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1.
Toshitaka Fujihara Yoshifumi Mizobuchi Kohei Nakajima Teruyoshi Kageji Kazuhito Matsuzaki Keiko T. Kitazato Ryotaro Otsuka Keijiro Hara Hideo Mure Toshiyuki Okazaki Kazuyuki Kuwayama Shinji Nagahiro Yasushi Takagi 《Journal of neuro-oncology》2018,139(2):323-332
Background
Glioblastoma multiforme (GBM) is the most malignant of brain tumors. Acquired drug resistance is a major obstacle for successful treatment. Earlier studies reported that expression of the multiple drug resistance gene (MDR1) is regulated by YB-1 or NFκB via the JNK/c-Jun or Akt pathway. Over-expression of the Dickkopf (DKK) family member DKK3 by an adenovirus vector carrying DKK3 (Ad-DKK3) exerted anti-tumor effects and led to the activation of the JNK/c-Jun pathway. We investigated whether Ad-DKK3 augments the anti-tumor effect of temozolomide (TMZ) via the regulation of MDR1.Methods
GBM cells (U87MG and U251MG), primary TGB105 cells, and mice xenografted with U87MG cells were treated with Ad-DKK3 or TMZ alone or in combination.Results
Ad-DKK3 augmentation of the anti-tumor effects of TMZ was associated with reduced MDR1 expression in both in vivo and in vitro studies. The survival of Ad-DKK3-treated U87MG cells was inhibited and the expression of MDR1 was reduced. This was associated with the inhibition of Akt/NFκB but not of YB-1 via the JNK/c-Jun- or Akt pathway.Conclusions
Our results suggest that Ad-DKK3 regulates the expression of MDR1 via Akt/NFκB pathways and that it augments the anti-tumor effects of TMZ in GBM cells.2.
Steffen?D?rfel Claus-Christoph?Steffens Dirk?Meyer Hans?Tesch Lisa?Kruggel Melanie?Frank Martina?J?nicke Norbert?Marschner The TMK-Group 《Breast cancer (Tokyo, Japan)》2018,25(3):275-283
Background
Several regimens for which efficacy was established in randomized controlled trials are recommended in current treatment guidelines for early breast cancer. However, knowledge on use and effectiveness of commonly administered chemotherapeutic agents in real-life care and across all breast cancer subtypes is limited.Methods
The prospective, multicentre German TMK cohort study (Tumour Registry Breast Cancer) recruited patients in 148 oncology outpatient-centres. Data from 1650 patients who completed adjuvant chemotherapy were analysed regarding treatment regimens and taxane use from 2007 to 2014. The association of patient characteristics with application of taxane-free regimens was examined with a multivariate regression model.Results
The preferred adjuvant treatment shifted from fluorouracil, anthracycline and cyclophosphamide containing regimens to anthracycline/taxane combinations. Taxane use increased for all subtypes, and the greatest rise was among node-negative patients. Older age, node-negativity, lower grading, HR-positive/HER2-negative subtype and earlier start year of therapy were significantly associated with taxane-free therapy.Conclusions
Treatment with anthracycline/taxane-based chemotherapy in Germany has been rising for every subtype. The increased taxane use reflects updated guideline recommendations over the past decade. Cohort studies like the TMK provide insight into real-life treatment of patients outside of clinical trials.3.
Yan Gao Jacson Shen Edwin Choy Henry Mankin Francis Hornicek Zhenfeng Duan 《Cellular oncology (Dordrecht)》2017,40(3):209-218
Purpose
Overexpression of cyclin-dependent kinase (CDK) 4 has been observed in a variety of cancers and has been found to contribute to tumor cell growth and proliferation. However, the effect of inhibition of CDK4 in ovarian cancer is unknown. We investigated the therapeutic effect of the CDK4 inhibitor palbociclib in combination with paclitaxel in ovarian cancer cells.Methods
Cell viabilities were determined by MTT assay after exposure to different dosages of palbociclib and/or paclitaxel. Western blot, immunofluorescence, and Calcein AM assays were conducted to determine the mechanisms underlying the cytotoxic effects of palbociclib in combination with paclitaxel. CDK4 siRNA was used to validate the outcome of targeting CDK4 by palbociclib in ovarian cancer cells.Results
We found that combinations of palbociclib and paclitaxel significantly enhanced drug sensitivity in both Rb-positive (SKOV3TR) and Rb-negative (OVCAR8TR) ovarian cancer-derived cells. When combined with paclitaxel, palbociclib induced apoptosis in both SKOV3TR and OVCAR8TR cells. We also found that palbociclib inhibited the activity of P-glycoprotein (Pgp), and that siRNA-mediated CDK4 knockdown sensitized multidrug resistant (MDR) SKOV3TR and OVCAR8TR cells to paclitaxel.Conclusions
Inhibition of CDK4 by palbociclib can enhance paclitaxel sensitivity in both Rb-positive and Rb-negative MDR ovarian cancer cells by increasing apoptosis. CDK4 may serve as a promising target in the treatment of ovarian cancer.4.
