To evaluate the efficacy and safety of the chemotherapy program of docetaxel combined with lobaplatin for Chinese patients with pulmonary and hepatic metastasis of nasopharyngeal carcinoma (NPC). This study included 37 NPC patients with pulmonary and hepatic metastasis. The chemotherapy program included docetaxel (75 mg/m2, day 1) plus lobaplatin (30 mg/m2, day 1). Cycle repetition was every 21 days. Patients were monitored for 7-41 months, with a median follow-up duration of 18 months. The total efficiency of this group was 67.6% and the disease control rate was 81.1%. The median progression-free survival was 9.4 months (95% confidence interval, 6.8-14.3 months), the median overall survival was 18.3 months (95% confidence interval, 13.7-22.8 months), and the 2-year survival rate was 37.8%. The main hematological toxicities were leukopenia (91.9%), anemia (81.1%), and thrombocytopenia (70.3%); other adverse reactions were mild. Changes in Epstein-Barr-DNA levels can basically reflect the dynamic changes in the efficacy of chemotherapy. Docetaxel combined with lobaplatin has a favorable outcome for the treatment of pulmonary and hepatic metastatic NPC. It has been a convenient regimen with tolerable toxicity. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 18 Απριλίου 2016
Characterize subtypes of HPV-positive head and neck cancers
Purpose:There is substantial heterogeneity within human papillomavirus (HPV) associated head and neck cancer (HNC) tumors that predispose them to different outcomes, however the molecular heterogeneity in this subgroup is poorly characterized due to various historical reasons. Experimental Design:We performed unsupervised gene expression clustering on deeply-annotated (transcriptome and genome) HPV(+) HNC samples from two cohorts (84 total primary tumors), including 18 HPV(-) HNC samples, to discover subtypes and characterize the differences between subgroups in terms of their HPV characteristics, pathway activity, whole-genome somatic copy number alterations and mutation frequencies. Results:We identified two distinct HPV(+) subtypes (namely HPV-KRT and HPV-IMU). HPV-KRT is characterized by elevated expression of genes in keratinocyte differentiation and oxidation-reduction process, whereas HPV-IMU has strong immune response and mesenchymal differentiation. The differences in expression are likely connected to the differences in HPV characteristics and genomic changes. HPV-KRT has more genic viral integration, lower E2/E4/E5 expression levels and higher ratio of spliced to full length HPV oncogene E6 than HPV-IMU; the subgroups also show differences in copy number alterations and mutations, in particular the loss of chr16q in HPV-IMU and gain of chr3q and PIK3CA mutation in HPV-KRT. Conclusions:Our characterization of two subtypes of HPV(+) HNC tumors provides valuable molecular level information that point to two main carcinogenic paths. Together, these results shed light on stratifications of the HPV(+) HNCs and will help to guide personalized care for HPV(+) HNC patients.
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Novel gene-modified effector T cells for mogamulizumab
Purpose:Mogamulizumab (Mog), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody (mAb) that mediates antibody-dependent cellular cytotoxicity (ADCC) using FcR IIIa (CD16)-expressing effector cells, has recently been approved for treatment of CCR4-positive adult T-cell leukemia (ATL) in Japan. However, Mog failure has sometimes been observed in patients who have accompanying chemotherapy-associated lymphocytopenia. In this study, we examined whether adoptive transfer of artificial ADCC effector cells combined with Mog would overcome this drawback. Experimental Design:We lentivirally gene-modified peripheral blood T cells from healthy volunteers and ATL patients expressing the affinity-increased chimeric CD16-CD3 receptor (cCD16-T cells). Subsequently we examined the ADCC effect mediated by those cCD16-T cells in the presence of Mog against ATL tumor cells both in vitro and in vivo. Results:cCD16-T cells derived from healthy donors killed in vitro Mog-opsonized ATL cell line cells (n=7) and primary ATL cells (n=4) depending on both the number of effector cells and the dose of the antibody. cCD16-T cells generated from ATL patients (n=3) also exerted cytocidal activity in vitro against Mog-opsonized autologous ATL cells. Using both intravenously disseminated model (n=5) and subcutaneously inoculated model (n=4), co-administration of Mog and human cCD16-T cells successfully suppressed tumor growth in xenografted immunodeficient mice, and significantly prolonged their survival (p<0.01 and p=0.02, respectively). Conclusions:These data strongly suggest clinical feasibility of the novel combined adoptive immunotherapy using cCD16-T cells and Mog for treatment of aggressive ATL, particularly in patients who are ineligible for allo-HSCT.
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Anti-CEA DNA Fusion Vaccination
Purpose: We have clinically evaluated a DNA fusion vaccine to target the HLA-A*0201 binding peptide CAP-1 from carcinoembryonic antigen (CEA<sub>605-613</sub>) linked to an immunostimulatory domain (DOM) from fragment C of tetanus toxin Experimental Design: Twenty-seven patients with CEA-expressing carcinomas were recruited: 15 patients with measurable disease (Arm-I) and 12 patients without radiological evidence of disease (Arm-II). Six intramuscular vaccinations of naked DNA (1mg/dose) were administered up to week 12. Clinical and immunological follow-up was to week 64 or clinical/radiological disease. Results: DOM-specific immune responses demonstrated successful vaccine delivery. All patients without measurable disease compared to 60% with advanced disease responded immunologically, while 58% and 20% expanded anti-CAP-1 CD8<sup>+</sup> T-cells, respectively. CAP-1-specific T-cells were only detectable in the blood post-vaccination, but could also be identified in previously resected cancer tissue. The gastrointestinal adverse event diarrhea was reported by 48% of patients and linked to more frequent decreases in CEA (p<0.001) and improved global immunological responses (anti-DOM responses of greater magnitude (p<0.001), frequency (p=0.004) and duration) compared to patients without diarrhea. In advanced disease patients, decreases in CEA were associated with better overall survival (HR=0.14, p=0.017). CAP-1 peptide was detectable on MHC class I of normal bowel mucosa and primary colorectal cancer tissue by mass-spectrometry, offering a mechanistic explanation for diarrhea through CD8<sup>+</sup> T-cell attack. Conclusions: Our data suggest that DNA vaccination is able to overcome peripheral tolerance in normal and tumor tissue and warrants testing in combination studies, for example, by vaccinating in parallel to treatment with an anti-PD1 antibody.
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Examining adaptive tumor response during BRAF inhibition
Purpose: Treatment of BRAF-mutated melanoma tumors with BRAF inhibitor-based therapy produces high response rates, but of limited duration in the vast majority of patients. Published investigations of resistance mechanisms suggest numerous examples of tumor adaptation and signal transduction bypass mechanisms, but without insight into biomarkers that would predict which mechanism will predominate. Monitoring phenotypic response of multiple adaptive mechanisms simultaneously within the same tumor as it adapts during treatment has been elusive. Experimental Design: This study reports on a method to provide a more complete understanding of adaptive tumor responses. We simultaneously measured in vivo anti-tumor activity of 12 classes of inhibitors which are suspected of enabling adaptive escape mechanisms, at various time points during systemic BRAF inhibition. We used implantable microdevices to release multiple compounds into distinct regions of a tumor to measure the efficacy of each compound independently, and repeated these measurements as tumors progressed on systemic BRAF treatment. Results: We observed varying phenotypic responses to specific inhibitors before, during and after prolonged systemic treatment with BRAF inhibitors. Our results specifically identify PI3K, PDGFR, EGFR and HDAC inhibitors as becoming significantly more efficacious during systemic BRAF inhibition. The sensitivity to other targeted inhibitors remained mostly unchanged, while local incremental sensitivity to PLX4720 declined sharply. Conclusions: These findings suggest redundancy of several resistance mechanisms and may help identify optimal constituents of more effective combination therapy in BRAF-mutant melanoma. They also represent a new paradigm for dynamic measurement of adaptive signaling mechanisms within the same tumor during therapy.
