Bone metastases are common in patients with advanced cancer. Bisphosphonates (BPs) could prevent or delay the development of skeleton-related events (SREs). The present study aimed to identify the clinical fea...
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 25 Απριλίου 2016
A multicenter, retrospective epidemiologic survey of the clinical features and management of bone metastatic disease in China
Hormonal therapy might be a better choice as maintenance treatment than capecitabine after response to first-line capecitabine-based combination chemotherapy for patients with hormone receptor-positive and HER2-negative, metastatic breast cancer
Both hormonal therapy (HT) and maintenance capecitabine monotherapy (MCT) have been shown to extend time to progression (TTP) in patients with metastatic breast cancer (MBC) after failure of taxanes and anthra...
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Dose escalation study of proton beam therapy with concurrent chemotherapy for stage III non-small cell lung cancer
Summary
The purpose of this study is to determine the recommended dose (RD) of proton beam therapy (PBT) for inoperable stage III non-small cell lung cancer (NSCLC). We tested two prescribed doses of PBT;66 Gy (relative biological effectiveness; RBE) in 33 fractions and 74 Gy (RBE) in 37 fractions in arms 1 and 2, respectively. The planning target volume (PTV) included the primary tumor and metastatic lymph nodes with adequate margins. Concurrent chemotherapy included intravenous cisplatin (60 mg/m2, day 1) and oral S-1 (80, 100 or 120 mg based on body surface area, days 1-14), repeated as 4 cycles every 4 weeks. Dose-limiting toxicity (DLT) was defined as grade 3 or severe toxicities related to PBT during days 1-90. Each dose level was performed in 3 patients, and then escalated to the next level if no DLT occurred. When 1 patient developed a DLT, 3 additional patients were enrolled. Overall, nine patients (5 men, 4 women; median age, 72 years) were enrolled, including 6 in arm 1 and 3 in arm 2. The median follow-up time was 43 months, and the median progression-free survival was 15 months. In arm 1, grade 3 infection occurred in 1 of 6 patients, but no other DLT was reported. Similarly, no DLT occurred in arm 2. However, 1 patient in arm 2 developed grade 3 esophageal fistula at 9 months after the initiation of PBT. Therefore, we determined that 66 Gy (RBE) is the RD from overall clinical viewpoints. Clinical trial registration no.:UMIN000005585.
This article is protected by copyright. All rights reserved.
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Prion protein binding to HOP modulates the migration and invasion of colorectal cancer cells
Abstract
Colorectal cancer (CRC) is one of the most frequently diagnosed malignancies. The generation of conventional treatments has improved, but approximately 50 % of patients with CRC who undergo potentially curative surgery ultimately relapse and die, usually as a consequence of metastatic disease. Our previous findings showed that engagement of the cellular prion protein (PrPC) to its ligand HSP70/90 heat shock organizing protein (HOP) induces proliferation of glioblastomas. In addition, PrPC has been described as an important modulator of colorectal tumor growth. Here, we investigated the biological relevance of the PrPC-HOP interaction in CRC cells. We demonstrate that HOP induced the migration and invasion of CRC cell lines in a PrPC-dependent manner and that phosphorylation of the ERK1/2 pathway is a downstream mediator of these effects. Additionally, we show that a HOP peptide with the ability to bind PrPC and abolish the PrPC-HOP interaction inhibited the migration and invasion of CRC cells. Together, these data indicate that the disruption of the PrPC-HOP complex could be a potential therapeutic target for modulating the migratory and invasive cellular properties that lead to metastatic CRC.
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Clinical Case Report: Yoga for Fatigue in Five Young Adult Survivors of Childhood Cancer
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Deliveries After Malignant Disease Before Pregnancy: Maternal Characteristics, Pregnancy, and Delivery Complications
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Double primary malignant fibrous histiocytoma and squamous cell carcinoma of the larynx treated with laser laryngeal conservation surgery
PD Karkos, S Dova, S Sotiriou, K Markou and I Kostopoulos
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Unmet Needs for Psychosocial Care in Hematologic Malignancies and Hematopoietic Cell Transplant
Abstract
Individuals diagnosed with hematologic malignancies experience significant unmet psychological, physical, informational, financial, and spiritual needs. The goal of the current review is to summarize and highlight recent research focused on these issues in the diagnosis and treatment periods and beyond. The review also describes the needs of adolescent and young adult (AYA) and pediatric patients. While a large body of research has reported on unmet needs among adult hematologic cancer patients, there is far less data regarding the challenges confronted by AYA and pediatric populations. Available data suggests that among all age groups, hematopoietic cell transplantation (HCT) is a risk factor for greater unmet needs. Recommendations for screening and evidence-based interventions to prevent or ameliorate unmet needs are provided. Future research is needed to develop additional evidence-based psychosocial interventions with a focus on hematologic cancer.
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Neoadjuvant treatment for rectal cancer—A value-based proposition
Over the last decade, the use of neoadjuvant chemo-radiation has been an integral part of the care of patients with locally advanced rectal cancer. However, emerging data are beginning to challenge the current treatment paradigm of neoadjuvant chemo-radiation followed by radical resection and subsequent adjuvant chemotherapy. Going forward, the challenge will be to identify patients for whom radiation can be safely omitted and those for whom it can potentially provide added oncologic value. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
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Efficacy and safety of stereotactic body radiation therapy for the treatment of pulmonary metastases from sarcoma: A potential alternative to resection
Background/Objectives
Oligometastatic sarcoma pulmonary metastases (PM) are typically treated with resection and/or chemotherapy. We hypothesize that stereotactic body radiotherapy (SBRT) can be an alternative to surgery that can achieve high rates of local control (LC) with limited toxicity.
Methods
Thirty consecutive sarcoma patients received SBRT to 39 PM's from 2011 to 2015 at two university hospitals to a median dose of 50 Gy in 4–5 fractions with CyberKnife or linear accelerator. Patients underwent CT or PET/CT scans q3 months after SBRT.
Results
77% received prior chemotherapy, 70% had 1–3 prior pulmonary resections, and 26% received prior thoracic radiotherapy. Median lesion size was 2.4 cm (range 0.5–8.1 cm). Median follow-up was 16 and 23 months for patients alive at last follow-up. At 12 and 24 months, LC was 94% and 86%, and OS was 76% and 43%. LC and OS did not differ by SBRT technique, fractionation regimen, lesion location, histology, or size (all P > 0.05). Three developed grade 2 chest-wall toxicity with no other grade ≥2 toxicities.
Conclusions
This is the largest series on SBRT for sarcoma PM's and demonstrates that SBRT is well-tolerated with excellent LC across tumor locations and sizes. SBRT should be considered in these patients, and prospective studies are warranted. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
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Outcomes of one-side versus two-sides recipient vessels for bilateral breast reconstructions with bilateral DIEP flaps
Background
This study was to compare the use of one-side versus two-sides recipient vessels in either bilateral breast reconstructions or unilateral breast reconstruction with contralateral augmentation using bilateral DIEP flaps.
Patients and Methods
A retrospective review including all cases of bilateral breast reconstructions and unilateral reconstruction with contralateral augmentation with DIEP flaps was performed. Patient's demographics, surgical variables, and outcome were collected. Two distinct cohorts based on the recipient vessel techniques, one-side versus two-sides, were compared.
Results
A total of 25 patients with 50 split-DIEP flaps were included, with one-side recipient vessels used in 19 patients and two-sides recipient vessels in 6 patients. Ischemia time was significantly reduced in one-side recipient group compared to two-sides recipient vessels group (62.4 ± 21.3 vs. 105.9 ± 32.5, P < 0.001). There was no statistic difference in venous congestion, partial flap loss, or fat necrosis in both groups.
Conclusions
Using one-side recipient vessels for bilateral breast reconstructions with unilateral breast reconstruction with contralateral augmentation using differentially split DIEP flaps presents a high success rate, acceptable ischemia time, and minimal complications for small to medium volume breast reconstructions. Utilizing this method can reduce the ischemia time and spare one side internal mammary vessels. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
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Control of primary lesions using resection or radiotherapy can improve the prognosis of metastatic colorectal cancer patients
Background
Control of the primary lesions in metastatic colorectal cancer (mCRC) is still controversial. For rectal cancer patients, not only resection but also irradiation is expected to provide palliative effects. We investigated the effects of resection and irradiation of primary lesions (local control) on the prognosis of mCRC patients.
Patients
Forty-seven patients with mCRC at our institute were examined, with 34 in the local controlled group and 13 in the uncontrolled group.
Results
The median survival time (MST) of the local controlled and uncontrolled groups were 2.90 and 1.39 years (P = 0.028). Cox proportional hazard regression analysis showed that local control was an independent prognostic factor (P < 0.05). The patients who underwent primary lesion resection had significantly longer MST (2.90 vs. 1.39 years, P = 0.032) than those in the uncontrolled group. In rectal cancer patients, the patients who underwent irradiation to control the primary lesions had a significantly longer MST than the uncontrolled patient group (1.97 vs. 1.39 years, P = 0.019).
Conclusions
Local control of primary lesions may improve the prognosis in mCRC patients. In rectal cancer patients with metastasis, not only resection but also irradiation of the primary lesions may be a useful therapeutic strategy. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
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Programmed death ligand-1 expression is associated with poor disease free survival in salivary gland carcinomas
Background and Objectives
The immune checkpoint ligand programmed death ligand-1 (PD-L1) is expressed in various carcinomas and allows carcinoma cells to elude the immune system. PD-L1 expression is associated with the response to anti-programmed death 1 (PD-1)/PD-L1 drugs. This study aimed to clarify the relationship between PD-L1 expression and clinicopathological factors of salivary gland carcinomas (SGCs) and identify its clinical significance.
Methods
PD-L1 expression was examined by immunohistochemical analysis using a tissue microarray comprised of 219 surgically resected SGC specimens. Detailed clinicopathological factors, including patient outcome, were available for all cases.