5.
M. Martín A. Hinojar L. Cerezo J. García M. Lopez J. Prada A. Marín C. Gamallo 《Clinical & translational oncology》2016,18(8):825-830
Background
Aldehyde dehydrogenase isoform 1 (ALDH1) has been shown to be a marker of cancer stem cells (CSCs). These stem cells may be responsible for tumour perpetuation as well as local and distant invasion. Several studies have shown that CSCs are more chemoradiotherapy (CRT)-resistant and may be responsible for tumour recurrence. Other studies, in contrast, have found ALDH1 expression to be indicative of a better prognosis.Methods
We retrospectively evaluated 84 patients diagnosed and treated for laryngeal cancer between 2006 and 2011. All patients underwent curative-intent radiotherapy or CRT at our institution. 57 of the 84 tumour samples contained sufficient material for ALDH1 assessment.Results
ALDH1 expression was detected in 17.5 % (10/57) of the tissue samples. None of the tumours from stage I patients tested positive for ALDH1. The relapse rate in ALDH1 + patients was 10 versus 51.2 % for ALDH1?. No differences in overall survival were observed between the groups; however, disease-free survival was 90 % for the ALDH1 + group versus 48.9 % for ALDH1? patients (p = 0.034).Conclusion
The patients in this study with ALDH1 + tumours had better outcomes than their counterparts with ALDH1? tumours. This finding suggests that not all CSCs are resistant to conventional cancer treatments. It may also imply that new methods of correctly identifying these cells are needed.6.
Purpose of Review
Acute myeloid leukemia (AML) is a hematologic neoplasia consisting of incompletely differentiated hematopoietic cells of the myeloid lineage that proliferate in the bone marrow, blood, and/or other tissues. Clinical implementation of fluorescence in situ hybridization (FISH) in cytogenetic laboratories allows for high-resolution analysis of recurrent structural chromosomal rearrangements specific to AML, especially in AML with normal karyotypes, which comprises approximately 33–50% of AML-positive specimens. Here, we review the use of several FISH probe strategies in the diagnosis of AML. We also review the standards and guidelines currently in place for use by clinical cytogenetic laboratories in the evaluation of AML.Recent Findings
Updated standards and guidelines from the WHO, ACMG, and NCCN have further defined clinically significant, recurring cytogenetic anomalies in AML that are detectable by FISH.Summary
FISH continues to be a powerful technique in the diagnosis of AML, with higher resolution than conventional cytogenetic analysis, rapid turnaround time, and a considerable diagnostic and prognostic utility.7.
8.
Antonia Wenners Felix Hartmann Arne Jochens Anna Maria Roemer Ibrahim Alkatout Wolfram Klapper Marion van Mackelenbergh Christoph Mundhenke Walter Jonat Maret Bauer 《International journal of clinical oncology / Japan Society of Clinical Oncology》2016,21(3):548-556
Background
Stromal fibroblasts influence tumor growth and progression. We evaluated two aldo–keto reductases, AKR1C1 and AKR1C2, in stromal fibroblasts and carcinoma cells as prognostic factors in primary human breast cancer. They are involved in intratumoral progesterone metabolism.Methods
Immunohistochemistry was performed on tissue microarrays from 504 core biopsies from breast cancer patients. Primary endpoints were disease-free (DFS) and overall (OS) survival.Results
AKR1C1 and AKR1C2 expression in fibroblasts and tumor cells correlated with favorable tumor characteristics, such as small tumor size and negative nodal status. In univariate analysis, AKR1C1 expression in carcinoma cells correlated positively with DFS und OS; AKR1C2 expression in both fibroblasts and tumor cells also showed a positive correlation with DFS and OS. In multivariate analysis, AKR1C1 expression in carcinoma cells was an independent prognostic marker.Conclusion
It can be assumed that our observations are due to the independent regulatory function of AKR1C1/2 in progesterone metabolism and therefore provide a basis for new hormone-based therapy options for breast cancer patients, independent of classic hormone receptor status.9.