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Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first line treatment of patients with metastatic colorectal cancer - the AFFIRM study
In the AFFIRM study, the addition of aflibercept to mFOLFOX6 did not demonstrate a benefit in first-line therapy in patients with mCRC but higher toxity.
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Tumor Heterogeneity of Fibroblast Growth Factor Receptor 3 (FGFR3) Mutations in Invasive Bladder Cancer: Implications for Peri-Operative anti-FGFR3 Treatment
FGFR3 is a major potential actionable target in urothelial bladder cancer (BC). We found that FGFR3 mutations appeared conserved in primary BC and corresponding lymph-node metastases. We also showed that the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. This suggests that personalized anti-FGFR3 therapy may improve BC treatment in the peri-operative setting.
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Patients with classical Hodgkin lymphoma experiencing disease progression after treatment with brentuximab vedotin have poor outcomes
Patients with BV-resistant cHL have poor outcomes. These data serve as a reference for newer agents active in BV-resistant disease
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Overexpression of JAK2: a predictor of unfavorable prognosis for nasopharyngeal carcinoma
Future Oncology Ahead of Print.
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Immunology of infusion reactions in the treatment of patients with acute lymphoblastic leukemia
Future Oncology Ahead of Print.
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Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy
Future Oncology Ahead of Print.
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ROBUST: Lenalidomide-R-CHOP versus placebo-R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma
Future Oncology Ahead of Print.
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Overexpression of JAK2: a predictor of unfavorable prognosis for nasopharyngeal carcinoma
Future Oncology Ahead of Print.
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Immunology of infusion reactions in the treatment of patients with acute lymphoblastic leukemia
Future Oncology Ahead of Print.
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Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy
Future Oncology Ahead of Print.
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ROBUST: Lenalidomide-R-CHOP versus placebo-R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma
Future Oncology Ahead of Print.
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Bisulfite oligonucleotide-capture sequencing for targeted base- and strand-specific absolute 5-methylcytosine quantitation
Abstract
Epigenetic regulation through DNA methylation (5mC) plays an important role in development, aging, and a variety of diseases. Genome-wide studies of base- and strand-specific 5mC are limited by the extensive sequencing required. Targeting bisulfite sequencing to specific genomic regions through sequence capture with complimentary oligonucleotide probes retains the advantages of bisulfite sequencing while focusing sequencing reads on regions of interest, enables analysis of more samples by decreasing the amount of sequence required per sample, and provides base- and strand-specific absolute quantitation of CG and non-CG methylation levels. As an example, an oligonucleotide capture set to interrogate 5mC levels in all rat RefSeq gene promoter regions (18,814) and CG islands, shores, and shelves (18,411) was generated. Validation using whole-genome methylation standards and biological samples demonstrates enrichment of the targeted regions and accurate base-specific quantitation of CG and non-CG methylation for both forward and reverse genomic strands. A total of 170 Mb of the rat genome is covered including 6.6 million CGs and over 67 million non-CG sites, while reducing the amount of sequencing required by ~85 % as compared to existing whole-genome sequencing methods. This oligonucleotide capture targeting approach and quantitative validation workflow can also be applied to any genome of interest.
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Variability in spine radiosurgery treatment planning – results of an international multi-institutional study
The aim of this study was to quantify the variability in spinal radiosurgery (SRS) planning practices between five international institutions, all member of the Elekta Spine Radiosurgery Research Consortium.
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The Best. First. Anti-EGFR before anti-VEGF, in the first-line treatment of RAS wild-type metastatic colorectal cancer: from bench to bedside
Abstract
Background
Since 2013, informative trials exploring the optimal use of available biologic agents in the first-line setting of metastatic colorectal cancer (mCRC) have been presented. These trials have opened a stimulating debate on the biological effect that first-line therapies may have on subsequent lines of treatment even long after the first-line progression.
Materials and methods
We reviewed available preclinical and clinical data on the effect of different sequences of the biological drugs approved for use in mCRC patients. The importance of molecular selection of patients based on RAS mutational status and toxicity and quality-of-life issues were also analyzed.
Results
Convincing evidence exists on the optimal therapeutic effect obtained by using anti-EGFR agents in first-line treatment before anti-VEGF agents. On the contrary, up-front anti-VEGF agents' use seems to determine biological changes that increase the risk of acquired resistance to subsequent EGFR inhibitors. This hypothesis is confirmed by the scarce evidence of EGFR inhibitor activity in second-line treatment. Such a therapeutic optimum is subject to a fine molecular selection based on RAS mutational status.
Conclusion
There is accumulating evidence suggesting that, after precise and well-established molecular selection, anti-EGFR agents deliver their maximum efficacy in mCRC patients when given early in the treatment strategy. Their toxicity profile seems manageable under the supervision of experienced physicians. Large randomized trials prospectively confirming the impact of different sequencing strategies are eagerly awaited.
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Fractionated stereotactic radiotherapy of benign skull-base tumors: a dosimetric comparison of volumetric modulated arc therapy with Rapidarc® versus non-coplanar dynamic arcs
Abstract
Background
Benign tumors of the skull base are a challenge when delivering radiotherapy. An appropriate choice of radiation technique may significantly improve the patient's outcomes. Our study aimed to compare the dosimetric results of fractionated stereotactic radiotherapy between non-coplanar dynamic arcs and coplanar volumetric modulated arctherapy (Rapidarc®).
Methods
Thirteen patients treated with Novalis TX® were analysed: six vestibular schwannomas, four pituitary adenomas and three meningioma. Two treatment plans were created for each case: dynamic arcs (4–5 non coplanar arcs) and Rapidarc® (2 coplanar arcs). All tumors were >3 cm and accessible to both techniques. Patients had a stereotactic facemask (Brainlab) and were daily repositioned by Exactrac®. GTV and CTV were contoured according to tumor type. A 1-mm margin was added to the CTV to obtain PTV. Radiation doses were 52.2–54 Gy, using 1.8 Gy per fraction. Treatment time was faster with Rapidarc®.
Results
The mean PTV V95 % was 98.8 for Rapidarc® and 95.9 % for DA (p = 0.09). Homogeneity index was better with Rapidarc®: 0.06 vs. 0.09 (p = 0.01). Higher conformity index values were obtained with Rapidarc®: 75.2 vs. 67.9 % (p = 0.04). The volume of healthy brain that received a high dose (V90 %) was 0.7 % using Rapidarc® vs. 1.4 % with dynamic arcs (p = 0.05). Rapidarc® and dynamic arcs gave, respectively, a mean D40 % of 10.5 vs. 18.1 Gy (p = 0.005) for the hippocampus and a Dmean of 25.4 vs. 35.3 Gy (p = 0.008) for the ipsilateral cochlea. Low-dose delivery with Rapidarc® and dynamic arcs were, respectively, 184 vs. 166 cm3 for V20 Gy (p = 0.14) and 1265 vs. 1056 cm3 for V5 Gy (p = 0.67).
