Vitamin D Status in Chronic Kidney Disease - UVB Irradiation Is Superior to Oral Supplementation

Background: In chronic kidney disease (CKD) a deficiency of 1,25-dihydroxyvitamin D is common. The aim of this review was to compare vitamin D status after oral supplementation of vitamin D₃ to that of serial suberythemal irradiation in end-stage kidney disease (ESKD) patients. Patients and Methods: Ninety-five patients, with a mean age of 62 (range=35-82) years, were treated with a mean dose of 35,000 (20,000–60,000) IU vitamin D₃ per week for a period of 18 months. Fourteen patients, with a mean age of 51 (range=41-57) years, were whole-body UVB irradiated for over 6 months. From 3 hemodialysis patients skin biopsies were performed. Results: With oral supplementation 25(OH)D₃ increased by 60%. With UV irradiation 25(OH)D₃ increased by 400%. Gene expression analysis demonstrated an improvement in the vitamin D receptor (VDR) by 0.65 fold, in 1-alpha-hydroxylase (CYP27B1) by 1.0 fold, and in 25-hydroxylase (CYP2R) by 1.2 fold. Conclusion: Serial suberythemal UVB irradiation of patients with CKD on dialysis is capable to improve serum 25(OH)D₃ and 1,25(OH)₂D₃ by enhancing the skin's ability to activate vitamin D.

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Extracorporeal Photopheresis for Non-skin GvHD

Graft versus host disease (GvHD) is one of the most feared adverse events of allogeneic hematopoietic stem cell transplantation. In severe grades of GvHD patients die from infections due to impairment of their immune defense or therapy-refractory involvement of intestines, liver and lung. Extracorporeal photopheresis is an effective treatment for acute and chronic graft versus host disease without severe impairment of the recipient's immune system. It is generally better known for its effect on skin GvHD but all other manifestations of GvHD can respond as well. Herein we report a brief review of its history and give an overview of the current knowledge of extracorporeal photopheresis in non-skin GvHD.

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Light - Instead of UV Protection: New Requirements for Skin Cancer Prevention

The requirements on sunscreens have essentially changed, since some years ago it was demonstrated that approximately 50% of free radicals, that are formed in the skin by solar radiation, originate from the visible and infrared regions of the solar spectrum. In addition, a critical radical concentration threshold could be found. If this concentration, the free radical threshold value (FRTV), is exceeded, sunburn, immunosuppression and skin cancer may develop. Application of sunscreens and lotions protects against sunburn in the UV region of the solar spectrum and therefore is frequently used to extend people's stay in the sun. However, this behaviour can enhance the concentration of free radicals formed in the visible and infrared regions of the solar spectrum, so that the critical radical threshold is exceeded and the skin may be damaged.

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Carfilzomib Triple Combination Therapy: A Review in Relapsed Multiple Myeloma

Abstract

Carfilzomib (Kyprolis®) is a proteasome inhibitor that binds selectively and irreversibly to the 20S proteasome (the proteolytic core particle within the 26S proteasome), inducing growth arrest and apoptosis. This intravenous drug is approved in the EU and the USA as combination therapy with oral lenalidomide and intravenous or oral dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. In the multinational, phase III ASPIRE study in this patient population, carfilzomib triple combination therapy significantly prolonged progression-free survival (PFS), reflecting a clinically relevant gain in PFS of 8.7 months, compared with lenalidomide plus dexamethasone. Improvements in overall response rate and patients' global health status were also observed with carfilzomib triple combination therapy. A significant improvement in overall survival (OS) is yet to be demonstrated, with the prespecified stopping boundary not crossed at the time of the prespecified interim analysis, although OS data were not mature by the cut-off date. Carfilzomib triple combination therapy had a manageable tolerability profile. The incidences of the most frequently reported grade 3 or higher adverse events of special interest (with the exception of neutropenia, anaemia and thrombocytopenia) were low in both the carfilzomib triple combination therapy and lenalidomide plus dexamethasone groups. Although final OS data are awaited, current evidence suggests carfilzomib in combination with lenalidomide and dexamethasone is a welcome addition to the treatment options currently available for patients with relapsed multiple myeloma.

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HIV Drug to Aid Melanoma Therapies?

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Hyungsoo Kim, Ze'ev A. Ronai
The HIV1 protease inhibitor nelfinavir is being investigated as a cancer therapeutic. In this issue of Cancer Cell, Smith et al. (2016) report that nelfinavir suppresses MITF expression induced by MAPK pathway inhibition in melanoma cells and sensitizes melanoma cells with NRAS or BRAF plus NRAS mutations to MEK inhibitors.