Results
A case showing complete membranous expression of PD-L1 in more than 1% of whole carcinoma cells was considered positive by ROC analysis. A total of 50 (22.8%) patients showed PD-L1 expression in SGC cells. Positive PD-L1 expression was significantly associated with poor disease free survival (P < 0.001) and overall survival (P < 0.001). Multivariate analysis revealed that positive PD-L1 expression was one of the independent predictors for poor disease free survival (hazard ratio = 2.287, 95% confidence interval = 1.24–4.15; P = 0.008).
Conclusions
Positive PD-L1 expression was significantly associated with poor disease free survival of SGCs, suggesting that antibody therapies targeting PD-1/PD-L1 may have potential application in SGCs. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
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Prognostic significance of TIE2-expressing monocytes in hilar cholangiocarcinoma
Background and Objectives
Angiopoietins (Angs) play a pivotal role in angiogenesis and inflammation, and are associated with prognosis in malignancies. Monocyte express Ang-receptor TIE2 and correlate with prognosis in cancer. We aimed to investigate the prognostic value of Angs and TIE2-expressing monocytes (TEMs) in cholangiocarcinoma.
Methods
We analyzed surgically resected tumor specimens of hilar cholangiocarcinoma (n = 47) for distribution of Angs (Ang 1/Ang 2) and TEMs, as defined by co-expression of CD14 and Ang receptor TIE2. Ang expression and abundance of TEMs were correlated with clinicopathologic characteristics, tumor recurrence and patients' survival.
Results
High Ang 1 expression correlated with reduced metastasis (P < 0.05). Patients characterized by invading Ang-receptor bearing TEMs in tumor showed lower tumor recurrence (P < 0.05). Furthermore, TEMs in tumor and tumor invasive front correlated with increased survival (P < 0.05). TEMs in tumor invasive front were confirmed as independent prognosticator in multivariate survival analysis (P < 0.05).
Conclusions
High Ang 1 expression in hilar cholangiocarcinoma and infiltration of TEMs defines a subgroup of patients with beneficial tumor characteristics and prolonged survival. Besides suggested functional links between Ang expression and recruitment of TEMs, our data have possible clinical implications as novel diagnostic tools. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
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What made hyperthermic intraperitoneal chemotherapy an effective curative treatment for peritoneal surface malignancy: A 25-year experience with 1,125 procedures
Objective
To review our 25-year experience with hyperthermic intra-peritoneal chemotherapy (HIPEC).
Background
Combining cytoreductive surgery (CRS) and HIPEC as local treatments for peritoneal carcinomatosis (PC) was proposed 25 years ago.
Methods
A prospective database of all patients undergoing HIPEC for PC since 1989 was searched for clinicopathological data, 90-day morbidity and mortality, and survival.
Results
Among 1,125 HIPEC procedures, PC origin was colorectal (342; 30%), ovarian (271; 24%), pseudomyxoma peritonei (189; 17%), gastric (127; 11%), malignant mesothelioma (84; 8%), or other (112; 10%). Between 2004–2009 (n = 321) and 2010–2015 (n = 560), the median peritoneal cancer index decreased (11 vs. 8; P < 0.001), fewer patients underwent incomplete cytoreduction (CC2-3: 4% vs. 0.5%; P < 0.001), and more were included in randomized trials (5% vs. 16%; P < 0.001). Postoperative morbidity (52% vs. 50%, P = 0.672) was not different, but mortality significantly decreased (5% vs. 2%; P = 0.030). Median overall-survival was 42 months, and improved significantly for each 5-year period except for 2006–2010 vs. 2011–2015 (P = 0.097). The 10-year survival without recurrence was 53%, 14%, 4%, 10%, and 9% for pseudomyxoma, mesothelioma, ovarian, colorectal, and gastric PC, respectively.
Conclusion
This study demonstrated that CRS and HIPEC provide long-term survival irrespective of PC origin, and survival improves with experience. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
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Acupuncture for Dyspnea in Lung Cancer: Results of a Feasibility Trial
Purpose. Dyspnea is a common and distressing symptom for patients with lung cancer (LC) because of disease burden, therapy toxicity, and comorbid illnesses. Acupuncture is a centuries-old therapy with biological plausibility for relief of dyspnea in this setting. This pilot study aimed to evaluate the feasibility and preliminary effectiveness of acupuncture for dyspnea among patients with LC. Methods. Eligible patients had a diagnosis of LC and clinically significant dyspnea without a clear organic cause. The treatment consisted of 10 weekly acupuncture sessions, with a follow-up visit 4 weeks after therapy. The primary outcome was dyspnea severity as measured using a validated Numerical Rating Scale (NRS) of 0 to 10 (10 being "most severe shortness of breath imaginable"). Results. We enrolled 12 patients in the study. The median age was 64.5 years; 66.7% of the patients were female, and 66.7% were Caucasians. Among those enrolled, 10 (83.3%) were able to complete all 10 acupuncture sessions. Acupuncture was well tolerated; adverse events were mild and self-limited. Mean (SD) dyspnea scores on the NRS improved from 6.3 (1.7) at baseline to 3.6 (1.9; P = .003) at the end of treatment and 3.2 (2.3; P = .008) at follow-up. Fatigue and quality of life also improved significantly with acupuncture (P < .05). Conclusion. Among patients with LC, acupuncture was well tolerated and exhibited promising preliminary beneficial effects in the treatment of dyspnea, fatigue, and quality of life. Performing a trial in this population appears feasible.
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Retrospective analysis of bevacizumab-induced hypertension and clinical outcome in patients with colorectal cancer and lung cancer
Abstract
Bevacizumab(Avastin®), a humanized therapeutic monoclonal antibody that targets vascular endothelial growth factor, is widely used in cancer treatment. Patients who are treated with bevacizumab have an increased risk of developing systemic hypertension. However, the relationship between bevacizumab-induced hypertension and clinical outcome remains unclear. We aimed to evaluate the effect of bevacizumab-induced hypertension in terms of prognosis in patients with colorectal cancer and non-small cell lung cancer. The study included 632 patients, 317 patients with non-small cell lung cancer and 315 patients with colorectal cancer. All patients were treated with bevacizumab in combination with standard chemotherapy protocols, between April 2007 and December 2014. Blood pressure was measured before each treatment cycle. In the patient group with colorectal cancer, treated with bevacizumab, Grade 2–3 hypertension was present in 27.6%. In hypertensive patients with colorectal cancer, median overall survival was 42.6 months, compared with 20.6 months for normotensive patients in this group (P = 0.00071). In the patient group with non-small cell lung cancer, treated with bevacizumab, Grade 2–3 hypertension was present in 20.5%. In hypertensive patients with non-small cell lung cancer, median overall survival was 43.0 months, compared with 26.3 months for normotensive patients in this group (P = 0.00451). Patients who developed hypertension during treatment with bevacizumab for colorectal cancer and non-small cell lung cancer had significantly prolonged overall survival when compared with normotensive patients. Bevacizumab-induced hypertension may represent a biomarker for clinical benefit in cancer patients treated with bevacizumab.
The most common bevacizumab-related adverse event was hypertension. Patients who developed hypertension during treatment with bevacizumab for colorectal cancer and non-small lung cancer had significantly prolonged overall survival.
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Flow cytometry-based characterization of underlying clonal B and plasma cells in patients with light chain amyloidosis
Abstract
Systemic amyloid light chain (AL) amyloidosis is a life-threatening protein deposition disorder; however, effective therapy can dramatically improve the prognosis of AL patients. Therefore, accurate diagnosis of the underlying hematologic disease is important. Multi-parameter flow cytometry (MFC) is a reliable method to analyze lymphatic neoplasias and to detect even a small lymphatic clone. We analyzed the presence of clonal plasma cell (PC) and B cells in the bone marrow of 63 patients with newly diagnosed AL amyloidosis by MFC. We compared the results with the levels of monoclonal protein, the histopathology and cytogenetic results. As reference of light chain restriction, we used the immunohistochemical results of κ or λ positive amyloid deposits in various tissues. MFC identified underlying clonal lymphatic cells in all but two patients (61 of 63, 97%). Sixty-one patients harbored malignant PCs, whereas B-cell lymphomas were identified in two patients. Furthermore, MFC indicated at least one putative immunotherapeutical target (CD20, CD38, CD52, or SLAMF7) on malignant PCs in all but one patient. These results demonstrate that MFC is a reliable tool for an accurate diagnosis of the underlying hematologic disease and the detection of potential immunotherapeutical targets in patients with AL amyloidosis.
Systemic amyloid light chain (AL) amyloidosis is a life-threatening protein deposition disorder and an accurate diagnosis of the underlying hematologic disease is important to provide effective therapy. We analyzed the presence of clonal plasma cell (PC) and B cells in the bone marrow of 63 patients with newly diagnosed AL-amyloidosis by multi-parameter flow cytometry (MFC). MFC identified underlying clonal lymphatic cells in all but two patients (61 of 63, 97%). Sixty-one patients harbored malignant PCs, whereas B-cell lymphomas were identified in two patients. These results demonstrate that MFC is a reliable tool for an accurate diagnosis of the underlying hematologic disease in patients with AL amyloidosis.
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Adherence to cancer screening guidelines in Australian survivors of allogeneic blood and marrow transplantation (BMT)
Abstract
Allogeneic Blood and Marrow Transplant (BMT) survivors are at high risk of secondary cancers. Although current guidelines endorse survivors following Country-specific general population screening recommendations to mitigate this risk, little is known about cancer screening adherence in Australian BMT survivors. We conducted a cross-sectional survey of 441 BMT survivors who were >1 year post transplant, to explore rates of screening for secondary cancers and to identify barriers to cancer screening recommendations. Survey instruments included the Sydney Post-BMT Survey, FACT-BMT, DASS 21, The Chronic Graft versus Host Disease (GVHD) Activity Assessment–Patient Self-Report (Form B), the Lee Chronic GVHD Symptom Scale, Fear of Cancer Recurrence Scale, and The Post Traumatic Growth Inventory. Fifty-seven percent of respondents were male, median age 54 years, and 40% were >6 years post-BMT. Rates of cancer screening adherence were as follows: cervical 63.4%, breast 53.3%, skin 52.4%, and bowel 32.3%. Older BMT survivors and those >2 years post transplant were more likely to undergo cancer screening. Improved quality of life was associated with screening for skin, breast, and cervical cancer. Fear of cancer recurrence negatively impacted on cervical screening. For those who had not undergone screening, the majority reported not being advised to do so by their treatment team. This study is the largest and most comprehensive to date exploring cancer screening adherence in BMT survivors in Australia. These data provide the basis for health service reform to better meet the needs of BMT survivors and provide evidence to support counseling and education of both patients and professionals.