Conclusions
Fractionated stereotactic radiotherapy using Rapidarc® for large benign tumors of the skull base provided target volume coverage that was at least equal to that of dynamics arcs, with better conformity and homogeneity and faster treatment time. Rapidarc® also offered better sparing of the ipsilateral cochlea and hippocampus. Low-dose delivery were similar between both techniques.
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The clinical results of proton beam therapy in patients with idiopathic pulmonary fibrosis: a single center experience
Abstract
Background
The purpose of this study is to retrospectively evaluate the incidence of lung toxicities after proton beam therapy (PBT) in patients with idiopathic pulmonary fibrosis (IPF).
Methods
Patients diagnosed with primary lung cancer or lung metastasis who were treated with PBT between January 2009 and May 2015 were recruited from our database retrospectively. Cases of pneumonitis (excluding infection-related pneumonitis) were evaluated using the Common Terminology Criteria for Adverse Events version 4.0, and the Fletcher-Hugh-Jones classification of respiratory status was used to evaluate pretreatment and posttreatment respiratory function.
Results
Sixteen IPF patients received PBT for lung tumors, 15 received PBT for primary lung cancer, and one patient received PBT for metastasis from lung cancer. The cohort was composed of 14 men and 2 women, with a median age of 76 years (range: 63–89 years). The median follow-up time was 12 months (range: 4–39 months). The median dose of PBT was 80.0 Gy relative biological dose effectiveness (RBE) (range: 66.0–86.4 Gy [RBE]). The cumulative incidence of pneumonitis was 19.8 % (95 % confidence interval [CI]: 0–40.0 %), including one case of grade 5 pneumonitis. Reduced respiratory function was observed after PBT in seven patients, including one patient with pleural dissemination; five of these patients required home oxygen therapy.
Conclusions
This study suggests that PBT can be performed more safely in IPF patients than surgery or X-ray irradiation. Although PBT has become a treatment choice for lung tumors of patients with IPF, the adverse events warrant serious attention.
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Variability in spine radiosurgery treatment planning – results of an international multi-institutional study
Abstract
Background
The aim of this study was to quantify the variability in spinal radiosurgery (SRS) planning practices between five international institutions, all member of the Elekta Spine Radiosurgery Research Consortium.
Methods
Four institutions provided one representative patient case each consisting of the medical history, CT and MR imaging. A step-wise planning approach was used where, after each planning step a consensus was generated that formed the basis for the next planning step. This allowed independent analysis of all planning steps of CT-MR image registration, GTV definition, CTV definition, PTV definition and SRS treatment planning. In addition, each institution generated one additional SRS plan for each case based on intra-institutional image registration and contouring, independent of consensus results.
Results
Averaged over the four cases, image registration variability ranged between translational 1.1 mm and 2.4 mm and rotational 1.1° and 2.0° in all three directions. GTV delineation variability was 1.5 mm in axial and 1.6 mm in longitudinal direction averaged for the four cases. CTV delineation variability was 0.8 mm in axial and 1.2 mm in longitudinal direction. CTV-to-PTV margins ranged between 0 mm and 2 mm according to institutional protocol. Delineation variability was 1 mm in axial directions for the spinal cord. Average PTV coverage for a single fraction18 Gy prescription was 87 ± 5 %; Dmin to the PTV was 7.5 ± 1.8 Gy averaged over all cases and institutions. Average Dmax to the PRV_SC (spinal cord + 1 mm) was 10.5 ± 1.6 Gy and the average Paddick conformity index was 0.69 ± 0.06.
Conclusions
Results of this study reflect the variability in current practice of spine radiosurgery in large and highly experienced academic centers. Despite close methodical agreement in the daily workflow, clinically significant variability in all steps of the treatment planning process was demonstrated. This may translate into differences in patient clinical outcome and highlights the need for consensus and established delineation and planning criteria.
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The relationship between coping strategies, quality of life, and mood in patients with incurable cancer
BACKGROUND
Patients with incurable cancer face many physical and emotional stressors, yet little is known about their coping strategies or the relationship between their coping strategies, quality of life (QOL), and mood.
METHODS
As part of a randomized trial of palliative care, this study assessed baseline QOL (Functional Assessment of Cancer Therapy–General), mood (Hospital Anxiety and Depression Scale), and coping (Brief COPE) in patients within 8 weeks of a diagnosis of incurable lung or gastrointestinal cancer and before randomization. To examine associations between coping strategies, QOL, and mood, we used linear regression, adjusting for patients' age, sex, marital status, and cancer type.
RESULTS
There were 350 participants (mean age, 64.9 years), and the majority were male (54.0%), were married (70.0%), and had lung cancer (54.6%). Most reported high utilization of emotional support coping (77.0%), whereas fewer reported high utilization of acceptance (44.8%), self-blame (37.9%), and denial (28.2%). Emotional support (QOL: β = 2.65, P < .01; depression: β = –0.56, P = .02) and acceptance (QOL: β = 1.55, P < .01; depression: β = –0.37, P = .01; anxiety: β = –0.34, P = .02) correlated with better QOL and mood. Denial (QOL: β = –1.97, P < .01; depression: β = 0.36, P = .01; anxiety: β = 0.61, P < .01) and self-blame (QOL: β = –2.31, P < .01; depression: β = 0.58, P < .01; anxiety: β = 0.66, P < .01) correlated with worse QOL and mood.
CONCLUSIONS
Patients with newly diagnosed, incurable cancer use a variety of coping strategies. The use of emotional support and acceptance coping strategies correlated with better QOL and mood, whereas the use of denial and self-blame negatively correlated with these outcomes. Interventions to improve patients' QOL and mood should seek to cultivate the use of adaptive coping strategies. Cancer 2016. © 2016 American Cancer Society.
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Glioblastoma in the Canton of Zurich, Switzerland revisited: 2005 to 2009
BACKGROUND
A population-based analysis of patients with glioma diagnosed between 1980 and 1994 in the Canton of Zurich in Switzerland confirmed the overall poor prognosis of glioblastoma. To explore changes in outcome, registry data were reevaluated for patients diagnosed between 2005 and 2009.
METHODS
Patients with glioblastoma who were diagnosed between 2005 and 2009 were identified by the Zurich and Zug Cancer Registry. The prognostic significance of epidemiological and clinical data, isocitrate dehydrogenase 1 (IDH1)R132H mutation status, and O6 methylguanine DNA methyltransferase (MGMT) promoter methylation status was analyzed using the Kaplan-Meier method and the Cox proportional hazards model.
RESULTS
A total of 264 patients with glioblastoma were identified, for an annual incidence of 3.9 compared with the previous incidence of 3.7. The mean age of the patients at the time of diagnosis was 59.5 years in the current cohort compared with 61.3 years previously. The overall survival (OS) rate was 46.4% at 1 year, 22.5% at 2 years, and 14.4% at 3 years in the current study compared with 17.7% at 1 year, 3.3% at 2 years, and 1.2% at 3 years as reported previously. The median OS for all patients with glioblastoma was 11.5 months compared with 4.9 months in the former patient population. The median OS was 1.9 months for best supportive care, 6.2 months for radiotherapy alone, 6.7 months for temozolomide alone, and 17.0 months for radiotherapy plus temozolomide. Multivariate analysis revealed age, Karnofsky performance score, extent of tumor resection, first-line treatment, year of diagnosis, and MGMT promoter methylation status were associated with survival in patients with IDH1R132H-nonmutant glioblastoma.
