after NAC in the responders ( P= 0.006), but not in the non-responders. Met-ctDNA after NAC was found to be significantly ( P =0.008) correlated to the extent of residual tumor burden. Of the seven patients who showed an increase in met-ctDNA at one year after surgery, three developed recurrences. Conclusions Met-ctDNA is a more sensitive marker than CEA and CA15-3, and it might be useful in monitoring the clinical tumor response to NAC. In addition, the potential use of met-ctDNA as a tumor marker for monitoring the postoperative recurrence has been suggested.
One-step nucleic acid amplification (OSNA) is a newly developed procedure for detection of node metastasis by targeting CK19 mRNA. This study aimed to compare the prognosis of ...ER-positive/HER2-negative (ER+/HER2-) breast cancer patients with negative sentinel lymph node (SLN), as determined by OSNA with that determined by pathology.
A total of 508 patients who underwent breast surgery and SLN biopsy were enrolled. Of 263 patients with negative SLN by OSNA (osN0), 239 were treated with endocrine therapy alone (osN0-ET), and of 107 with negative SLN by pathology (pN0), 103 were treated with endocrine therapy alone (pN0-ET).
Distant relapse-free survival (DRFS) of osN0-ET group (99.5% at 6 years) was significantly better (p=0.044) than that of pN0-ET group. Multivariate analysis revealed that osN0 was significantly associated (p=0.019) with favorable DRFS.
ER+/HER2- breast cancer patients with negative SLN by OSNA show an excellent prognosis with endocrine therapy alone.
Aim: To investigate the feasibility of hookwire-guided sentinel lymph node biopsy (SLNB) using contrast-enhanced ultrasonography (CEUS) followed by a one-step nucleic acid amplification (OSNA) assay. ...Patients and Methods: Clinical T1-2N0M0 breast cancer patients scheduled to undergo SLNB participated in this study. Both Sonazoid® and dye were used as tracers, and the most upstream sentinel lymph node (SLN) at each lymphatic flow detected by CEUS (First-SLN) was sampled under hookwire guidance, a procedure called "Sona-Hook". Results: In each of the 50 cases, at least one First-SLN was extracted by "Sona-Hook". All contrast-enhanced SLNs (CE-SLNs) were dye-positive, and the mean number of CE-SLNs sampled per patient was lower than that of dye-positive SLNs (1.48 vs. 1.88, p<0.01). Through OSNA, qualitative assessment of tumor metastasis between First-SLNs and all SLNs completely matched together. Conclusion: "Sona-Hook" for First-SLN followed by an OSNA assay may be a feasible minimally invasive SLNB strategy.
Hypovascularization in tumors such as liver metastases originating from breast and other organs correlates with poor chemotherapeutic response and higher mortality. Poor prognosis is linked to ...impaired transport of both low- and high-molecular weight drugs into the lesions and to high washout rate. Nanoparticle albumin-bound-paclitaxel (nAb-PTX) has demonstrated benefits in clinical trials when compared to paclitaxel and docetaxel. However, its therapeutic efficacy for breast cancer liver metastasis is disappointing. As macrophages are the most abundant cells in the liver tumor microenvironment, we design a multistage system employing macrophages to deliver drugs into hypovascularized metastatic lesions, and perform in vitro, in vivo, and in silico evaluation. The system encapsulates nAb-PTX into nanoporous biocompatible and biodegradable multistage vectors (MSV), thus promoting nAb-PTX retention in macrophages. We develop a 3D in vitro model to simulate clinically observed hypo-perfused tumor lesions surrounded by macrophages. This model enables evaluation of nAb-PTX and MSV-nab PTX efficacy as a function of transport barriers. Addition of macrophages to this system significantly increases MSV-nAb-PTX efficacy, revealing the role of macrophages in drug transport. In the in vivo model, a significant increase in macrophage number, as compared to unaffected liver, is observed in mice, confirming the in vitro findings. Further, a mathematical model linking drug release and retention from macrophages is implemented to project MSV-nAb-PTX efficacy in a clinical setting. Based on macrophage presence detected via liver tumor imaging and biopsy, the proposed experimental/computational approach could enable prediction of MSV-nab PTX performance to treat metastatic cancer in the liver.
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