We conducted a cross-sectional survey of 441 Blood and Marrow Transplant (BMT) survivors who were >1 year post transplant, to explore rates of screening for secondary cancers and to identify barriers to adherence with cancer screening recommendations. Rates of cancer screening uptake were as follows: cervical 63.4%, breast 53.3%, skin 52.4%, and bowel 32.3%. Improved quality of life was associated with screening for skin, breast, and cervical cancer. Fear of cancer recurrence negatively impacted on cervical screening. For those who had not undergone screening, the majority reported not being advised to do so by their treatment team.
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Are parenting behaviors associated with child sleep problems during treatment for acute lymphoblastic leukemia?
Abstract
Sleep disturbance is a recognized common side effect in children treated for acute lymphoblastic leukemia (ALL). Although associated with treatment factors such as hospitalization and corticosteroids, sleep problems may also be influenced by modifiable environmental factors such as parenting behaviors. The purpose of this study was to examine sleep problems in children undergoing treatment for ALL compared to healthy children and whether parenting practices are associated with sleep difficulties. Parents of 73 children aged 2–6 years who were (1) in the maintenance phase of ALL treatment (ALL group, n = 43) or (2) had no major medical illness (healthy control group, n = 30) participated in the study. Parents completed questionnaires measuring their child's sleep behavior and their own parenting practices. Parents of children undergoing ALL treatment reported significantly more child sleep problems; 48% of children with ALL compared to 23% of healthy children had clinical levels of sleep disturbance. Parents of the ALL group also reported significantly more lax parenting practices and strategies associated with their child's sleep including co-sleeping, comforting activities, and offering food and drink in the bedroom. Results of multivariate regression analysis indicated that, after controlling for illness status, parent–child co-sleeping was significantly associated with child sleep difficulties. Strategies employed by parents during ALL treatment may be a potential modifiable intervention target that could result in improved child sleep behaviors. Future research aimed at developing and testing parenting interventions aimed to improve child sleep in the context of oncology treatment is warranted.
This study examined sleep problems in children undergoing treatment for acute lymphoblastic leukemia (ALL) compared to healthy children and whether parenting practices are associated with sleep difficulties. Parents of children with ALL reported significantly more child sleep problems and parent–child co-sleeping was significantly associated with child sleep difficulties. Strategies employed by parents during ALL treatment may be a potential modifiable intervention target that could result in improved child quality of life.
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Circulating CD14+HLA-DR-/low myeloid-derived suppressor cells in leukemia patients with allogeneic hematopoietic stem cell transplantation: novel clinical potential strategies for the prevention and cellular therapy of graft-versus-host disease
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population that includes immature myeloid cells and the progenitor cells of macrophages, dendritic cells (DCs), monocytes, and neutrophils. The expansion and functional importance of MDSCs in patients with cancer and noncancer pathogenic conditions has been recognized. As a result, there has been growing interest in understanding their roles in acute graft-versus-host disease (aGVHD) after allogenetic hematopoietic stem cell transplantation (allo-HSCT). In order to evaluate possible effects of MDSCs on aGVHD development and clinical outcomes, this study systematically detected the dynamic changes of MDSCs accumulation in patients during the first 100 days after allo-HSCT, and investigated the levels of other cell types and relative cytokines during MDSCs accumulation. Results showed that accumulation of MDSCs in the graft and in peripheral blood when engraftment might contribute to patients' overall immune suppression and result in the successful control of severe aGVHD and long-term survival without influence on risk of recurrence after allo-HSCT. But MDSCs levels in the graft had more favorable predictive abilities. Furthermore, MDSCs proportion significantly increased in patients developing aGVHD after allo-HSCT. It might be caused by secondary inflammatory response, especially related to high concentrations of IL-6 and TNF-α. But this accumulation would not be able to counterbalance the aggravation of aGVHD and would not have influence on clinical outcomes and risk of relapse. Overall, MDSCs might be considered as potential new therapeutic option for aGVHD and achieve long-term immunological tolerance and survival.
This study revealed that MDSCs might be considered as a novel prognostic factor in patients with allo-HSCT and potential new approaches to regulate transplant rejection and achieve the recipient host long-term acceptance and survival. The understanding of the activation and differentiation of MDSCs in human will help to develop inhibitors during their unwanted activity, such as preventing relapse, but also provide options for therapeutical intervention in aGVHD after allo-HSCT.
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Prognostic microRNA signatures derived from The Cancer Genome Atlas for head and neck squamous cell carcinomas
Abstract
Identification of novel prognostic biomarkers typically requires a large dataset which provides sufficient statistical power for discovery research. To this end, we took advantage of the high-throughput data from The Cancer Genome Atlas (TCGA) to identify a set of prognostic biomarkers in head and neck squamous cell carcinomas (HNSCC) including oropharyngeal squamous cell carcinoma (OPSCC) and other subtypes. In this study, we analyzed miRNA-seq data obtained from TCGA patients to identify prognostic biomarkers for OPSCC. The identified miRNAs were further tested with an independent cohort. miRNA-seq data from TCGA was also analyzed to identify prognostic miRNAs in oral cavity squamous cell carcinoma (OSCC) and laryngeal squamous cell carcinoma (LSCC). Our study identified that miR-193b-3p and miR-455-5p were positively associated with survival, and miR-92a-3p and miR-497-5p were negatively associated with survival in OPSCC. A combined expression signature of these four miRNAs was prognostic of overall survival in OPSCC, and more importantly, this signature was validated in an independent OPSCC cohort. Furthermore, we identified four miRNAs each in OSCC and LSCC that were prognostic of survival, and combined signatures were specific for subtypes of HNSCC. A robust 4-miRNA prognostic signature in OPSCC, as well as prognostic signatures in other subtypes of HNSCC, was developed using sequencing data from TCGA as the primary source. This demonstrates the power of using TCGA as a potential resource to develop prognostic tools for improving individualized patient care.
Prognostic microRNA signatures were identified for head and neck cancers by analysis of public profiling data from The Cancer Genome Atlas (TCGA). This work demonstrates the power of using TCGA as a potential resource to develop prognostic tools for improving individualized patient care.
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Phase II evaluation of sunitinib in the treatment of recurrent or refractory high-grade glioma or ependymoma in children: a children's Oncology Group Study ACNS1021
Abstract
Sunitinib malate is a small multi-targeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem cell factor receptor (KIT), which are highly expressed by some high-grade brain tumors. We conducted a phase II study to estimate the efficacy and further characterize the pharmacokinetics of sunitinib in pediatric patients with recurrent or refractory high-grade glioma (Stratum A) or ependymoma (Stratum B). This was a prospective, multicenter Phase II trial conducted through the Children's Oncology Group (ClinicalTrials.gov Identifier NCT01462695). Sunitinib, 15 mg/m2, was orally administered once daily for 4 weeks every 6 weeks. The safety and tolerability of sunitinib, an estimate of progression-free survival (PFS), analyses of sunitinib pharmacokinetics (PK) and pharmacodynamics modulation of plasma VEGF and VEGFR2 were also assessed. Thirty eligible patients (17 patients on Stratum A, 13 patients on Stratum B) were enrolled and 29 patients were evaluable for response. Sunitinib was reasonably well tolerated in children with recurrent ependymoma or high-grade glioma. Most adverse events were of mild-to-moderate severity and manageable with supportive treatment. While there was a statistically significant modulation of plasma VEGFR2 with sunitinib exposure, there were no sustained tumor responses. Both strata were closed at time of planned interim analysis as there was not sufficient efficacy associated with sunitinib in children with recurrent brain tumors. Sunitinib was well tolerated in children and young adults with recurrent high-grade glioma or ependymoma but had no single agent objective antitumor activity in these patients.
This Phase II study of sunitinib reports the safety, tolerability and pharmacokinetic disposition in pediatric patients with recurrent high-grade glioma and ependymoma. While there was sufficient level of sunitinib in peripheral blood to modulate plasma vascular endothelial growth factor receptor (VEGFR)2, there were no sustained responses and no single agent activity in this patient cohort.
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Κυριακή 24 Απριλίου 2016
New Treatment Target Identified for Key Prostate Cancer Driver
Researchers have identified a potential alternative approach to blocking the activity of a key molecular driver of an advanced form of prostate cancer, called androgen-independent or castration-resistant prostate cancer.
In prostate cancer cell lines and in several mouse models of prostate cancer, treatment with drug-like small molecules that target a protein called ROR-γ disrupted the activity of the androgen receptor (AR), the researchers showed. Signaling through AR is the chief means by which prostate cancer cells grow and spread.
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Bridging the gap between non-targeted stable isotope labeling and metabolic flux analysis
Abstract
Background
Metabolism gained increasing interest for the understanding of diseases and to pinpoint therapeutic intervention points. However, classical metabolomics techniques only provide a very static view on metabolism. Metabolic flux analysis methods, on the other hand, are highly targeted and require detailed knowledge on metabolism beforehand.
Results
We present a novel workflow to analyze non-targeted metabolome-wide stable isotope labeling data to detect metabolic flux changes in a non-targeted manner. Furthermore, we show how similarity-analysis of isotopic enrichment patterns can be used for pathway contextualization of unidentified compounds. We illustrate our approach with the analysis of changes in cellular metabolism of human adenocarcinoma cells in response to decreased oxygen availability. Starting without a priori knowledge, we detect metabolic flux changes, leading to an increased glutamine contribution to acetyl-CoA production, reveal biosynthesis of N-acetylaspartate by N-acetyltransferase 8-like (NAT8L) in lung cancer cells and show that NAT8L silencing inhibits proliferation of A549, JHH-4, PH5CH8, and BEAS-2B cells.