CONCLUSIONS
The OS of patients newly diagnosed with glioblastoma in the Canton of Zurich in Switzerland markedly improved from 1980 through 1994 to 2005 through 2009. Cancer 2016. © 2016 American Cancer Society.
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Comparative effectiveness of stereotactic radiosurgery versus whole-brain radiation therapy for patients with brain metastases from breast or non–small cell lung cancer
BACKGROUND
The optimal treatment for patients with brain metastases remains controversial as the use of stereotactic radiosurgery (SRS) alone, replacing whole-brain radiation therapy (WBRT), has increased. This study determined the patterns of care at multiple institutions before 2010 and examined whether or not survival was different between patients treated with SRS and patients treated with WBRT.
METHODS
This study examined the overall survival of patients treated with radiation therapy for brain metastases from non–small cell lung cancer (NSCLC; initially diagnosed in 2007-2009) or breast cancer (initially diagnosed in 1997-2009) at 5 centers. Propensity score analyses were performed to adjust for confounding factors such as the number of metastases, the extent of extracranial metastases, and the treatment center.
RESULTS
Overall, 27.8% of 400 NSCLC patients and 13.4% of 387 breast cancer patients underwent SRS alone for the treatment of brain metastases. Few patients with more than 3 brain metastases or lesions ≥ 4 cm in size underwent SRS. Patients with fewer than 4 brain metastases less than 4 cm in size (n = 189 for NSCLC and n = 117 for breast cancer) who were treated with SRS had longer survival (adjusted hazard ratio [HR] for NSCLC, 0.58; 95% confidence Interval [CI], 0.38-0.87; P = .01; adjusted HR for breast cancer, 0.54; 95% CI, 0.33-0.91; P = .02) than those treated with WBRT.
CONCLUSIONS
Patients treated for fewer than 4 brain metastases from NSCLC or breast cancer with SRS alone had longer survival than those treated with WBRT in this multi-institutional, retrospective study, even after adjustments for the propensity to undergo SRS. Cancer 2016. © 2016 American Cancer Society.
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Cytologic features of angiosarcoma: A review of 26 cases diagnosed on FNA
BACKGROUND
This study describes the cytologic features of 26 angiosarcomas diagnosed on fine-needle aspiration.
METHODS
Twenty-six angiosarcomas from 20 patients were confirmed by cytomorphology and immunocytochemical (immunohistochemistry) positivity for at least 2 of 3 vascular markers. Specimens were examined for spindled/epithelioid/plasmacytoid single cells, 3-dimensional clusters, multiple prominent/bar-shaped nucleoli (5 times longer than their width), chromatin strands, abnormal mitoses, necrosis, and vasoformative features.
RESULTS
Eight males and 12 females with a mean age of 52 years (range, 2-94 years) underwent aspiration of tumors in the following: soft tissue or skin/subcutis (n = 10), bone (n = 4), nodes (n = 5), lung (n = 2), liver (n = 2), heart (n = 1), parotid gland (n = 1), and pleural fluid (n = 1). An angiosarcoma diagnosis was rendered for 24 of the 26 cases (92%); 1 was diagnosed as "atypical cells, cannot exclude angiosarcoma," and another was diagnosed as a malignant vascular neoplasm. Abnormal mitoses were most frequent (85%), and they were followed by single malignant cells (81%: epithelioid [69%], spindled [62%], and plasmacytoid [19%]), 3-dimensional clusters (54%), multiple prominent (62%) or bar-shaped nucleoli (54%), and chromatin strands (31%). Vasoformative features, including hemophagocytosis (54%), cytoplasmic lumina/vacuoles (69%) containing red blood cells (54%)/neutrophils (31%), and endothelial wrapping (69%), were seen in 88%; 23% had all vasoformative features, 88% had at least 1, and 12% had none.
CONCLUSIONS
Angiosarcomas show a range of cytomorphologic features that make them potentially recognizable on cytology. Although vasoformative features are highly suggestive, they are not specific for angiosarcoma and may be seen in some nonvascular neoplasms. Immunohistochemistry and a high index of suspicion are required for an accurate diagnosis. Cancer Cytopathol 2016. © 2016 American Cancer Society.
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Acute adrenal insufficiency secondary to bilateral adrenal B-cell lymphoma: a case report and review of the literature
Carlos De Miguel Sánchez, Luis Ruiz, Jose Luis González and Jose Luis Hernández
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Equol inhibits prostate cancer growth via degradation of the androgen receptor by Skp2
Summary
Chemo-preventative and potential therapeutic effects of soy isoflavones have been shown to be effective in numerous pre-clinical studies as well as clinical studies in prostate cancer. Although the inhibition of androgen receptor signaling has been supposed as one mechanism underlying their effects, the precise mechanism of androgen receptor inhibition remains unclear. Thus, this study aimed to clarify their mechanism. Among soy isoflavones, equol suppressed androgen receptor as well as prostate-specific antigen expression most potently in androgen-dependent LNCaP cells. However, the inhibitory effect on androgen receptor expression and activity was less prominent in castration-resistant CxR and 22Rv1 cells. Consistently, cell proliferation was suppressed and cellular apoptosis was induced by equol in LNCaP cells, but less in CxR and 22Rv1 cells. We revealed that the proteasome pathway via Skp2 was responsible for androgen receptor suppression. Taken together, soy isoflavones, especially equol, appear to be promising as chemopreventative and therapeutic agents for prostate cancer based on the fact that equol augments Skp2-mediated androgen receptor degradation. Moreover, because Skp2 expression was indicated to be crucial for the effect of soy isoflavones, soy isoflavones may be applicable for pre-cancerous and cancerous prostates.
This article is protected by copyright. All rights reserved.
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Prognosis of metastatic renal cell carcinoma with first-line Interferon-α therapy in the era of molecular-targeted therapy
Abstract
The RCC-SELECT study showed the correlation between single nucleotide polymorphisms (SNPs) in STAT3 gene and survival in metastatic renal cell carcinoma (mRCC) patients with first-line interferon-α (IFN-α). In that study, even patients with STAT3 SNPs linked to shorter overall survival (OS) exhibited remarkably improved prognosis. All 180 patients evaluated in the above study were further analysed for correlation between OS and demographics/clinicopathological parameters. OS was estimated using the Kaplan-Meier method. Associations between OS and potential prognostic factors were assessed using the log-rank test and the Cox proportional hazards model. The median OS was 42.8 months. Univariate analysis showed that worse Eastern Cooperative Oncology Group-performance status (ECOG-PS), high T stage, regional lymph node metastasis, distant metastasis, higher grade, infiltrative growth pattern, the presence of microscopic vascular invasion (MVI), hypercalcemia, anemia, thrombocytopenia and elevated C-reactive protein were significantly associated with OS. Multivariate analysis revealed that ECOG-PS [hazard ratio (HR) = 3.665, P = 0.0004], hypercalcemia [HR = 6.428, P = 0.0005] and the presence of MVI [HR = 2.668, P = 0.0109] were jointly significant poor prognostic factors. This is the first study analysing prognostic factors of mRCC patients with first-line IFN-α using large cohort of the prospective study. The present study suggests that first-line IFN-α is still a useful therapy for mRCC even in the era of molecular targeted therapy.