H. G. Zhang X. W. Xu X. P. Shi B. W. Han Z. H. Li W. H. Ren P. J. Chen Y. F. Lou B. Li X. Y. Luo 《Clinical & translational oncology》2016,18(5):527-532
Background
The forkhead box M1 (FOXM1), an important regulator of cell differentiation and proliferation, is overexpressed in a number of aggressive human carcinomas. However, the clinical significance of FOXM1 signaling in human colorectal cancer (CRC) pathogenesis remains unknown. The aim of this study was to evaluate the role of FOXM1 in CRC tumorigenesis.Methods
We investigated FOXM1 expression in 103 cases of primary CRC and matched normal tissue specimens and explored the underlying mechanisms of altered FOXM1 expression and the impact of this altered expression on CRC proliferation and metastasis using in vitro models of CRC.Results
The results showed that high expression of FOXM1 staining was 85.44 % (88/103) in 103 cases of CRC and 20.39 % (21/103) in 103 cases of adjacent non-cancerous tissue samples; the difference of FOXM1 expression between two groups was statistically significant (P < 0.001). Silencing of FOXM1 inhibited the proliferation of CRC cells, and the invasion and migration of CRC cells were distinctly suppressed. Furthermore, FOXM1 knockdown led to substantial reductions in VEGF-A levels in CRC cell lines.Conclusions
Our data suggest that the pathogenesis of CRC maybe mediated by FOXM1, and FOXM1 could represent selective targets for the molecularly targeted treatments of CRC.10.
L. Ceniceros J. Aristu E. Castañón C. Rolfo J. Legaspi A. Olarte G. Valtueña M. Moreno I. Gil-Bazo 《Clinical & translational oncology》2016,18(3):259-268
Introduction
Lung cancer is the most frequent neoplasm in humans. Surgery is considered the best therapeutic approach for stage I non-small lung cell cancer (NSCLC). However, a remarkable amount of patients are considered as inoperable. Stereotactic body radiotherapy (SBRT) has risen as an option for those patients, rendering excellent results in quality of life and survival.Materials and methods
We analyzed clinical studies published between 2002 and 2015 which included SBRT as a treatment modality. Our own clinical series was analyzed as well. The patterns of failure following SBRT were investigated, together with the outcomes and the toxicity observed.Results
SBRT has proven to maintain an excellent local control. The analysis showed the tumor size and the histology as determinant factors for the response to treatment.Conclusion
According to the published evidence as well as our own experience, SBRT is a safe and feasible approach for early NSCLC. Its results may be comparable with surgery treatment.11.
Joseph Bubalo 《Current hematologic malignancy reports》2018,13(2):109-113
Purpose of Review
To highlight the breadth and types of mental distress experienced by hematopoietic stem cell transplant (HSCT) patients and highlight the need for better prevention and management of delirium.Recent Findings
Recent publications highlight additional risks factors which predict for mental distress during the HSCT process. Despite new medications and additional psychological reports, there is little progress in non-pharmacologic or medication therapy in the prevention and treatment of delirium.Summary
Mental distress, especially delirium, is common during the HSCT process. The morbidity associated with delirium and other mental distress can still be significant at 6–12 months after the completion of the procedure affecting patient functioning and quality of life (QOL). Medication interventions may be helpful but should be used sparingly for targeted patients during HSCT. Additional interventions are needed to prevent and treat delirium in HSCT patients.12.
Wojciech Lubiński Stanisław Zajączek Zbigniew Sych Krzysztof Penkala Olgierd Palacz Jan Lubiński 《Hereditary cancer in clinical practice》2004,2(4):193-196
Purpose
To asses the retinal pigment epithelium (RPE) function measured by EOG testing in patients with neurofibromatosis type 1 (NF-1). Our preliminary EOG results suggested dysfunction of the RPE in individuals with NF-1. In order to confirm our initial results we performed EOG examination on a larger group of NF-1 patients.Patients
Studies were performed on 36 patients with clinically diagnosed NF-1 and compared to normal healthy controls.Methods
Standard EOG recordings were performed in accordance with the International Society for Clinical Electrophysiology of Vision (ISCEV) standards.Results
In NF-1 patients the Arden indexes of the EOG test were significantly higher primarily due to the lower values of dark troughs. Supernormal EOGs (exceeding the value of the mean + 2 SD from the control group) were present in 58% of NF-1 patients.Conclusions
Dysfunction of the RPE is a characteristic feature of individuals with NF-1.13.