Conclusions
Differential stable isotope labeling analysis provides qualitative metabolic flux information in a non-targeted manner. Furthermore, similarity analysis of enrichment patterns provides information on metabolically closely related compounds. N-acetylaspartate and NAT8L are important players in cancer cell metabolism, a context in which they have not received much attention yet.
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Σάββατο 23 Απριλίου 2016
YSL-12, a novel microtubule-destabilizing agent, exerts potent anti-tumor activity against colon cancer in vitro and in vivo
Abstract
Purpose
Microtubules play a central role in various fundamental cell functions and thus become an attractive target for cancer therapy. A novel compound YSL-12 is a combretastatin A-4 (CA-4) analogue with more stability. We investigated its anti-tumor activity and mechanisms in vitro and in vivo for the first time.
Methods
Cytotoxicity was evaluated by MTT method. In vitro microtubule polymerization assay was performed using a fluorescence-based method by multifunction fluorescence microplate reader. Intracellular microtubule network was detected by immunofluorescence method. Cell cycle analysis and apoptosis were measured by flow cytometry. Metabolic stability was recorded by liquid chromatography–ultraviolet detection and liquid chromatography–mass spectrometry. In vivo anti-tumor activity was assessed using HT-29 colon carcinoma xenografts established in BALB/c nude mice.
Results
YSL-12 displayed nanomolar-level cytotoxicity against various human cancer cell lines. A high selectivity toward normal cells and potent activity toward drug-resistant cells were also observed. YSL-12 was identified as tubulin polymerization inhibitor evidenced by effectively inhibits tubulin polymerization and heavily disrupted microtubule networks in living HT-29 cells. YSL-12 displayed potent disruption effect of pre-established tumor vasculature in vitro. In addition, YSL-12 treatment also caused cell cycle arrest in the G2/M phase and induced cell apoptosis in a dose-dependent manner. In vitro metabolic stability study revealed YSL-12 displayed considerable better stability than CA-4 in liver microsomes. In vivo, YSL-12 delayed tumor growth with 69.4 % growth inhibition.
Conclusions
YSL-12 is a promising microtubule inhibitor that has great potential for the treatment of colon carcinoma in vitro and in vivo and worth being a candidate for further development of cancer therapy.
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Potential Role of TRAIL in Metastasis of Mutant KRAS Expressing Lung Adenocarcinoma
Abstract
Apo2L/tumor necrosis factor (TNF)-α-related apoptosis-inducing ligand (TRAIL, TNFSF10) is an important cytokine in the tumor microenvironment and plays a major role in the balance of cell survival/death pathways. Bioinformatic analyses of 839 adenocarcinoma (AC) and 356 squamous cell lung carcinoma patient data (SCC) by cBioPortal (genomic analyses) shows that TRAIL expression leads to differential outcomes of disease free survival in AC and SCC. Oncomine datamining (transcript analyses) reveal that TRAIL is upregulated in 167 SCC as compared to 350 AC patients from six data sets. Genomic analyses using cBioPortal revealed high rates of KRAS mutation in AC accompanied by higher incidence of metastasis and increased amplifications of TRAIL gene in SCC. Bioinformatic analyses of an additional lung cancer patient database also showed that risk of disease progression was significantly increased with high TRAIL expression in AC (461 samples). In vitro studies demonstrated that TRAIL increased phosphorylation of ERK only in adenocarcinoma cell lines with mutant KRAS. This was associated with increased migration that was abrogated by MEK inhibitor PD98059. Effects of increased migration induced by TRAIL persisted even after exposure to ionizing radiation with suppression of DNA damage response. These results help understand the role of TRAIL signaling in metastasis which is essential to develop strategies to revert these signals into pro-apoptotic pathways.
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Progesterone Receptors, Pathological Complete Response and Early Outcome for Locally Advanced Breast Cancer – a Single Centre Study. (PPLB – 01)
Abstract
Neoadjuvant chemotherapy (NACT) for locally advanced breast cancer (LABC), apart from increasing breast conservation rates, also provides an opportunity to assess tumour response to chemotherapy, with Pathological Complete Response (pCR) described as an independent prognostic factor and a surrogate marker for better outcome and survival. Our primary aim was to identify clinical and pathological factors associated with pCR following NACT in patients with LABC treated at our institution. Our secondary aim was to analyze the impact of pCR and associated factors on disease free survival (DFS) and overall survival (OS). A retrospective analysis of LABC patients treated with NACT between Jun 2011 and Dec 2013. Clinical and histological variables were analyzed for association with pCR (no invasive or in situ carcinoma in breast or axillary lymph nodes). Kaplan-Meier curves and Cox regression model was used for survival analysis. All values were twosided, and statistical significance was defined as p < 0.05. 240 patients were included. The median tumor size was 6 cm, with T4 disease in 49.8 %. 45 % of tumors were of low grade (G1 + G2) and 53.8 % of high grade (G3). Estrogen Receptor (ER) was positive in 70.8 %, progesterone receptor (PR) in 53.3 % and Her2 in 38.8 %. The preferred NACT regimen was sequential anthracycline and taxane and 88.8 % of patients received this regimen. Of 93 potential Her2 Positive patients, only 23 received trastuzumab. Overall 23.2 % patients had pCR. At median follow up of 21 months (range, 3–42), 16.3 % of patients had recurrent disease, and 6.7 % had died. High tumor grade (p = 0.04), PR negative status (p < 0.01) and trastuzumab treatment (p = 0.01) were significant predictors of pCR in univariate analysis. On multivariate analysis PR negativity (OR 3.2, 95 % CI = 1.6 to 6.04, p = 0.001) and Trastuzumab use (OR 0.24, 95 % CI = 0.1 to 0.6, p = 0.004) were significant. Patients with pCR had positive associations with survival (p < .02,OS& .02,DFS) and interestingly PR positivity had positive association with DFS (p = 0.02) in Kaplan-Meier curves. On Cox regression, PR positivity (HR = 0.3, p < 0.01) and pCR (HR = 0.2, p < 0.01) correlated with DFS, though not with early OS. for the PR positive patients were paradoxical. Though less likely to have pCR (15 %, vs 32 % if PR negative), they had better DFS (p = 0.02), and achieving pCR had no survival benefit in this group. In contrast, PR negative patients, irrespective of ER status, had a high pCR rate, and achieving pCR had survival advantage (p < 0.05,DFS& p < 0.02,OS). PR negative patients without pCR had the worst DFS (p < 0.01) among all. High grade and Trastuzumab treatment as predictors of pCR, and pCR as a surrogate marker for survival are well recognized, and are supported by our findings. In present cohort, PR negativity showed prognostic importance independent of ER status. However these results were derived from sub-group, post-hoc analysis of data from a pre-existing cohort, without 'a-priori' hypothesis for survival analysis in relation to PR. These "hypothesis generating" results need confirmation by a well-designed prospective cohort or a randomized trial.
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Multipotent mesenchymal stromal cells are fully permissive for human cytomegalovirus infection
Abstract
Congenital human cytomegalovirus (HCMV) infection is a leading infectious cause of birth defects. Previous studies have reported birth defects with multiple organ maldevelopment in congenital HCMV-infected neonates. Multipotent mesenchymal stromal cells (MSCs) are a group of stem/progenitor cells that are multi-potent and can self-renew, and they play a vital role in multi-organ formation. Whether MSCs are susceptible to HCMV infection is unclear. In this study, MSCs were isolated from Wharton's jelly of the human umbilical cord and identified by their plastic adherence, surface marker pattern, and differentiation capacity. Then, the MSCs were infected with the HCMV Towne strain, and infection status was assessed via determination of viral entry, replication initiation, viral protein expression, and infectious virion release using western blotting, immunofluorescence assays, and plaque forming assays. The results indicate that the isolated MSCs were fully permissive for HCMV infection and provide a preliminary basis for understanding the pathogenesis of HCMV infection in non-nervous system diseases, including multi-organ malformation during fetal development.
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Relation between aerobic fitness and brain structures in amnestic mild cognitive impairment elderly
Abstract
Mild cognitive impairment (aMCI) is a clinical condition, with high risk to develop Alzheimer's disease. Physical exercise may have positive effect on cognition and brain structure in older adults. However, it is still under research whether these influences are true on aMCI subjects with low Ab_42 and high total tau in cerebrospinal fluid (CSF), which is considered a biomarker for AD. Therefore, we aimed to investigate a possible relation between aerobic fitness (AF) and gray matter (GM) volume and AF and white matter (WM) integrity in aMCI with a CSF biomarker. Twenty-two participants with aMCI acquired the images on a 3.0-T MRI. AF was assessed by a graded exercise test on a treadmill. Voxel-based morphometry and tract-based spatial statistic methods were used to analyze the GM volume and WM microstructural integrity, respectively. We correlated AF and GM volume and WM integrity in aMCI (p < 0.05, FWE corrected, cluster with at least five voxels). There was a positive relation between AF and GM volume mostly in frontal superior cortex. In WM integrity, AF was positively correlated with fractional anisotropy and negatively correlated with mean diffusivity and radial diffusivity, all in the same tracts that interconnect frontal, temporal, parietal, and occipital areas (longitudinal fasciculus, fronto-occipital fasciculus, and corpus callosum). These results suggest that aerobic fitness may have a positive influence on protection of brain even in aMCI CSF biomarker, a high-risk population to convert to AD.
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TDRG1 regulates chemosensitivity of seminoma TCam-2 cells to cisplatin via PI3K/Akt/mTOR signaling pathway and mitochondria-mediated apoptotic pathway.
TDRG1 regulates chemosensitivity of seminoma TCam-2 cells to cisplatin via PI3K/Akt/mTOR signaling pathway and mitochondria-mediated apoptotic pathway.