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Prognostic and predictive value of extended RAS mutation and mismatch repair status in stage III colorectal cancer
Abstract
The prognostic and predictive value of KRAS gene mutations in stage III colorectal cancer is controversial because many recent clinical trials have not involved a surgery-alone arm. Additionally, data on the significance of extended RAS (KRAS/NRAS) mutations in stage III cancer are not available. Hence, we performed a combined analysis of two phase 3 randomized trials, in which the usefulness of adjuvant chemotherapy with UFT was evaluated, as compared with surgery alone. We determined the association of extended RAS and mismatch repair (MMR) status with the effectiveness of adjuvant chemotherapy. Mutations in KRAS exons 2, 3, 4 and NRAS exons 2, 3 were detected by direct DNA sequencing. Tumor MMR status was determined by immunohistochemistry. Total RAS mutations were detected in 134/304 (44%) patients. In patients with RAS mutations, a significant benefit was associated with adjuvant UFT in RFS (HR=0.49 (0.27-0.91); p=0.02) and OS (HR=0.51 (0.26-0.97); p=0.03). In contrast, among patients without RAS mutations, there was no difference in RFS and OS between the adjuvant UFT group and surgery-alone group. MMR deficiency (dMMR) was detected in 23/304 (8%) patients. MMR status was neither prognostic nor predictive for adjuvant chemotherapy, although the small number of dMMR tumors might have affected. An interaction analysis showed that there was a better RFS among patients treated with UFT with RAS mutations, but not for those without RAS mutations. Extended RAS (KRAS/NRAS) mutations are proposed be predictive indicators with respect to the efficacy of adjuvant UFT chemotherapy in patients with resected stage III colorectal cancer.
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B7-H4 facilitates proliferation of esophageal squamous cell carcinoma cells through promoting IL-6/STAT3 pathway activation
Summary
B7-H4, one of the costimulatory molecules of B7 family, has been found to be widely expressed in many kinds of tumor tissues and to play an important part in tumor progression and poor prognosis. However, the role of B7-H4 in esophageal squamous cell carcinoma (ESCC) cells has not been elucidated. In this study, we found that, compared with normal esophageal tissue, B7-H4 was highly expressed in three ESCC cell lines, Eca109, TE1 and TE13. Besides, B7-H4 silence suppressed cells proliferation and colony formation. Additionally, compared with control cells, B7-H4 silence cells showed higher apoptosis rate, Bcl-2 and Survivin upregulation as well as BAX downregulation. Further study demonstrated that B7-H4 silence cells also exhibited reduction of IL-6 secretion, STAT3 activation and p-STAT3 translocation from cytoplasm to nucleus. Moreover, B7-H4 depletion inhibited the IL-6 secretion of control cells but not JAK2/STAT3 inhibitor FLLL32 treated cells. IL-6 receptor antagonist Tocilizumab didn't block the p-JAK2 and p-STAT3 downregulation induced by B7-H4 silence. It was suggested that B7-H4 silence suppressed IL-6 secretion through JAK2/STAT3 inactivation. Furthermore, cells proliferation and colony formation were downregulated by Tocilizumab in control cells but not B7-H4 silence cells demonstrating that IL-6 upregulation induced by B7-H4 was necessary for cells growth. On the other hand, B7-H4 expression was downregulated by Tocilizumab. In all, our study provided the first evidence that B7-H4 facilitated ESCC cells proliferation through promoting IL-6/STAT3 positive loopback pathway activation.
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miR-124-3p regulates cell proliferation, invasion, apoptosis and bioenergetics by targeting PIM1 in astrocytoma
Abstract
PIM1 is an important regulator of cell proliferation, the cell cycle, apoptosis, and metabolism in various human cancers. MicroRNAs (miRNAs) are powerful post-transcriptional gene regulators that function via translational repression or transcript destabilization. Therefore, we aimed to identify whether a close relationship exists between PIM1 and miRNAs. The PIM1 protein levels and mRNA levels were significantly upregulated in astrocytoma tissues, indicating the oncogenic role of PIM1 in astrocytoma. Further bioinformatics analysis indicated that miR-124-3p targeted the 3′-untranslated region (3′-UTR) of PIM1. We also observed an inverse correlation between the miR-124-3p levels and PIM1 protein or mRNA levels in astrocytoma samples. Next, we experimentally confirmed that miR-124-3p directly recognizes the 3′-UTR of the PIM1 transcript and regulates PIM1 expression at both the protein and mRNA levels. Furthermore, we examined the biological consequences of miR-124-3p targeting PIM1 in vitro. We demonstrated that the repression of PIM1 in astrocytoma cancer cells by miR-124-3p suppressed proliferation, invasion, and aerobic glycolysis and promoted apoptosis. We observed that the restoration or inhibition of PIM1 activity resulted in effects that were similar to those induced by miR-124-3p inhibitors or mimics in cancer cells. Finally, overexpression of PIM1 rescued the inhibitory effects of miR-124-3p. In summary, these findings aid in understanding the tumor suppressive role of miR-124-3p in astrocytoma pathogenesis through the inhibition of PIM1 translation.
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Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis
Abstract
Asbestos-induced mesothelial carcinogenesis is currently a profound social issue due to its extremely long incubation period and high mortality rate. Therefore, procedures to prevent malignant mesothelioma in people already exposed to asbestos are important. In previous experiments, we established an asbestos-induced rat peritoneal mesothelioma model, which revealed that local iron overload is a major cause of pathogenesis and that the induced genetic alterations were similar to human counterparts. Furthermore, we showed that oral administration of deferasirox modified the histology from sarcomatoid to the more favorable epithelioid subtype. Here, we used intraperitoneal administration of desferal to evaluate its effects on asbestos-induced peritoneal inflammation and iron deposition, as well as oxidative stress. Nitrilotriacetate (NTA) was used to promote an iron-catalyzed Fenton reaction as a positive control. Desferal significantly decreased peritoneal fibrosis, iron deposition and nuclear 8-hydroxy-2′-deoxyguanosine levels in mesothelial cells, whereas NTA significantly increased all of them. Desferal was more effective in rat peritoneal mesothelial cells (RPMCs) to counteract asbestos-induced cytotoxicity than in RAW264.7. Furthermore, rat sarcomatoid mesothelioma cells were more dependent on iron for proliferation than RPMCs. Because inflammogenicity of a fiber is proportionally associated with subsequent mesothelial carcinogenesis, iron elimination from the mesothelial environment can confer dual merits for preventing asbestos-induced mesothelical carcinogenesis by suppressing inflammation and mesothelial proliferation simultaneously.
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Identification of cooperative genes for E2A-PBX1 to develop acute lymphoblastic leukemia
Abstract
E2A-PBX1 is a chimeric gene product detected in t(1;19)-bearing acute lymphoblastic leukemia (ALL) with B-cell lineage. To investigate the leukemogenic process, we generated conditional knock-in (cKI) mice for E2A-PBX1, in which E2A-PBX1 is inducibly expressed under the control of the endogenous E2A promoter. Despite the induced expression of E2A-PBX1, no hematopoietic disease was observed, strongly suggesting that additional genetic alterations are required to develop leukemia. To address this possibility, retroviral insertional mutagenesis was employed. Virus infection efficiently induced T-cell, B-cell and biphenotypic ALL in E2A-PBX1 cKI mice. Inverse PCR identified eight retroviral common integration sites, in which enhanced expression was observed in the Gfi1, Mycn and Pim1 genes. In addition, it is of note that viral integration and overexpression of Zfp521 gene was detected in one tumor with B-cell lineage, since we previously identified Zfp521 as a cooperative gene with E2A-HLF, another E2A-involving fusion gene with B-lineage ALL. The cooperative oncogenicity of E2A-PBX1 with overexpressed Zfp521 in B-cell tumorigenesis was demonstrated by the finding that E2A-PBX1 cKI, Zfp521 transgenic compound mice developed B-lineage ALL. Moreover, upregulation of ZNF521 the human counterpart of Zfp521, was found in several human leukemic cell lines bearing t(1;19). These results indicate that E2A-PBX1 cooperates with additional gene alterations to develop ALL, and among them, enhanced expression of ZNF521 may play a clinically relevant role in E2A fusion genes to develop B-lineage ALL.
