Purpose
This randomized phase II study was conducted to investigate the efficacy of cryotherapy in preventing peripheral neuropathy and dermatological adverse events in breast cancer patients treated ...with weekly paclitaxel.
Methods
Patients treated with 12 weekly doses of paclitaxel for breast cancer were randomized (1:1) into a cryotherapy or control group. The primary endpoint was the percentage of patients with a marked decrease in the Functional Assessment of Cancer Therapy-Neurotoxicity (FACT-NTX) score. The secondary endpoints were Patient Neurotoxicity Questionnaire (PNQ), Common Terminology Criteria for Adverse Event (CTCAE) for peripheral neuropathy, and FACT-Taxane score.
Results
Forty-four patients were randomly assigned to the cryotherapy (
n
= 22) or control groups (
n
= 22). The percentage of patients with a marked decrease in FACT-NTX scores was significantly lower in the cryotherapy group than in the control group (41 vs. 73%,
p
= 0.03). The incidence of CTCAE grade ≥ 2 sensory (
p
= 0.001) and motor peripheral neuropathy (
p
= 0.01), and PNQ grade D or higher for sensory peripheral neuropathy (
p
= 0.02), and decrease in the FACT-Taxane score (
p
= 0.02) were also significantly lower in the cryotherapy group than in the control group. There were no serious side effects associated with cryotherapy.
Conclusion
Cryotherapy is an effective approach for prevention of peripheral neuropathy and dermatological adverse events in breast cancer patients treated with weekly paclitaxel.
Uveal melanoma patients with metastatic disease usually die within one year, emphasizing an urgent need to develop new treatment strategies for this cancer. MEK inhibitors improve survival in ...cutaneous melanoma patients but show only modest efficacy in metastatic uveal melanoma patients. In this study, we screened for growth factors that elicited resistance in newly characterized metastatic uveal melanoma cell lines to clinical-grade MEK inhibitors, trametinib and selumetinib. We show that neuregulin 1 (NRG1) and hepatocyte growth factor (HGF) provide resistance to MEK inhibition. Mechanistically, trametinib enhances the responsiveness to NRG1 and sustained HGF-mediated activation of AKT. Individually targeting ERBB3 and cMET, the receptors for NRG1 and HGF, respectively, overcome resistance to trametinib provided by these growth factors and by conditioned medium from fibroblasts that produce NRG1 and HGF. Inhibition of AKT also effectively reverses the protective effect of NRG1 and HGF in trametinib-treated cells. Uveal melanoma xenografts growing in the liver in vivo and a subset of liver metastases of uveal melanoma patients express activated forms of ERBB2 (the coreceptor for ERBB3) and cMET. Together, these results provide preclinical evidence for the use of MEK inhibitors in combination with clinical-grade anti-ERBB3 or anti-cMET monoclonal antibodies in metastatic uveal melanoma.
Objective This study examined the pharmacokinetics, safety and anti-tumor activity of docetaxel at a dose of 100 mg/m2 in Japanese patients with advanced or recurrent breast cancer. Methods Japanese ...patients with advanced or recurrent breast cancer received docetaxel at a dose of 100 mg/m2 intravenously every three weeks. The pharmacokinetics were assessed during the first cycle. The patients were allowed to receive supportive care drugs based on the indications and dosages in Japan. Results Six eligible patients aged 39-65 years old and 27 treatment cycles were analyzed. All patients experienced one or more adverse events (AEs). The common AEs were neutropenia, thrombocytopenia, alopecia, rash, diarrhea, neuropathy (sensory), fatigue, nausea, fever, hypoalbuminemia, alanine transaminase (ALT) increased, constipation, and taste alteration. Grade 3 or 4 AEs included neutropenia, leukopenia, anemia, lymphopenia, decreased appetite, γ-glutamyl transpeptidase (GTP) increased, aspartate transaminase (AST) increased, ALT increased, hypertension and cellulitis which were all reversible. There were no cases of febrile neutropenia, serious AEs or deaths. The median number of cycles was six. Dose reductions were not observed and most cycles were administered at their intended doses. No complete response and three partial responses were observed in four assessable patients with evaluable lesions. The maximum concentration and area under the blood concentration-time curve were 3,417.5 ng/mL and 4.35 μg・hr/mL (mean), respectively. Conclusion Docetaxel at a dose of 100 mg/m2 was tolerable with acceptable safety profiles and effective for Japanese patients with advanced or recurrent breast cancer with appropriate supportive therapies, and pharmacokinetic (PK) profiles which corresponded approximately with the findings of previous clinical studies.
The prognostic value of sentinel lymph node (SLN) metastases may be minimized by the limited disease burden of lymph node metastases and tailoring adjuvant therapy based on breast cancer biology. The ...aim of this study is to assess the prognostic significance of SLN metastasis in patients with cT1-2N0M0 breast cancer.
Between January 2006 and December 2015, 582 patients underwent SLN biopsy for cT1-2N0M0 breast cancers. cN0 was essentially diagnosed by ultrasound sonography. The prognostic values of SLN metastases were retrospectively evaluated.