Cancer Biol Ther. 2016 Apr 22;:0
Authors: Gan Y, Wang Y, Tan Z, Zhou J, Kitazawa R, Jiang X, Tang Y, Yang J
Abstract
We previously identified TDRG1 (testis developmental related gene 1), a novel gene with exclusive expression in testis, promoted the proliferation and progression of cultured human seminoma cells through PI3K/Akt/mTOR signaling. As increasing evidence reveal that aberrant activation of this signaling is involved in cisplatin resistance. Then, in this study, we further explored whether TDRG1 regulated the chemosensitivity of seminoma TCam-2 cells to cisplatin. Our researches showed TDRG1 could regulate the viability of TCam-2 cells following cisplatin treatment in vitro through control of both cell apoptosis and cell cycle. Mechanistically, we observed TDRG1 positively regulated the expression levels of the key elements in PI3K/Akt/mTOR pathway including p-PI3K, p-Akt and p-mTOR and also affected the translocation of nuclear p-Akt in TCam-2 cells during cisplatin treatment. Meanwhile, the levels of Bad, cytochrome c, caspase-9 ratio (activated/total), caspase-3 ratio (activated/total) and cleaved-PARP were negatively modulated by TDRG1, which meant the involvement of mitochondria-mediated apoptotic pathway. Furthermore, we found the effect of TDRG1 knockdown or TDRG1 overexpression could be reversed by IGF-1, a PI3K signaling activator, or LY294002, a inhibitor of this pathway, respectively. Similar effects of TDRG1 on cisplatin chemosensitivity and associated molecular mechanism were also confirmed in vivo by employing xenograft assays. In addition, the positive correlation between TDRG1 and p-PI3K, or p-Akt, was found in tumor tissues from seminoma patients. In conclusion, we uncover that TDRG1 regulates chemosensitivity of TCam-2 cells to cisplatin through PI3K/Akt/mTOR signaling and mitochondria-mediated apoptotic pathway both in vitro and in vivo.
PMID: 27104982 [PubMed - as supplied by publisher]
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Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.
Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.
Cancer Biol Ther. 2016 Apr 22;:0
Authors: Sunakawa Y, Yang D, Moran M, Astrow SH, Tsuji A, Stephens C, Zhang W, Cao S, Takahashi T, Denda T, Shimada K, Kochi M, Nakamura M, Kotaka M, Segawa Y, Masuishi T, Takeuchi M, Fujii M, Nakajima T, Ichikawa W, Lenz HJ
Abstract
Several studies have reported that epidermal growth factor receptor (EGFR)-related molecules may serve as predictors of cetuximab treatment for metastatic colorectal cancer (mCRC), such as EGFR gene copy number (GCN), expression of two ligands of EGFR, amphiregulin (AREG) and epiregulin (EREG), and EGFR CA simple sequence repeat 1 (CA-SSR1) polymorphism; however, these biomarkers still remain not useful in clinical practice since they have been evaluated using cohorts with patients treated in various settings of chemotherapy. We therefore analyzed associations of mRNA expression of AREG and EREG, EGFR GCN, and CA-SSR1 polymorphism [short (S;≤19) / long (L;≥20)] with clinical outcomes in 77 Japanese patients with KRAS exon 2 wild-type mCRC enrolled in phase II trials of FOLFOX (n=28/57, UMIN000004197) or SOX (n=49/67, UMIN000007022) plus cetuximab as first-line therapy. High AREG expression correlated with significantly better progression-free survival (median 11.6 vs. 6.6 months, HR 0.52, P=0.037); moreover, it remained statistically significant in multivariate analysis (HR: 0.48, P=0.027). S/S genotype of CA-SSR1 predicted severe skin toxicity (P=0.040). Patients with both AREG-low and EGFR low-GCN had significantly shorter overall survival than the others (median 22.2 vs. 42.8 months, HR 2.34, P=0.042). The multivariate analysis showed that molecular status with both AREG-low and EGFR low-GCN was a predictor of worse survival (P=0.006). In conclusion, AREG mRNA expression and EGFR CA-SSR1 polymorphism predict survival and skin toxicity, respectively, of initial chemotherapy with cetuximab. Our results also suggest potential prognostic value of the combined assessment of AREG and EGFR GCN for first-line cetuximab treatment.
PMID: 27104867 [PubMed - as supplied by publisher]
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GUCY2C Ligand Replacement to Prevent Colorectal Cancer.
GUCY2C Ligand Replacement to Prevent Colorectal Cancer.
Cancer Biol Ther. 2016 Apr 22;:0
Authors: Blomain ES, Pattison AM, Waldman SA
Abstract
Despite advances in screening and prevention strategies, colorectal cancer (CRC) remains the second-leading cause of cancer-related death in the United States. Given this continued public health burden of CRC, there is a clear need for improved disease prevention. CRC initiates and progresses over decades, canonically proceeding via a series of stepwise molecular events that turn a normal epithelium into a dysfunctional epithelium, then subsequently into an adenoma, and finally an invasive adenocarcinoma. An emerging paradigm suggests that guanylyl cyclase C (GUCY2C) functions as a tumor suppressor in the intestine, and that the loss of hormone ligands for this receptor causes epithelial dysfunction and represents an important step in the disease process. In that context, GUCY2C ligand replacement therapy has been proposed as a strategy to prevent colorectal cancer, a translational opportunity that is underscored by the recent regulatory approval of the oral GUCY2C ligand linaclotide (Linzess™, Forest Laboratories and Ironwood Pharmaceuticals, Inc.).
PMID: 27104761 [PubMed - as supplied by publisher]
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Bortezomib-related Neuropathy masking CNS relapse in Multiple Myeloma; A unique case report and review of the Literature.
Bortezomib-related Neuropathy masking CNS relapse in Multiple Myeloma; A unique case report and review of the Literature.
Cancer Biol Ther. 2016 Apr 22;:0
Authors: Abid MB, De Mel S, Abid MA, Bing TK, Joo CW
Abstract
BACKGROUND: Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system (CNS) relapse in MM remains exceedingly rare and carries a dismal prognosis. We present an unusual case of bortezomib related neuropathy masking a CNS relapse of MM.
PRESENTATION: A 57-year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement. She was treated with four cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a VGPR, after which she underwent an autologous stem cell transplant (ASCT) followed by bortezomib maintenance. Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse.
DISCUSSION: CNS involvement in MM (CNS-MM) is uncommon and is considered an aggressive disease. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis. Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib-based therapy. The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement.
CONCLUSION: In the era of proteasome inhibitor (PI)/immunomodulator (IMID)-based therapy for MM which carries neurologic adverse effects, it is prudent to consider CNS relapse early. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration.
PMID: 27105248 [PubMed - as supplied by publisher]
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Role of EZH2 histone methyltrasferase in melanoma progression and metastasis.
Role of EZH2 histone methyltrasferase in melanoma progression and metastasis.
Cancer Biol Ther. 2016 Apr 22;:0
Authors: Mahmoud F, Shields B, Makhoul I, Hutchins LF, Shalin SC, Tackett AJ
Abstract
There is accumulating evidence that the histone methyltransferase enhancer of zeste homologue 2 (EZH2), the main component of the polycomb-repressive complex 2 (PRC2), is involved in melanoma progression and metastasis. Novel drugs that target and reverse such epigenetic changes may find a way into the management of patients with advanced melanoma. We provide a comprehensive up-to-date review of the role and biology of EZH2 on gene transcription, senescence/apoptosis, melanoma microenvironment, melanocyte stem cells, the immune system, and micro RNA. Furthermore, we discuss EZH2 inhibitors as potential anti-cancer therapy.
PMID: 27105109 [PubMed - as supplied by publisher]
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TDRG1 regulates chemosensitivity of seminoma TCam-2 cells to cisplatin via PI3K/Akt/mTOR signaling pathway and mitochondria-mediated apoptotic pathway.
TDRG1 regulates chemosensitivity of seminoma TCam-2 cells to cisplatin via PI3K/Akt/mTOR signaling pathway and mitochondria-mediated apoptotic pathway.
Cancer Biol Ther. 2016 Apr 22;:0
Authors: Gan Y, Wang Y, Tan Z, Zhou J, Kitazawa R, Jiang X, Tang Y, Yang J
Abstract
We previously identified TDRG1 (testis developmental related gene 1), a novel gene with exclusive expression in testis, promoted the proliferation and progression of cultured human seminoma cells through PI3K/Akt/mTOR signaling. As increasing evidence reveal that aberrant activation of this signaling is involved in cisplatin resistance. Then, in this study, we further explored whether TDRG1 regulated the chemosensitivity of seminoma TCam-2 cells to cisplatin. Our researches showed TDRG1 could regulate the viability of TCam-2 cells following cisplatin treatment in vitro through control of both cell apoptosis and cell cycle. Mechanistically, we observed TDRG1 positively regulated the expression levels of the key elements in PI3K/Akt/mTOR pathway including p-PI3K, p-Akt and p-mTOR and also affected the translocation of nuclear p-Akt in TCam-2 cells during cisplatin treatment. Meanwhile, the levels of Bad, cytochrome c, caspase-9 ratio (activated/total), caspase-3 ratio (activated/total) and cleaved-PARP were negatively modulated by TDRG1, which meant the involvement of mitochondria-mediated apoptotic pathway. Furthermore, we found the effect of TDRG1 knockdown or TDRG1 overexpression could be reversed by IGF-1, a PI3K signaling activator, or LY294002, a inhibitor of this pathway, respectively. Similar effects of TDRG1 on cisplatin chemosensitivity and associated molecular mechanism were also confirmed in vivo by employing xenograft assays. In addition, the positive correlation between TDRG1 and p-PI3K, or p-Akt, was found in tumor tissues from seminoma patients. In conclusion, we uncover that TDRG1 regulates chemosensitivity of TCam-2 cells to cisplatin through PI3K/Akt/mTOR signaling and mitochondria-mediated apoptotic pathway both in vitro and in vivo.
PMID: 27104982 [PubMed - as supplied by publisher]
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Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.
Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.