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Chronic mesothelial reaction and toxicity of potassium octatitanate fibers in the pleural cavity in mice and F344 rats
Summary
Fiber shaped particles of potassium octatitanate (trade name TISMO; chemical formula K2O･6TiO2), which are morphologically similar to asbestos particles, were shown to induce severe proliferative reactions in the pleural mesothelium in a previous experiment conducted over 21 weeks. The present study aims to determine whether these fibers induce malignant mesotheliomas in rodents or not, and to examine chronic toxicity induced. Additionally, we investigated the specific differences observable between the biological responses to the direct infusion of the fibers alone into the pleural cavity and those induced by the co-administration of the fibers with a known carcinogen.
To detect the induction of malignant pleural mesotheliomas, two experiments were conducted. In Experiment 1, 4 strains of mice, A/J, C3H, ICR, and C57BL, were examined for 52 weeks after experimental treatment with TISMO. In Experiment 2, the F344 rats were treated with TISMO, the lung carcinogen N-bis (2-hydroxypropyl) nitrosamine (DHPN), both TISMO and DHPN, or left untreated and were then examined for 52 weeks. In this experiment, malignant lesion induction was expected in the co-administration group.
TISMO fibers were observed in the alveoli, indicating penetration through the visceral pleura in mice and rats. The histopathological detection of TISMO fibers in the liver and kidneys of mice and rats indicated migration of the fibers out of the pleural cavity. Atypical mesothelial cells with severe pleural proliferation were observed, but malignant mesotheliomas were not detected. Among the rats, there were no observed malignant alterations in the mesothelium induced by DHPN-TISMO co-administration.
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Adherence to Long-Term Interferon Beta-1b Injection Therapy in Patients with Multiple Sclerosis Using an Electronic Diary
Abstract
Introduction
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system requiring long-term treatment, which is often hampered by non-adherence to self-applicable therapies, provoking continued disease activity and health care system burdens. This study assessed the influence of a personal digital assistant (PDA) with diary function (n = 339 patients) on persistence and adherence to an interferon beta treatment regimen in comparison to a paper patient diary (n = 330 patients).
Methods
Patients who recently started with subcutaneous injections of interferon beta-1b were recruited in this prospective, non-interventional, national cohort study for an observational period of 2 years after successful completion of the initial dose escalation.
Results
Therapy persistence as assessed by the drop-out rate within 104 weeks was about 50% in both study cohorts. In male patients, the drop-out rate was 10% lower when using a PDA compared to the non-PDA group. Use of a PDA with an injection reminder function increased adherence to the injection schedule (every other day) by a mean of 24.5 injections over 24 months in comparison to use of a PDA without injection reminder function.
Conclusion
Persistence in this study was in the published range of observational MS studies. Furthermore, in male patients continuation of therapy might be positively influenced by use of a PDA, and both female and male patients might benefit from an integrated reminder function. In conclusion, electronic diaries reminding patients of upcoming injections can promote an improved adherence to MS therapy.
Trial registration
ClinicalTrials.gov identifier: NCT00902135.
Funding
Bayer Vital GmbH.
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Downregulation of YAP-dependent Nupr1 promotes tumor-repopulating cell growth in soft matrices
Downregulation of YAP-dependent Nupr1 promotes tumor-repopulating cell growth in soft matrices
Oncogenesis 5, e220 (April 2016). doi:10.1038/oncsis.2016.29
Authors: Q Jia, W Zhou, W Yao, F Yang, S Zhang, R Singh, J Chen, J J Chen, Y Zhang, F Wei, Y Zhang, H Jia & N Wang
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Overexpression of caspase 7 is ERα dependent to affect proliferation and cell growth in breast cancer cells by targeting p21Cip
Overexpression of caspase 7 is ERα dependent to affect proliferation and cell growth in breast cancer cells by targeting p21Cip
Oncogenesis 5, e219 (April 2016). doi:10.1038/oncsis.2016.12
Authors: S Chaudhary, B Madhukrishna, A K Adhya, S Keshari & S K Mishra
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The challenges associated with molecular targeted therapies for glioblastoma
Abstract
Glioblastoma (GBM) is the most aggressive malignant brain tumor in adults. Improvements in the treatment of GBM have remained static since the advent of the standard therapy which includes radiation with concurrent and adjuvant temozolomide treatment. Developing treatment and diagnostic or companion biomarker combinations is transforming the way we treat numerous cancers. However, can this emerging paradigm be also effective for GBM? Can GBM be treated the same way as other cancers? Here we review the challenges for a personalized molecular targeted therapeutic approach in GBM. The specific challenges for establishing a personalized molecular targeted medicine program for GBM patients include overcoming the blood brain barrier, unravelling the intra- and inter-heterogeneity that exists and the importance of developing more relevant animal models that recapitulate a patient's GBM tumor.
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Enhancing tumor apparent diffusion coefficient histogram skewness stratifies the postoperative survival in recurrent glioblastoma multiforme patients undergoing salvage surgery
Abstract
Objective To determine the value of apparent diffusion coefficient (ADC) histogram parameters for the prediction of individual survival in patients undergoing surgery for recurrent glioblastoma (GBM) in a retrospective cohort study. Methods Thirty-one patients who underwent surgery for first recurrence of a known GBM between 2008 and 2012 were included. The following parameters were collected: age, sex, enhancing tumor size, mean ADC, median ADC, ADC skewness, ADC kurtosis and fifth percentile of the ADC histogram, initial progression free survival (PFS), extent of second resection and further adjuvant treatment. The association of these parameters with survival and PFS after second surgery was analyzed using log-rank test and Cox regression. Results Using log-rank test, ADC histogram skewness of the enhancing tumor was significantly associated with both survival (p = 0.001) and PFS after second surgery (p = 0.005). Further parameters associated with prolonged survival after second surgery were: gross total resection at second surgery (p = 0.026), tumor size (0.040) and third surgery (p = 0.003). In the multivariate Cox analysis, ADC histogram skewness was shown to be an independent prognostic factor for survival after second surgery. Conclusion ADC histogram skewness of the enhancing lesion, enhancing lesion size, third surgery, as well as gross total resection have been shown to be associated with survival following the second surgery. ADC histogram skewness was an independent prognostic factor for survival in the multivariate analysis.