Among 582 patients with cT1-2N0M0 breast cancer, 111 patients (19.1%) were positive for SLN metastasis, including 39 cases (6.7%) of micrometastasis and 72 cases (12.4%) of macrometastases. The median size of SLN metastasis was 3.0 mm (range 0.2-16 mm, mean 4.1 mm). In log-rank test, presence of SLN metastasis was not associated with breast cancer recurrence (p = 0.21); 5-year and 10-year recurrence-free survival (RFS) were 93.0% and 96.5%, and 93.0% and 90.4% in the SLN-positive and SLN-negative groups, respectively. In the propensity score matching cohort (n = 178), there was no significant difference in RFS between the SLN-positive and SLN-negative groups (p = 0.90). In Cox regression analysis, a continuous value of Ki67 expression was a significant prognostic factor (HR 1.03; 95% CI 1.01-1.05, p = 0.017).
SLN metastasis has a minimal impact on RFS for patients with cT1-2N0M0 breast cancer in the modern medical era. A proliferation marker is a better factor for poor prognosis than the presence of SLN metastases in this population.
Pollution with trace metals (TM) has been shown to affect diversity and/or composition of plant and animal communities. While ecotoxicological studies have estimated the impact of TM contamination on ...plant and animal communities separately, ecological studies have widely demonstrated that vegetation is an important factor shaping invertebrate communities. It is supposed that changes in invertebrate communities under TM contamination would be explained by both direct impact of TM on invertebrate organisms and indirect effects due to changes in plant communities. However, no study has clearly investigated which would more importantly shape invertebrate communities under TM contamination. Here, we hypothesized that invertebrate communities under TM contamination would be affected more importantly by plant communities which constitute their habitat and/or food than by direct impact of TM. Our analysis showed that diversity and community identity of flying invertebrates were explained only by plant diversity which was not affected by TM contamination. Diversity of ground-dwelling (GD) invertebrates in spring was explained more importantly by plant diversity (27% of variation) than by soil characteristics including TM concentrations (8%), whereas their community identity was evenly explained by plant diversity and soil characteristics (2–7%). In autumn, diversity of GD invertebrates was only explained by plant diversity (12%), and their identity was only explained by soil characteristics (8%). We conclude that vegetation shapes invertebrate communities more importantly than direct effects of TM on invertebrates. Vegetation should be taken into account when addressing the impacts of environmental contamination on animal communities.
Metastatic uveal melanoma is a highly fatal disease; most patients die from their hepatic metastasis within 1 year. A major drawback in the development of new treatments for metastatic uveal melanoma ...is the difficulty in obtaining appropriate cell lines and the lack of appropriate animal models. Patient-derived xenograft (PDX) tumor models, bearing ectopically implanted tumors at a subcutaneous site, have been developed. However, these ectopically implanted PDX models have obstacles to translational research, including a low engraftment rate, slow tumor growth, and biological changes after multiple passages due to the different microenvironment. To overcome these limitations, we developed a new method to directly transplant biopsy specimens to the liver of immunocompromised mice.
By using two metastatic uveal melanoma cell lines, we demonstrated that the liver provides a more suitable microenvironment for tumor growth compared to subcutaneous sites and that surgical orthotopic implantation (SOI) of tumor pieces allows the creation of a liver tumor in immunocompromised mice. Subsequently, 10 of 12 hepatic metastasis specimens from patients were successfully xenografted into the immunocompromised mice (83.3% success rate) using SOI, including 8 of 10 needle biopsy specimens (80%). Additionally, four cryopreserved PDX tumors were re-implanted to new mice and re-establishment of PDX tumors was confirmed in all four mice. The serially passaged xenograft tumors as well as the re-implanted tumors after cryopreservation were similar to the original patient tumors in histologic, genomic, and proteomic expression profiles. CT imaging was effective for detecting and monitoring PDX tumors in the liver of living mice. The expression of Ki67 in original patient tumors was a predictive factor for implanted tumor growth and the success of serial passages in PDX mice.
Surgical orthotopic implantation of hepatic metastasis from uveal melanoma is highly successful in the establishment of orthotopic PDX models, enhancing their practical utility for research applications. By using CT scan, tumor growth can be monitored, which is beneficial to evaluate treatment effects in interventional studies.
Background
Intraoperative evaluations of sentinel lymph node (SLN) metastases are performed for providing appropriate and immediate axillary treatments in breast cancer patients who do not meet Z0011 ...criteria; however, standard intraoperative procedure has not yet been established.
Methods
We consecutively performed intraoperative evaluation for SLN metastases using both a cytokeratin immunohistochemistry (CK-IHC) assay on serial frozen sections and a one-step nucleic acid amplification (OSNA) assay of the remaining whole node in patients with invasive breast cancer. In this article, we compared the intraoperative diagnostic ability of CK-IHC assay, the OSNA assay, and in combination.