Cancer Biol Ther. 2016 Apr 22;:0
Authors: Sunakawa Y, Yang D, Moran M, Astrow SH, Tsuji A, Stephens C, Zhang W, Cao S, Takahashi T, Denda T, Shimada K, Kochi M, Nakamura M, Kotaka M, Segawa Y, Masuishi T, Takeuchi M, Fujii M, Nakajima T, Ichikawa W, Lenz HJ
Abstract
Several studies have reported that epidermal growth factor receptor (EGFR)-related molecules may serve as predictors of cetuximab treatment for metastatic colorectal cancer (mCRC), such as EGFR gene copy number (GCN), expression of two ligands of EGFR, amphiregulin (AREG) and epiregulin (EREG), and EGFR CA simple sequence repeat 1 (CA-SSR1) polymorphism; however, these biomarkers still remain not useful in clinical practice since they have been evaluated using cohorts with patients treated in various settings of chemotherapy. We therefore analyzed associations of mRNA expression of AREG and EREG, EGFR GCN, and CA-SSR1 polymorphism [short (S;≤19) / long (L;≥20)] with clinical outcomes in 77 Japanese patients with KRAS exon 2 wild-type mCRC enrolled in phase II trials of FOLFOX (n=28/57, UMIN000004197) or SOX (n=49/67, UMIN000007022) plus cetuximab as first-line therapy. High AREG expression correlated with significantly better progression-free survival (median 11.6 vs. 6.6 months, HR 0.52, P=0.037); moreover, it remained statistically significant in multivariate analysis (HR: 0.48, P=0.027). S/S genotype of CA-SSR1 predicted severe skin toxicity (P=0.040). Patients with both AREG-low and EGFR low-GCN had significantly shorter overall survival than the others (median 22.2 vs. 42.8 months, HR 2.34, P=0.042). The multivariate analysis showed that molecular status with both AREG-low and EGFR low-GCN was a predictor of worse survival (P=0.006). In conclusion, AREG mRNA expression and EGFR CA-SSR1 polymorphism predict survival and skin toxicity, respectively, of initial chemotherapy with cetuximab. Our results also suggest potential prognostic value of the combined assessment of AREG and EGFR GCN for first-line cetuximab treatment.
PMID: 27104867 [PubMed - as supplied by publisher]
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GUCY2C Ligand Replacement to Prevent Colorectal Cancer.
GUCY2C Ligand Replacement to Prevent Colorectal Cancer.
Cancer Biol Ther. 2016 Apr 22;:0
Authors: Blomain ES, Pattison AM, Waldman SA
Abstract
Despite advances in screening and prevention strategies, colorectal cancer (CRC) remains the second-leading cause of cancer-related death in the United States. Given this continued public health burden of CRC, there is a clear need for improved disease prevention. CRC initiates and progresses over decades, canonically proceeding via a series of stepwise molecular events that turn a normal epithelium into a dysfunctional epithelium, then subsequently into an adenoma, and finally an invasive adenocarcinoma. An emerging paradigm suggests that guanylyl cyclase C (GUCY2C) functions as a tumor suppressor in the intestine, and that the loss of hormone ligands for this receptor causes epithelial dysfunction and represents an important step in the disease process. In that context, GUCY2C ligand replacement therapy has been proposed as a strategy to prevent colorectal cancer, a translational opportunity that is underscored by the recent regulatory approval of the oral GUCY2C ligand linaclotide (Linzess™, Forest Laboratories and Ironwood Pharmaceuticals, Inc.).
PMID: 27104761 [PubMed - as supplied by publisher]
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Pluripotency markers are differentially induced by MEK inhibition in thyroid and melanoma BRAFV600E cell lines
10.1080/15384047.2016.1139230<br/>Emma R. Dorris
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Decreased MicroRNA-26a expression causes cisplatin resistance in human non-small cell lung cancer
10.1080/15384047.2015.1095405<br/>Yong Yang
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Bortezomib-related Neuropathy masking CNS relapse in Multiple Myeloma; A unique case report and review of the Literature.
Bortezomib-related Neuropathy masking CNS relapse in Multiple Myeloma; A unique case report and review of the Literature.
Cancer Biol Ther. 2016 Apr 22;:0
Authors: Abid MB, De Mel S, Abid MA, Bing TK, Joo CW
Abstract
BACKGROUND: Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system (CNS) relapse in MM remains exceedingly rare and carries a dismal prognosis. We present an unusual case of bortezomib related neuropathy masking a CNS relapse of MM.
PRESENTATION: A 57-year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement. She was treated with four cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a VGPR, after which she underwent an autologous stem cell transplant (ASCT) followed by bortezomib maintenance. Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse.
DISCUSSION: CNS involvement in MM (CNS-MM) is uncommon and is considered an aggressive disease. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis. Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib-based therapy. The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement.
CONCLUSION: In the era of proteasome inhibitor (PI)/immunomodulator (IMID)-based therapy for MM which carries neurologic adverse effects, it is prudent to consider CNS relapse early. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration.
PMID: 27105248 [PubMed - as supplied by publisher]
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Role of EZH2 histone methyltrasferase in melanoma progression and metastasis.
Role of EZH2 histone methyltrasferase in melanoma progression and metastasis.
Cancer Biol Ther. 2016 Apr 22;:0
Authors: Mahmoud F, Shields B, Makhoul I, Hutchins LF, Shalin SC, Tackett AJ
Abstract
There is accumulating evidence that the histone methyltransferase enhancer of zeste homologue 2 (EZH2), the main component of the polycomb-repressive complex 2 (PRC2), is involved in melanoma progression and metastasis. Novel drugs that target and reverse such epigenetic changes may find a way into the management of patients with advanced melanoma. We provide a comprehensive up-to-date review of the role and biology of EZH2 on gene transcription, senescence/apoptosis, melanoma microenvironment, melanocyte stem cells, the immune system, and micro RNA. Furthermore, we discuss EZH2 inhibitors as potential anti-cancer therapy.
PMID: 27105109 [PubMed - as supplied by publisher]
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TDRG1 regulates chemosensitivity of seminoma TCam-2 cells to cisplatin via PI3K/Akt/mTOR signaling pathway and mitochondria-mediated apoptotic pathway.
TDRG1 regulates chemosensitivity of seminoma TCam-2 cells to cisplatin via PI3K/Akt/mTOR signaling pathway and mitochondria-mediated apoptotic pathway.
Cancer Biol Ther. 2016 Apr 22;:0
Authors: Gan Y, Wang Y, Tan Z, Zhou J, Kitazawa R, Jiang X, Tang Y, Yang J
Abstract
We previously identified TDRG1 (testis developmental related gene 1), a novel gene with exclusive expression in testis, promoted the proliferation and progression of cultured human seminoma cells through PI3K/Akt/mTOR signaling. As increasing evidence reveal that aberrant activation of this signaling is involved in cisplatin resistance. Then, in this study, we further explored whether TDRG1 regulated the chemosensitivity of seminoma TCam-2 cells to cisplatin. Our researches showed TDRG1 could regulate the viability of TCam-2 cells following cisplatin treatment in vitro through control of both cell apoptosis and cell cycle. Mechanistically, we observed TDRG1 positively regulated the expression levels of the key elements in PI3K/Akt/mTOR pathway including p-PI3K, p-Akt and p-mTOR and also affected the translocation of nuclear p-Akt in TCam-2 cells during cisplatin treatment. Meanwhile, the levels of Bad, cytochrome c, caspase-9 ratio (activated/total), caspase-3 ratio (activated/total) and cleaved-PARP were negatively modulated by TDRG1, which meant the involvement of mitochondria-mediated apoptotic pathway. Furthermore, we found the effect of TDRG1 knockdown or TDRG1 overexpression could be reversed by IGF-1, a PI3K signaling activator, or LY294002, a inhibitor of this pathway, respectively. Similar effects of TDRG1 on cisplatin chemosensitivity and associated molecular mechanism were also confirmed in vivo by employing xenograft assays. In addition, the positive correlation between TDRG1 and p-PI3K, or p-Akt, was found in tumor tissues from seminoma patients. In conclusion, we uncover that TDRG1 regulates chemosensitivity of TCam-2 cells to cisplatin through PI3K/Akt/mTOR signaling and mitochondria-mediated apoptotic pathway both in vitro and in vivo.
PMID: 27104982 [PubMed - as supplied by publisher]
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Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.
Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.
Cancer Biol Ther. 2016 Apr 22;:0
Authors: Sunakawa Y, Yang D, Moran M, Astrow SH, Tsuji A, Stephens C, Zhang W, Cao S, Takahashi T, Denda T, Shimada K, Kochi M, Nakamura M, Kotaka M, Segawa Y, Masuishi T, Takeuchi M, Fujii M, Nakajima T, Ichikawa W, Lenz HJ
Abstract
Several studies have reported that epidermal growth factor receptor (EGFR)-related molecules may serve as predictors of cetuximab treatment for metastatic colorectal cancer (mCRC), such as EGFR gene copy number (GCN), expression of two ligands of EGFR, amphiregulin (AREG) and epiregulin (EREG), and EGFR CA simple sequence repeat 1 (CA-SSR1) polymorphism; however, these biomarkers still remain not useful in clinical practice since they have been evaluated using cohorts with patients treated in various settings of chemotherapy. We therefore analyzed associations of mRNA expression of AREG and EREG, EGFR GCN, and CA-SSR1 polymorphism [short (S;≤19) / long (L;≥20)] with clinical outcomes in 77 Japanese patients with KRAS exon 2 wild-type mCRC enrolled in phase II trials of FOLFOX (n=28/57, UMIN000004197) or SOX (n=49/67, UMIN000007022) plus cetuximab as first-line therapy. High AREG expression correlated with significantly better progression-free survival (median 11.6 vs. 6.6 months, HR 0.52, P=0.037); moreover, it remained statistically significant in multivariate analysis (HR: 0.48, P=0.027). S/S genotype of CA-SSR1 predicted severe skin toxicity (P=0.040). Patients with both AREG-low and EGFR low-GCN had significantly shorter overall survival than the others (median 22.2 vs. 42.8 months, HR 2.34, P=0.042). The multivariate analysis showed that molecular status with both AREG-low and EGFR low-GCN was a predictor of worse survival (P=0.006). In conclusion, AREG mRNA expression and EGFR CA-SSR1 polymorphism predict survival and skin toxicity, respectively, of initial chemotherapy with cetuximab. Our results also suggest potential prognostic value of the combined assessment of AREG and EGFR GCN for first-line cetuximab treatment.
PMID: 27104867 [PubMed - as supplied by publisher]
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GUCY2C Ligand Replacement to Prevent Colorectal Cancer.
GUCY2C Ligand Replacement to Prevent Colorectal Cancer.