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Valproic acid, compared to other antiepileptic drugs, is associated with improved overall and progression-free survival in glioblastoma but worse outcome in grade II/III gliomas treated with temozolomide
Abstract
Valproic acid (VPA) is an anti-epileptic drug with properties of a histone deacetylase inhibitor (HDACi). HDACi play a key role in epigenetic regulation of gene expression and have been increasingly used as anticancer agents. Recent studies suggest that VPA is associated with improved survival in high-grade gliomas. However, effects on lower grade gliomas have not been examined. This study investigates whether use of VPA correlates with tumor grade, histological progression, progression-free and overall survival (OS) in grade II, III, and IV glioma patients. Data from 359 glioma patients (WHO II–IV) treated with temozolomide plus an antiepileptic drug (VPA or another antiepileptic drug) between January 1997 and June 2013 at the Massachusetts General Hospital was analyzed retrospectively. After confounder adjustment, VPA was associated with a 28 % decrease in hazard of death (p = 0.031) and a 28 % decrease in the hazard of progression or death (p = 0.015) in glioblastoma. Additionally, VPA dose correlated with reduced hazard of death by 7 % (p = 0.002) and reduced hazard of progression or death by 5 % (p < 0.001) with each 100 g increase in total dose. Conversely, in grade II and III gliomas VPA was associated with a 118 % increased risk of tumor progression or death (p = 0.014), and every additional 100 g of VPA raised the hazard of progression or death by 4 %, although not statistically significant (p = 0.064). Moreover, grade II and III glioma patients taking VPA had 2.17 times the risk of histological progression (p = 0.020), although this effect was no longer significant after confounder adjustment. In conclusion, VPA was associated with improved survival in glioblastoma in a dose-dependent manner. However, in grade II and III gliomas, VPA was linked to histological progression and decrease in progression-free survival. Prospective evaluation of VPA treatment for glioma patients is warranted to confirm these findings.
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Long-term exposure to irinotecan reduces cell migration in glioma cells
Abstract
In spite of considerable research into the therapies for glioblastoma multiforme this tumour type remains very difficult to treat. As well as having a tendency to be inherently resistant to chemotherapy, glioblastoma multiforme also displays local invasion. Cell line studies have a continued and important role to play in understanding the mechanisms associated with both chemotherapy resistance and invasion. In the current study we have utilized the C6 glioma cell line to investigate the response to long-term, clinically relevant application of topoisomerase I and II inhibitors. Treatment with etoposide resulted in an increase in resistance to this topoisomerase II inhibitor. By contrast, the continuous exposure to a topoisomerase I inhibitor did not result in increased drug resistance, but was associated with a reduction in cell migration. This data supports further investigation of topoisomerase I inhibition as a means to inhibit glioma invasion without the development of parallel chemoresistance.
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Phase I trial of panobinostat and fractionated stereotactic re-irradiation therapy for recurrent high grade gliomas
Abstract
Panobinostat is an oral HDAC inhibitor with radiosensitizing activity. We investigated the safety, tolerability and preliminary efficacy of panobinostat combined with fractionated stereotactic re-irradiation therapy (FSRT) for recurrent high grade gliomas. Patients with recurrent high grade gliomas were enrolled in a 3 + 3 dose escalation study to determine dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, tolerability, and preliminary efficacy. FSRT was prescribed to 30–35 Gy delivered in 10 fractions. Panobinostat was administrated concurrently with radiotherapy. Of 12 evaluable patients, 8 had recurrent GBM, and 4 had recurrent anaplastic astrocytoma. There were three grade 3 or higher toxicities in each the 10 and 30 mg cohorts. In the 30 mg cohort, there was one DLT; grade 4 neutropenia. One patient developed late grade 3 radionecrosis. The median follow up was 18.8 months. The PFS6 was 67, 33, and 83 % for 10, 20, and 30 mg cohorts, respectively. The median OS was 7.8, 6.1 and 16.1 months for the 10, 20 and 30 mg cohorts, respectively. Panobinostat administrated with FSRT is well tolerated at 30 mg. A phase II trial is warranted to assess the efficacy of panobinostat plus FSRT for recurrent glioma.
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Is a modification of the radiotherapeutic target volume necessary after resection of glioblastomas with opening of the ventricles?
Abstract
Extensive surgical resection of centrally localized, newly diagnosed glioblastoma can lead to opening ventricles and therefore carries a potential risk of spreading tumor cells into the cebrospinal fluid. However, whether ventricle opening consequently implies a greater frequency of distant tumor recurrence after radiation therapy—and, therefore, reduced survival—remains unknown. Therefore, is an adaption of target volumes in radiation therapy necessary to account for a potential tumor cell spread into the ventricle system? The present study assessed the resection statuses of 311 primary-glioblastoma patients who underwent radiation therapy. Overall, in 78 cases (25.1 %) the ventricle system was opened during surgical resection. This study assessed the connection between ventricle opening and progression-free survival, overall survival, and distant and multifocal recurrence. OS rates of patients that underwent gross total resection were superior to patients with subtotal resection (p = 0.002). PFS (p = 0.53) and OS (p = 0.18) did not differ due to ventricle opening during surgical resection. However, in a subsample of STR cases increased survival was observed when the ventricle system was opened (16.8 vs. 14.3 months; p = 0.03). The occurrence of distant (p = 0.75) and contralateral recurrence (p = 0.87) was not influenced by ventricle opening. Newly diagnosed glioblastoma patients whose ventricle systems were opened during microsurgical resection did not experience decreased survival or show increased likelihoods of distant and contralateral progressions following radiation therapy. In short, patients profit from surgical resections that are as extensive as reasonably possible, even if this entails ventricle opening. Thus, additional inclusion of the ventricles in the radiation therapy target volume after ventricle opening does not seem to be indicated.
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Cognitive screening in patients with intracranial tumors: validation of the BCSE
Abstract
This study presents the first validation of the Brief Cognitive Status Exam (BCSE) against two other screening tools for cognitive impairment in patients with intracranial tumors. 58 patients and 22 matched healthy controls completed the BCSE, the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Patients were additionally tested with a comprehensive neuropsychological battery. Based on this assessment, they were classified as cognitively impaired or unimpaired on five cognitive domains. Analyses revealed a comparable feasibility of the BCSE relative to the MoCA and the MMSE, but a smaller range of assessed functions (e.g., no correlation with the domain visual-spatial functions). The ability to separate patients and healthy controls was extremely poor for BCSE and MMSE (sensitivity of 38.6 % and less), but moderate for MoCA (sensitivity 68.97 %). Detection of cognitive impairment in patients was worst with BCSE (sensitivity 37 %; MoCA 92.9 %, MMSE 44.4 %) as compared to neuropsychological testing. Moreover, prediction of cognitive outcome was also worst for the BCSE (AUC = .713, NPV = 50 %). An optimal cut-off of 50.5 increased the results slightly. In summary, the BCSE showed good feasibility but no sufficient results in separating healthy individuals from patients or detecting cognitive impairment in patients. Consequently, as a screening measure, we would recommend the MoCA instead of the BCSE. However, since even the MoCA failed to detect cognitive impairment, our study supports the view that reliable results could only be obtained with a comprehensive neuropsychological battery.
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The optimal regimen of bevacizumab for recurrent glioblastoma: does dose matter?
Abstract
The FDA-approved schedule and dose of bevacizumab (BVZ) for recurrent glioblastoma (rGB) (10 mg/kg q 2 weeks) were adopted from systemic cancer protocols. No dose-defining studies have been performed for glioblastoma. We began using BVZ for the treatment of rGB in 2005 at the dose of 5 mg/kg every 2 weeks combined with irinotecan, and later as single agent. Our previous report of 20 patients treated with BVZ 5 mg/kg every 2 weeks showed similar response rates and overall survival (OS) compared to other BVZ treatment protocols, with less adverse effects. In this study we retrospectively reviewed our 7 year experience with BVZ in 162 rGB patients. Treatment outcomes were analyzed from 87 patients who received BVZ at 5 mg/kg and 75 patients at 10 mg/kg. While median age was similar in both groups, the median KPS was significantly higher in the group treated with 10 mg/kg BVZ (85 versus 60). There was no significant difference in OS or progression free survival (PFS) between the groups treated with BVZ 5 versus 10 mg/kg. Overall survival was significantly improved in the subgroup treated with cytotoxic therapy in addition to BVZ 10 mg/kg. There were more adverse events seen with BVZ 10 mg/kg. There is no significant difference in OS for rGB treated with BVZ 5 mg/kg versus 10 mg/kg when given as monotherapy. The smaller dose was slightly less toxic. Addition of cytotoxic therapy resulted in prolongation of OS in a small subgroup of BVZ 10 mg/kg.