Shoichiro Ohtani Takahiro Nakayama Tetsuhiro Yoshinami Ken-ichi Watanabe Fumikata Hara Yasuaki Sagara Hidetoshi Kawaguchi Kenji Higaki Nobuki Matsunami Yoshie Hasegawa Masato Takahashi Makiko Mizutani Takashi Morimoto Masako Sato Mitsuya Itoh Satoshi Morita Norikazu Masuda 《Breast cancer (Tokyo, Japan)》2018,25(4):438-446
Background
This study aimed to investigate whether schedule modification is safe and effective in patients intolerant to the standard eribulin dose and schedule.Methods
Patients with metastatic breast cancer (MBC) treated with both anthracycline and taxane and ≤ 3 prior regimens of chemotherapy for MBC received eribulin at the standard dose and schedule (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) in the first cycle; change of dosing schedule (1.4 mg/m2 on days 1 and 15 of a 28-day cycle) was determined by change in neutrophil count, platelet count, aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum creatinine, and non-hematological toxicity on day 8 of the first cycle or day 1 of the second cycle. Clinical benefit rate (CBR; primary endpoint), time to treatment failure (TTF), overall survival (OS), and safety were evaluated.Results
Of the 88 patients who were enrolled and received standard eribulin therapy in the first cycle, 42 patients were moved to the bi-weekly therapy group and 40 continued standard therapy. In the bi-weekly and standard therapy groups, mean relative dose intensity was 62.7 and 90.9%, CBR was 31.0 and 25.0%, median TTF was 81.5 and 75 days, and OS was 523 and 412 days, respectively. Neither group reported severe adverse events.Conclusion
This is the first study to show that a bi-weekly eribulin schedule is tolerable and has comparable efficacy in patients intolerant to the standard eribulin schedule.Clinical trial registration
University Hospital Medical Information Network (UMIN) Center (ID: UMIN 000008491).14.
X. Liu Z. Qiu Z. Wang W. Zuo Z. Gong C. Liu Q. Zeng Y. Qian L. Jiang Y. Li Y. Bu G. Hu 《Clinical & translational oncology》2018,20(4):534-541
Purpose
The objective of the study was to investigate the role of NFBD1 in the proliferation and apoptosis of laryngeal squamous cell carcinoma (LSCC) cells.Methods
Immunohistochemistry (IHC) and qRT-PCR was employed to determine the expressions of NFBD1 protein and mRNA in LSCC tissues and adjacent noncancerous tissues. After the downregulation of NFBD1 expression, the colony formation assay, MTS assay and apoptosis assay were used to investigate the changes in the proliferation and apoptosis of Hep2 cells. The mechanisms by which silencing NFBD1 promote apoptosis of Hep2 cells were examined by western blotting. Furthermore, xenograft models were used to evaluate the proliferation of Hep2 cells in vivo.Results
NFBD1 protein was upregulated in 55.6% of LSCC cancer tissues compared with adjacent normal tissues (26.7%). NFBD1 knockdown in Hep2 cells significantly impacted proliferation and apoptosis, and silencing NFBD1 might promote apoptosis of Hep2 cells by activating the mitochondrial apoptotic pathway. Xenograft models showed that silencing NFBD1 also significantly inhibited tumor growth.Conclusions
Our data highlight that NFBD1 participates in the regulation of proliferation and apoptosis in LSCC, and suggest that NFBD1 could be a promising therapy target.15.
M. I. Martínez-Fernández J. L. Pérez Gracia I. Gil-Bazo R. Martínez-Monge 《Clinical & translational oncology》2016,18(7):743-747
Purpose
To investigate whether bone metastases-directed stereotactic body radiation therapy (SBRT) delays the emergence of castration resistance in patients with oligometastatic prostate cancer (OPC).Methods and material
OPC is usually managed with androgen deprivation therapy (ADT). Migration to castration-resistant prostate cancer will inevitably occur in the majority of these patients. There are several strategies aimed to delay the emergence of castration resistance including intermittent ADT, second generation antiandrogens (abiraterone, enzalutamide) or metastases-directed SBRT. The present report describes two cases of patients with OPC that received SBRT 24 Gy/3Rx to the solitary bony lesion after ADT failure.Results
Both cases showed complete and durable biochemical response for 13 and 17 months, respectively.Conclusions
SBRT can be used to delay the emergence of castration resistance and the need for systemic therapy when used after ADT failure.16.