Cancer Biol Ther. 2016 Apr 22;:0
Authors: Blomain ES, Pattison AM, Waldman SA
Abstract
Despite advances in screening and prevention strategies, colorectal cancer (CRC) remains the second-leading cause of cancer-related death in the United States. Given this continued public health burden of CRC, there is a clear need for improved disease prevention. CRC initiates and progresses over decades, canonically proceeding via a series of stepwise molecular events that turn a normal epithelium into a dysfunctional epithelium, then subsequently into an adenoma, and finally an invasive adenocarcinoma. An emerging paradigm suggests that guanylyl cyclase C (GUCY2C) functions as a tumor suppressor in the intestine, and that the loss of hormone ligands for this receptor causes epithelial dysfunction and represents an important step in the disease process. In that context, GUCY2C ligand replacement therapy has been proposed as a strategy to prevent colorectal cancer, a translational opportunity that is underscored by the recent regulatory approval of the oral GUCY2C ligand linaclotide (Linzess™, Forest Laboratories and Ironwood Pharmaceuticals, Inc.).
PMID: 27104761 [PubMed - as supplied by publisher]
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[Expensive cancer drugs funding is undergoing turbulent times].
[Expensive cancer drugs funding is undergoing turbulent times].
Bull Cancer. 2016 Apr;103(4):313-4
Authors: Bay JO, L'Allemain G, Vignot S
PMID: 27102881 [PubMed - in process]
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Ultrasound and MR imaging findings in prenatal diagnosis of craniosynostosis syndromes
Abstract
Background
Craniosynostosis syndromes are uncommonly encountered in the prenatal period. Identification is challenging but important for family counseling and perinatal management.
Objective
This series examines prenatal findings in craniosynostosis syndromes, comparing the complementary roles of US and MRI and emphasizing clues easily missed in the second trimester.
Materials and methods
Six prenatal cases evaluated from 2002 through 2011 were retrospectively reviewed. Referral history, gestational age, and sonographic and MRI findings were reviewed by three pediatric radiologists. Abnormalities of the calvarium, hands, feet, face, airway and central nervous system were compared between modalities.
Results
The diagnosis was Apert syndrome in three, Pfeiffer syndrome in two and Carpenter syndrome in one. The gestational age at evaluation ranged from 21 to 33 weeks. All six were evaluated by MRI and US, with two undergoing repeat evaluation in the third trimester, yielding a total of eight MRIs and US exams. The referral history suggested cloverleaf skull in two cases but did not suggest craniosynostosis syndrome in any case. In four, the referral suggested central nervous system (CNS) findings that were not confirmed by MRI; additional CNS findings were discovered in the remaining two. In four cases, developing turricephaly resulted in a characteristic "lampshade" contour of the fetal head. Hypertelorism and proptosis were present in five, with proptosis better appreciated by MRI. Digit abnormalities were present in all, seen equally well by MRI and US. Lung abnormalities in the second trimester in one fetus resolved by the third trimester.
Conclusion
Prenatal diagnosis of craniosynostosis syndromes is difficult prior to the third trimester. MRI and US have complementary roles in evaluation of these patients.
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Role of percutaneous abscess drainage in the management of young patients with Crohn disease
Abstract
Background
Intra-abdominal abscess is a common complication of Crohn disease in children. Prior studies, primarily in adults, have shown that percutaneous abscess drainage is a safe and effective treatment for this condition; however, the data regarding this procedure and indications in pediatric patients is limited.
Objective
Our aim was to determine the success rate of percutaneous abscess drainage for abscesses related to Crohn disease in pediatric patients with a focus on treatment endpoints that are relevant in the era of biological medical therapy.
Materials and methods
We retrospectively reviewed 25 cases of patients ages ≤20 years with Crohn disease who underwent percutaneous abscess drainage. Technical success was defined as catheter placement within the abscess with reduction in abscess size on post-treatment imaging. Clinical success was defined as (1) no surgery within 1 year of drainage or (2) surgical resection following drainage with no residual abscess at surgery or on preoperative imaging. Multiple clinical parameters were analyzed for association with treatment success or failure.
Results
All cases were classified as technical successes. Nineteen cases were classified as clinical successes (76%), including 7 patients (28%) who required no surgery within 1 year of percutaneous drainage and 12 patients (48%) who had elective bowel resection within 1 year. There was a statistically significant association between resumption of immunosuppressive therapy within 8 weeks of drainage and both clinical success (P < 0.01) and avoidance of surgery after 1 year (P < 0.01).
Conclusion
Percutaneous abscess drainage is an effective treatment for Crohn disease-related abscesses in pediatric patients. Early resumption of immunosuppressive therapy is statistically associated with both clinical success and avoidance of bowel resection, suggesting a role for percutaneous drainage in facilitating prompt initiation of medical therapy and preventing surgical bowel resection.
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Incidental mastoid opacification in children on MRI
Abstract
Background
The opacification the mastoid cavity is frequently reported by radiologists on cross-sectional imaging done for non-otological indications. It is well known that presence of fluid the mastoid does not amount to mastoiditis. This study seeks to provide an evidence-based confirmation of this known finding.
Objective
The purpose of our study was to determine the prevalence of mastoid opacification in children undergoing outpatient brain MRI examination.
Materials and methods
Our study included 515 outpatient children who had brain MRI for indications other than mastoiditis or otitis media from January 2014 to March 2014. Children with history of skull base trauma or radiation were excluded. The age range was 15 days to 18 years. The overall prevalence of mastoid opacification was determined using one sample proportion and exact 95% Clopper-Pearson confidence intervals. The prevalence of mastoid opacification was analyzed based on gender, age and presenting symptoms using chi-square test of association.
Results
One hundred ten children (21.4%) had mastoid opacification. Younger patients tended to have higher opacification rates with the prevalence in children younger than 1 year of age and between 1 and 2 years of age as high as 41.7% (20/48) and 47.5% (38/80), respectively.
Conclusion
The diagnosis of mastoiditis in children should not be based upon a radiologist's report of finding fluid or mucosal thickening in the mastoid air cells as incidental opacification the mastoid is seen frequently.
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MSK1 as a candidate gene for PI3K/mTOR resistance
Glioblastoma (GBM) represents a compelling disease for kinase inhibitor therapy because most of these tumors harbor genetic alterations that result in aberrant activation of growth factor signaling pathways. The PI3K/mammalian target of rapamycin (mTOR) pathway is dysregulated in over 50% of human GBM but remains a challenging clinical target. Inhibitors against PI3K/mTOR mediators have limited clinical efficacy as single agents. We investigated potential bypass mechanisms to PI3K/mTOR inhibition using gene expression profiling before and after PI3K inhibitor treatment by Affymetrix microarrays. Mitogen- and stress-activated protein kinase 1 (MSK1) was markedly induced after PI3K/mTOR inhibitor treatment and disruption of MSK1 by specific shRNAs attenuated resistance to PI3K/mTOR inhibitors in glioma initiating cells (GICs). Further investigation showed that MSK1 phosphorylates β-catenin and regulates its nuclear translocation and transcriptional activity. The depletion of β-catenin potentiated PI3K/mTOR inhibitor-induced cytotoxicity and the inhibition of MSK1 synergized with PI3K/mTOR inhibitors to extend survival in an intracranial animal model and decreased phosphorylation of β-catenin at Ser552. These observations suggest that MSK1/β-catenin signaling serves as an escape survival signal upon PI3K/mTOR inhibition and provides a strong rationale for the combined use of PI3K/mTOR and MSK1/β-catenin inhibition to induce lethal growth inhibition in human GBM.
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Src inhibitor in biliary tract cancer
Src, a non-receptor tyrosine kinase, is involved in a number of cancer-related signaling pathways and aberrantly activated in biliary tract cancer (BTC). This study aimed to elucidate the potential role of Src as a therapeutic target in BTC. We tested bosutinib, an orally active c-Src/Abl kinase inhibitor, alone or in combination with cytotoxic agents using nine human BTC cell lines: SNU-245, SNU-308, SNU-478, SNU-869, SNU-1079, SNU-1196, HuCCT1, TFK-1, and EGI-1. Of these, SNU-308 and SNU-478 were relatively sensitive to bosutinib. Bosutinib abrogated phosphorylation of Src and its downstream molecules, significantly increased G1 cell-cycle arrest and apoptosis. Bosutinib significantly inhibited cell migration and invasion and decreased epithelial-mesenchymal transition markers. Bosutinib combined with gemcitabine or cisplatin showed synergistic anti-proliferative and anti-migratory effects. In addition, this combination further inhibited phosphorylation of Src and its downstream molecules and decreased epithelial-mesenchymal transition marker expression compared with bosutinib alone. We established a SNU-478 xenograft model for in vivo experiments, since SNU-478 was more tumorigenic than SNU-308. Bosutinib combined with gemcitabine or cisplatin showed significantly more potent anti-tumor effects than bosutinib alone. Bosutinib combined with gemcitabine further decreased Ki-67 expression and Src phosphorylation, and further increased TUNEL expression. Our data suggest that Src might be a potential therapeutic target in BTC. Bosutinib demonstrated promising anti-tumor activity alone or in combination with gemcitabine or cisplatin in BTC cells, which supports further clinical development in patients with advanced BTC.
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Παρασκευή 22 Απριλίου 2016
The Intestinal Microbiome and Estrogen Receptor-Positive Female Breast Cancer
The huge communities of residential microbes, including bacteria, viruses, Archaea, and Eukaryotes, that colonize humans are increasingly recognized as playing important roles in health and disease. A complex populous ecosystem, the human gastrointestinal (GI) tract harbors up to 1011 bacterial cells per gram of luminal content, whose collective genome, the gut metagenome, contains a vastly greater number of individual genes than the human genome. In health, the function of the microbiome might be considered to be in dynamic equilibrium with the host, exerting both local and distant effects. However, 'disequilibrium' may contribute to the emergence of disease, including malignancy. In this review, we discuss how the intestinal bacterial microbiome and in particular how an 'estrobolome,' the aggregate of enteric bacterial genes capable of metabolizing estrogens, might affect women's risk of developing postmenopausal estrogen receptor–positive breast cancer. Estrobolome composition is impacted by factors that modulate its functional activity. Exploring variations in the composition and activities of the estrobolome in healthy individuals and in women with estrogen-driven breast cancer may lead to development of microbiome-based biomarkers and future targeted interventions to attenuate cancer risk.