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Brain metastasis in breast cancer: a comprehensive literature review
Abstract
This comprehensive review provides information on epidemiology, size, grade, cerebral localization, clinical symptoms, treatments, and factors associated with longer survival in 14,599 patients with brain metastasis from breast cancer; the molecular features of breast cancers most likely to develop brain metastases and the potential use of these predictive molecular alterations for patient management and future therapeutic targets are also addressed. The review covers the data from 106 articles representing this subject in the era of modern neuroimaging (past 35 years). The incidence of brain metastasis from breast cancer (24 % in this review) is increasing due to advances in both imaging technologies leading to earlier detection of the brain metastases and introduction of novel therapies resulting in longer survival from the primary breast cancer. The mean age at the time of breast cancer and brain metastasis diagnoses was 50.3 and 48.8 years respectively. Axillary node metastasis was noted in 32.8 % of the patients who developed brain metastasis. The median time intervals between the diagnosis of breast cancer to identification of brain metastasis and from identification of brain metastasis to death were 34 and 15 months, respectively. The most common symptoms experienced in patients with brain metastasis consisted of headache (35 %), vomiting (26 %), nausea (23 %), hemiparesis (22 %), visual changes (13 %) and seizures (12 %). A majority of the patients had multiple metastases (54.2 %). Cerebellum and frontal lobes were the most common sites of metastasis (33 and 16 %, respectively). Of the primary tumors for which biomarkers were recorded, 37 % were estrogen receptor (ER)+, 41 % ER−, 36 % progesterone receptor (PR)+, 34 % PR−, 35 % human epithelial growth factor receptor 2 (HER2)+, 41 % HER2−, 27 % triple negative and 18 % triple positive (TP). Treatment in most patients consisted of a multimodality approach often with two or more of the following: whole brain radiation therapy (52 %), chemotherapy (51 %), stereotactic radiosurgery (20 %), surgical resection (14 %), trastuzumab (39 %) for HER2 positive tumors, and hormonal therapy (34 %) for ER and/or PR positive tumors. Factors that had an impact on prognosis included grade and size of the tumor, multiple metastases, presence of extra-cranial metastasis, triple negative or HER2+ biomarker status, and high Karnovsky score. Novel therapies such as application of agents to reduce tumor angiogenesis or alter permeability of the blood brain barrier are being explored with preliminary results suggesting a potential to improve survival after brain metastasis. Other potential therapies based on genetic alterations in the tumor and the microenvironment in the brain are being investigated; these are briefly discussed.
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In vivo multiphoton tomography and fluorescence lifetime imaging of human brain tumor tissue
Abstract
High resolution multiphoton tomography and fluorescence lifetime imaging differentiates glioma from adjacent brain in native tissue samples ex vivo. Presently, multiphoton tomography is applied in clinical dermatology and experimentally. We here present the first application of multiphoton and fluorescence lifetime imaging for in vivo imaging on humans during a neurosurgical procedure. We used a MPTflex™ Multiphoton Laser Tomograph (JenLab, Germany). We examined cultured glioma cells in an orthotopic mouse tumor model and native human tissue samples. Finally the multiphoton tomograph was applied to provide optical biopsies during resection of a clinical case of glioblastoma. All tissues imaged by multiphoton tomography were sampled and processed for conventional histopathology. The multiphoton tomograph allowed fluorescence intensity- and fluorescence lifetime imaging with submicron spatial resolution and 200 picosecond temporal resolution. Morphological fluorescence intensity imaging and fluorescence lifetime imaging of tumor-bearing mouse brains and native human tissue samples clearly differentiated tumor and adjacent brain tissue. Intraoperative imaging was found to be technically feasible. Intraoperative image quality was comparable to ex vivo examinations. To our knowledge we here present the first intraoperative application of high resolution multiphoton tomography and fluorescence lifetime imaging of human brain tumors in situ. It allowed in vivo identification and determination of cell density of tumor tissue on a cellular and subcellular level within seconds. The technology shows the potential of rapid intraoperative identification of native glioma tissue without need for tissue processing or staining.
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Cancers, Vol. 8, Pages 45: KRAS Mutant Pancreatic Cancer: No Lone Path to an Effective Treatment
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers with a dismal 7% 5-year survival rate and is projected to become the second leading cause of cancer-related deaths by 2020. KRAS is mutated in 95% of PDACs and is a well-validated driver of PDAC growth and maintenance. However, despite comprehensive efforts, an effective anti-RAS drug has yet to reach the clinic. Different paths to inhibiting RAS signaling are currently under investigation in the hope of finding a successful treatment. Recently, direct RAS binding molecules have been discovered, challenging the perception that RAS is an "undruggable" protein. Other strategies currently being pursued take an indirect approach, targeting proteins that facilitate RAS membrane association or downstream effector signaling. Unbiased genetic screens have identified synthetic lethal interactors of mutant RAS. Most recently, metabolic targets in pathways related to glycolytic signaling, glutamine utilization, autophagy, and macropinocytosis are also being explored. Harnessing the patient's immune system to fight their cancer is an additional exciting route that is being considered. The "best" path to inhibiting KRAS has yet to be determined, with each having promise as well as potential pitfalls. We will summarize the state-of-the-art for each direction, focusing on efforts directed toward the development of therapeutics for pancreatic cancer patients with mutated KRAS.
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[HPV DNA genotyping: A study of anogenital, head and neck and skin cancers in a population from west Algerian. HPV detection in different cancers from an Algerian population].
[HPV DNA genotyping: A study of anogenital, head and neck and skin cancers in a population from west Algerian. HPV detection in different cancers from an Algerian population].
Bull Cancer. 2016 Apr 13;
Authors: Nahet A, Boublenza L, Hassaine H, Masdoua N, Prétet JL, Belglaiaa E, Mougin C
Abstract
OBJECTIVES: To investigate the prevalence of human papillomaviruses (HPV) in cancers located at different sites in patients from west Algerian and collected between 2010 and 2014.
MATERIAL AND METHODS: Extracted DNA from archival formaldehyde-fixed and paraffin-embedded tissues was provided from 39 anogenital cancers, 10 head and neck cancers and 36 skin cancers. The viral DNA was detected using the INNO-LiPA HPV Genotyping Extra(®) kit.
RESULTS: The prevalence of HPV was 100% in cervical cancers, 40% in vaginal cancers, 17% in vulvar cancers, 33% in anal cancers, 0% in tonsil and larynx cancers and 6.4% in skin squamous cell carcinoma. In cervical cancers, the most prevalent genotypes were HPV16 (52%) and HPV18 (12%) as single infection.
CONCLUSION: The overall results agree partially with literature. Extensive research is necessary to promote HPV vaccine to reduce in particular the burden of cervical cancer in Algeria.
PMID: 27085765 [PubMed - as supplied by publisher]
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