E. Grande J. Santamaría Sandi J. Capdevila E. Navarro González C. Zafón Llopis T. Ramón y Cajal Asensio J. M. Gómez Sáez P. Jiménez-Fonseca G. Riesco-Eizaguirre J. C. Galofré 《Clinical & translational oncology》2016,18(8):769-775
Background
Of all thyroid cancers, <5 % are medullary (MTC). It is a well-characterized neuroendocrine tumor arising from calcitonin-secreting C cells, and RET gene plays a central role on its pathogeny.Methods
The electronic search was conducted using MEDLINE (PubMed), EMBASE and Cochrane Central Register of Controlled Trials. Quality assessments of selected current articles, guidelines and reviews of MTC were performed.Results
This consensus updates and summarizes biology, treatment and prognostic considerations of MTC.Conclusions
Multidisciplinary teams and specialized centers are recommended for the management of MTC patients. In the metastatic setting, those patients with large volume of disease are candidates to start systemic treatment mainly if they are symptomatic and the tumor has progressed in the last 12–14 months. Wait and see strategy should be offered to patients with: disseminated disease with only high levels of calcitonin and no macroscopic structural disease, low burden and absence of progression.17.
Mariko Kochi Takayuki Iwamoto Naoki Niikura Giampaolo Bianchini Shinobu Masuda Taeko Mizoo Tomohiro Nogami Tadahiko Shien Takayuki Motoki Naruto Taira Yutaka Tokuda Hiroyoshi Doihara Junji Matsuoka Toshiyoshi Fujiwara 《Breast cancer research and treatment》2018,167(1):39-47
Purpose
The present study evaluated whether morphological-measured stromal and intra-tumour tumour-infiltrating lymphocytes (TILs) levels were associated with gene expression profiles, and whether TILs-associated genomic signature (GS) could be used to predict clinical outcomes and response to therapies in several breast cancer subtypes.Methods
We retrospectively evaluated haematoxylin eosin (HE)-TILs levels and gene expression profiling data from 40 patients with primary breast cancer and extracted the 22 overexpressed genes in cases with high TILs scores as the TILs-GS. The TILs-GS were compared with breast cancer subtype and were evaluated predictive values for prognosis and response to therapies.Results
Higher TILs-GS expressions were observed for triple-negative and human epidermal growth factor receptor 2 (HER2) positive (+) breast cancers, compared to the luminal types (P < 0.001). With the exception of HER2+, the TILs-GS had no prognostic value in subtypes of breast cancers. The Wilcoxon test revealed significantly different TILs-GS levels between the cases with pathological complete response (pCR) and residual disease after anthracycline and taxane-based neoadjuvant chemotherapy, with the exception of the luminal-low proliferation subtype. In the multivariate analysis, pCR was independently associated with smaller tumour size, higher histological grade, ER negativity, HER2 positivity and higher TILs-GS scores (OR 2.02, 95% CI 1.30–3.14, P = 0.025).Conclusions
TILs-GS was associated with stromal and intra-tumour TILs levels, as evaluated using HE, which predicted prognosis and chemotherapy response in several breast cancer subtypes. Further studies are needed to perform stratification according to TILs-GS levels and the conventional breast cancer subtypes.18.
19.
Nobumoto Tomioka Manabu Azuma Mayuko Ikarashi Mitsugu Yamamoto Masako Sato Ken-ichi Watanabe Katsushige Yamashiro Masato Takahashi 《Breast cancer (Tokyo, Japan)》2018,25(1):34-42
Background
The status of tumor-infiltrating lymphocytes (TILs) is a prognostic factor for triple negative breast cancer (TNBC). Recent studies have shown that programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) is expressed on T lymphocytes or tumor cells modulating antitumor immunity. The regulation of immune checkpoints between tumor cells and T lymphocytes may serve as a target for improvement of TNBC prognosis. We investigated TILs and PD-L1 status in TNBCs before or after preoperative systemic therapy (PST) to elucidate the clinical significance of PD-L1 expression.Methods
Ninety patients received PST, and materials of core needle biopsies (CNB) taken before PST were available for 32 patients. TILs were scored as “% stromal”, and tumors were defined as High-TILs (≥30%) or Low-TILs (<30%). The expression of PD-L1 was assessed by immunohistochemistry.Results
TILs status in CNB is significant in pathological therapeutic grade: 1 vs. 2 or 3 (p = 0.0359). Disease-free survival (DFS) in patients with Low-TIL tumors were significantly worse than those with High-TIL tumors (p = 0.0383), but overall survival (OS) showed no significance (p = 0.0772). However, in patients with Low-TIL tumors, both DFS and OS in patients with High-PD-L1 expression were extremely unfavorable than in patients with Low-PD-L1 expression (p = 0.0032, p = 0.0002).Conclusion
The patients with TNBCs with combined Low-TILs and High-PD-L1 status in pre-PST situation showed unfavorable prognosis. The subset of TNBCs with Low-TILs and High-PD-L1 status could be the therapeutic target for immune checkpoint inhibitor.20.