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Dual FASN and EGFR blockade in TNBC
Abstract Purpose: Triple Negative Breast Cancer (TNBC) lacks an approved targeted therapy. Despite initial good response to chemotherapy, 30% of the patients relapse within 5 years after treatment. EGFR overexpression is a common marker in TNBC, and its expression has been correlated with poor outcome. Inhibition of Fatty Acid Synthase (FASN) activity leads to apoptosis of human carcinoma cells overexpressing FASN. We tested the hypothesis that blocking FASN in combination with anti-EGFR signaling agents would be an effective antitumor strategy in sensitive and chemoresistant TNBC. Experimental Design: Several TNBC cell lines and 29 primary tumors were included to determine whether FASN is a potential target in TNBC. Doxorubicin-resistant TNBC cell lines (231DXR and HCCDXR) have been developed and characterized in our laboratory. Cellular and molecular interactions of anti-FASN compounds (EGCG and C75) with cetuximab were analyzed. In vivo tumor growth inhibition was evaluated after cetuximab, EGCG or the combination in TNBC orthoxenograft models. Results: TNBC cell lines showed overexpression of FASN enzyme and its inhibiton correlated to FASN levels. FASN staining was observed in all of the 29 TNBC tumor samples. In vitro, EGCG and C75 plus cetuximab showed strong synergism in sensitive and chemoresistant cells. In vivo, the combination of EGCG with cetuximab displayed strong antitumor activity against the sensitive and chemoresistant TNBC orthoxenografts, without signs of toxicity. Conclusions: Our results show that the simultaneous blockade of FASN and EGFR is effective in preclinical models of sensitive and chemoresistant TNBC.
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Targeted therapy combined with radiotherapy in non-small-cell lung cancer: a review of the Oncologic Group for the Study of Lung Cancer (Spanish Radiation Oncology Society)
Abstract
In recent years, major advances in our understanding of the molecular biology of lung cancer, together with significant improvements in radiotherapy technologies, have revolutionized the treatment of non-small cell lung cancer (NSCLC). This has led to the development of new therapies that target molecular mutations specific to each tumor type, acting on the cell surface antigens or intracellular signaling pathways, or directly affecting cell survival. At the same time, ablative dose radiotherapy can be delivered safely in the context of metastatic disease. In this article, the GOECP/SEOR (Oncological Group for Study of Lung Cancer/Spanish Society of Radiation Oncology) reviews the role of new targeted therapies used in combination with radiotherapy in patients with locally advanced (stage III) NSCLC and in patients with advanced, metastatic (stage IV) NSCLC.
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Breast cancer screening disparities among immigrant women by world region of origin: a population-based study in Ontario, Canada
Abstract
Rates of mammography screening for breast cancer are disproportionately low in certain subgroups including low-income and immigrant women. The purpose of the study was to examine differences in rates of appropriate breast cancer screening (i.e., screening mammography every 2 years) among Ontario immigrant women by world region of origin and explore the association between appropriate breast cancer screening among these women groups and individual and structural factors. A cohort of 183,332 screening-eligible immigrant women living in Ontario between 2010 and 2012 was created from linked databases and classified into eight world regions of origin. Appropriate screening rates were calculated for each region by age group and selected sociodemographic, immigration, and healthcare-related characteristics. The association between appropriate screening across the eight regions of origin and selected sociodemographic, immigration, and health-related characteristics was explored using multivariate Poisson regression. Screening varied by region of origin, with South Asian women (48.5%) having the lowest and Caribbean and Latin American women (63.7%) the highest cancer screening rates. Factors significantly associated with lower screening across the world regions of origin included living in the lowest income neighborhoods, having a refugee status, being a new immigrant, not having a regular physical examination, not being enrolled in a primary care patient enrollment model, having a male physician, and having an internationally trained physician. Multiple interventions entailing cross-sector collaboration, promotion of patient enrollment models, community engagement, comprehensive and intensive outreach to women, and knowledge translation and transfer to physicians should be considered to address screening disparities among immigrant population. Consideration should be given to design and delivery of culturally appropriate and easily accessible cancer screening programs targeted at high- risk immigrant subgroups, such as women of South Asian origin, refugees, and new immigrants.
The study found differences in rates of breast cancer screening among Ontario immigrant women by world region of origin. South Asian women had the lowest cancer screening rates. Factors associated with lower screening included living in the lowest income neighborhoods, having a refugee status, being a new immigrant, not having a regular physical examination, not being enrolled in a primary care patient enrollment model, having a male physician, and having an internationally trained physician.
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High co-expression of PD-L1 and HIF-1α correlates with tumour necrosis in pulmonary pleomorphic carcinoma
Publication date: June 2016
Source:European Journal of Cancer, Volume 60
Author(s): Yih-Leong Chang, Ching-Yao Yang, Mong-Wei Lin, Chen-Tu Wu, Pan-Chyr Yang
BackgroundPulmonary pleomorphic carcinomas (PPCs) are uncommon malignant tumours characterised by an aggressive clinical course and poor survival. These neoplasms frequently exhibit marked confluent necrosis, in which hypoxia levels are extremely high, causing low responsiveness to chemotherapy and conferring basic resistance to anti-cancer drugs. Programmed death ligand 1 (PD-L1)–mediated immune escape may be an underlying source of resistance and a suitable target for specific therapy, but its role in PPCs is unclear.Materials and methodsIn total, 122 PPCs were investigated. Paraffin-embedded tumour sections were stained with PD-L1 and hypoxia-inducible factor-1α (HIF-1α) antibodies. Overexpression was denoted by moderate-to-strong PD-L1 membrane staining in ≥5% of tumour cells and HIF-1α nuclear staining in ≥10% of tumour cells. The presence of driver mutations in the epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B (BRAF), telomerase reverse harscriptase gene (TERT), phosphoinositide 3-kinase catalytic alpha (PIK3CA), anaplastic lymphoma kinase (ALK), and ROS1 (ROS1 proto-oncogene receptor tyrosine kinase) genes were examined.ResultsThe overall frequencies of PD-L1 and HIF-1α overexpression and EGFR mutation were 70.5, 75.4, and 22.1%, respectively. High PD-L1 expression was significantly correlated with that of HIF-1α (p < 0.001) and tumour necrosis (p < 0.001). HIF-1α expression was associated with EGFR mutation (p = 0.015). Advanced stage and high PD-L1 expression were two independent risks for poor overall survival.ConclusionsHigh PD-L1 and HIF-1α co-expression was observed in PPCs compared with their expression in conventional non-small-cell lung carcinoma. The aggressive behaviour of PPC could be partially related to PD-L1–mediated immune escape and intratumoural hypoxia. High PD-L1 expression correlates with poor prognosis and may provide a rationale for the use of targeted immunotherapy in this subtype of high-grade PPC.
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The Current Status of SPECT or SPECT/CT in South Korea
Abstract
The first step to nuclear medicine in Korea started with introduction of the gamma camera in 1969. Although planar images with the gamma camera give important functional information, they have the limitations that result from 2-dimensional images. Single-photon emission computed tomography (SPECT) due to its 3-dimensional image acquisition is superior to earlier planar gamma imaging in image resolution and diagnostic accuracy. As demand for a hybrid functional and anatomical imaging device has increased, integrated SPECT/CT systems have been used. In Korea, SPECT/CT was for the first time installed in 2003. SPECT/CT can eliminate many possible pitfalls on SPECT-alone images, making better attenuation correction and thereby improving image quality. Therefore, SPECT/CT is clinically preferred in many hospitals in various aspects. More recently, additional SPECT/CT images taken from the region with equivocal uptake on planar images have been helpful in making precise interpretation as part of their clinical workup in postoperative thyroid cancer patients. SPECT and SPECT/CT have various advantages, but its clinical application has gradually decreased in recent few years. While some researchers investigated the myocardial blood flow with cardiac PET using F-18 FDG or N-13 ammonia, myocardial perfusion SPECT is, at present, the radionuclide imaging study of choice for the risk stratification and guiding therapy in the coronary artery disease patients in Korea. New diagnostic radiopharmaceuticals for AD have received increasing attention; nevertheless, brain SPECT will remain the most reliable modality evaluating cerebral perfusion.
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Pan-cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274) - associations with gene expression, mutational load and survival
Abstract
Inhibition of the PD-L1 (CD274) – PD-1 axis has emerged as a powerful cancer therapy that prevents evasion of tumor cells from the immune system. While immunohistochemical detection of PD-L1 was introduced as a predictive biomarker with variable power, much less is known about copy number alterations (CNA) affecting PD-L1 and their associations with expression levels, mutational load and survival. To gain insight, we employed The Cancer Genome Atlas (TCGA) datasets to comprehensively analyze 22 major cancer types for PD-L1 CNAs. We observed a diverse landscape of PD-L1 CNAs, which affected focal regions, chromosome 9p or the entire chromosome 9. Deletions of PD-L1 were more frequent than gains (31% vs. 12%) with deletions being most prevalent in melanoma and non-small cell lung cancer. Copy number gains most frequently occurred in ovarian cancer, head and neck cancer, bladder cancer, cervical and endocervical cancer, sarcomas, and colorectal cancers. Fine-mapping of the genetic architecture revealed specific recurrently amplified and deleted regions across cancers with putative biological and clinical consequences. We noted a strong correlation between PD-L1 CNAs and mRNA expression levels for most cancers and found tumors with PD-L1 gains to harbor significantly higher mutational loads compared to non-amplified cases (median: 78 non-synonymous mutations vs. 40, p=7.1e-69). Moreover, we observed that, in general, both PD-L1 amplifications and deletions were associated with dismal prognosis.
In conclusion, PD-L1 CNAs, in particular PD-L1 copy number gains, represent frequent genetic alterations across many cancers, which influence PD-L1 expression levels, are associated with higher mutational loads, and may be exploitable as predictive biomarker for immunotherapy regimens. This article is protected by copyright. All rights reserved.
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