Results
Between August 2009 and May 2017, 1,103 SLNs from 499 consecutive clinically node-negative invasive breast cancers were intraoperatively evaluated for SLN metastases using an OSNA and CK-IHC assay. The detection rates of SLN metastases by the OSNA and CK-IHC assays and in combination were 11.8, 12.1, and 14.5%, respectively. The concordance rate between the intraoperative SLN findings of the OSNA and CK-IHC assays was 94.9% (95% confidence interval 93.6–96.2%). The false negative rate for the OSNA assay was 3.1% (30/973), including 3 (0.3%) macrometastases and 27 (2.8%) micrometastases, and for the CK-IHC assay was 2.7% (26/969), including 1 (0.1%) OSNA ++ and 25 (2.6%) OSNA +.
Conclusions
The CK-IHC assay and the OSNA assay have compatible diagnostic abilities in intraoperative evaluations for SLN metastases. The low incidence of false negative results with limited disease burden suggests that both assays can be reliable techniques for intraoperative diagnoses of SLN metastases in breast cancer patients.
Abstract Background The aim of this study was to evaluate the significance of18 F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for speculating the malignant level ...and prognostic value of operable breast cancers. Methods Of 578 consecutive patients with primary invasive breast cancer who underwent curative surgery between 2005 and 2010, 311 patients (53.8%) who received FDG-PET/CT before initial therapy were examined. Results Receiver operating characteristics (ROC) curve analysis showed the cutoff value of the maximum standardized uptake value (SUVmax ) to predict cancer recurrence was 3.8 in all patients and 8.6 in patients with the triple-negative subtype, respectively. In all patients, 3-year DFS rates were 98.8% for patients with a tumor of SUVmax ≤ 3.8 and 91.6% for patients with a tumor of SUVmax > 3.8 ( p < 0.001). High value of SUVmax was significantly associated with large tumor size ( p < 0.001), lymph node metastasis ( p = 0.040), high nuclear grade ( p < 0.001), lymphovascular invasion ( p = 0.032), negative hormone receptor status ( p < 0.001), and positive HER2 status ( p = 0.014). Based on the results of multivariate Cox analysis in all patients, high SUVmax ( p = 0.001) and negative hormone receptor status ( p = 0.005) were significantly associated with poor prognosis. In patients with triple-negative subtype, 3-year DFS rates were 90.9% for patients with a tumor of SUVmax ≤ 8.6 and 42.9% for patients with a tumor of SUVmax > 8.6 ( p = 0.002), and high SUVmax was the only significant independent prognostic factor ( p = 0.047). Conclusion FDG-PET/CT is useful for predicting malignant behavior and prognosis in patients with operable breast cancer, especially the triple-negative subtype.
Rice seeds are potentially useful hosts for the production of pharmaceutical proteins. However, low yields of recombinant proteins have been observed in many cases because recombinant proteins ...compete with endogenous storage proteins. Therefore, we attempt to suppress endogenous seed storage proteins by RNA interference (RNAi) to develop rice seeds as a more efficient protein expression system. In this study, human growth hormone (hGH) was expressed in transgenic rice seeds using an endosperm-specific promoter from a 10 kDa rice prolamin gene. In addition, an RNAi cassette for reduction of endogenous storage protein expressions was inserted into the hGH expression construct. Using this system, the expression levels of 13 kDa prolamin and glutelin were effectively suppressed and hGH polypeptides accumulated to 470 μg/g dry weight at the maximum level in transgenic rice seeds. These results suggest that the suppression of endogenous protein gene expression by RNAi could be of great utility for increasing transgene products.
Hormone receptor and human epidermal growth factor receptor 2 (HER2) protein tests in metastatic breast cancer tissue are recommended in the guidelines of the American Society of Clinical ...Oncology/American Pathology Association. As part of a multi-institutional study by the National Hospital Organization, we conducted an investigation to examine these molecular markers, using cytological specimens as a substitute for tissue specimens from breast cancer metastasis. To confirm the usefulness of receptors tested in metastatic lesions, the treatment course of registered metastatic breast cancer patients was analyzed. During the April 2015 to March 2016 registration period, there were 62 registrations. Types of metastatic lesions include pleural fluid (44 samples), ascites (14 samples), lymph nodes (2 samples), pericardial fluid (1 sample), and dorsal subcutaneous mass (1 sample). A stable test result was obtained by adopting the receptor examination method, using cell block for immunostaining cytological specimens. The discordance rates of estrogen receptor (ER), progesterone receptor (PR), and HER2 protein expression were 18.2% (95% confidence interval (CI): 7.9–28.8%), 36.4% (95% CI: 23.7–49.1%), and 8.2% (95% CI: 0.1–16.3%), respectively, between the primary tumor and metastatic lesion. Patients who changed from primary negative to metastatic positive ER status had taken a significantly longer time for metastatic foci to appear. Patients with positive ER status in metastatic lesions had significantly better prognosis than ER-negative cases (P = 0.030) by the Log-Rank test. The ER status of the metastatic lesion and the metastatic site were independent prognostic factors by Cox multivariate analysis. Receptor examination with cytological specimens in metastatic lesions has been useful as it provides guidance for the treatment of metastatic breast cancer.
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