Teaser

The HIV1 protease inhibitor nelfinavir is being investigated as a cancer therapeutic. In this issue of Cancer Cell, Smith et al. (2016) report that nelfinavir suppresses MITF expression induced by MAPK pathway inhibition in melanoma cells and sensitizes melanoma cells with NRAS or BRAF plus NRAS mutations to MEK inhibitors.


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KLF4 Initiates Acinar Cell Reprogramming and Is Essential for the Early Stages of Pancreatic Carcinogenesis

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Ravikanth Maddipati, Jonathan P. Katz
Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and is minimally responsive to current chemotherapies. In this issue of Cancer Cell, Xie et al. (2016) identify the transcription factor KLF4 as essential for the early stages of pancreatic carcinogenesis, expanding the repertoire of targets for early intervention strategies.

Teaser

Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and is minimally responsive to current chemotherapies. In this issue of Cancer Cell, Xie et al. (2016) identify the transcription factor KLF4 as essential for the early stages of pancreatic carcinogenesis, expanding the repertoire of targets for early intervention strategies.


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Mammary Ductal Environment Is Necessary for Faithful Maintenance of Estrogen Signaling in ER+ Breast Cancer

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Svasti Haricharan, Jonathan Lei, Matthew Ellis
In this issue of Cancer Cell, Sflomos et al. (2016) describe a robust preclinical animal model of ER⁺ breast cancer. The authors identify the critical role of the breast microenvironment in determining hormone response of ER⁺ breast cancer cells and in driving the luminal phenotype of breast cancer.

Teaser

In this issue of Cancer Cell, Sflomos et al. (2016) describe a robust preclinical animal model of ER⁺ breast cancer. The authors identify the critical role of the breast microenvironment in determining hormone response of ER⁺ breast cancer cells and in driving the luminal phenotype of breast cancer.


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Selective Targeting of the KRAS G12C Mutant: Kicking KRAS When It’s Down

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): G. Aaron Hobbs, Alfred Wittinghofer, Channing J. Der
Two recent studies evaluated a small molecule that specifically binds to and inactivates the KRAS G12C mutant. The new findings argue that the perception that mutant KRAS is persistently frozen in its active GTP-bound form may not be accurate.

Teaser

Two recent studies evaluated a small molecule that specifically binds to and inactivates the KRAS G12C mutant. The new findings argue that the perception that mutant KRAS is persistently frozen in its active GTP-bound form may not be accurate.


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Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Shom Goel, Qi Wang, April C. Watt, Sara M. Tolaney, Deborah A. Dillon, Wei Li, Susanne Ramm, Adam C. Palmer, Haluk Yuzugullu, Vinay Varadan, David Tuck, Lyndsay N. Harris, Kwok-Kin Wong, X. Shirley Liu, Piotr Sicinski, Eric P. Winer, Ian E. Krop, Jean J. Zhao
Using transgenic mouse models, cell line-based functional studies, and clinical specimens, we show that cyclin D1/CDK4 mediate resistance to targeted therapy for HER2-positive breast cancer. This is overcome using CDK4/6 inhibitors. Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC1 activity. This relieves feedback inhibition of upstream EGFR family kinases, resensitizing tumors to EGFR/HER2 blockade. Consequently, dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of TSC2 phosphorylation and hence mTORC1/S6K/S6RP activity. The suppression of both Rb and S6RP enhances G1 arrest and a phenotype resembling cellular senescence. In vivo, CDK4/6 inhibitors sensitize patient-derived xenograft tumors to HER2-targeted therapies and delay tumor recurrence in a transgenic model of HER2-positive breast cancer.

Teaser

Goel et al. show that cyclin D1/CDK4 mediate targeted therapy resistance in HER2⁺ breast cancer. CDK4/6 inhibition overcomes this resistance by increasing tumor cell dependence on EGFR family kinase signaling. CDK4/6 inhibitors resensitize PDX tumors to HER2-targeted therapies and delay tumor recurrence in vivo.


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CDK4/6 Inhibitors resTORe Therapeutic Sensitivity in HER2+ Breast Cancer

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Marcos Malumbres
CDK4/6 inhibitors have received approval for treating hormone-positive breast tumors, but whether other aggressive cancers respond to these molecules is not yet clear. In this issue of Cancer Cell, Goel et al. (2016) report an unexpected activity of CDK4/6 inhibitors in reducing mTOR function and re-sensitizing HER2-positive cancers to EGFR/HER2 blockade.

Teaser

CDK4/6 inhibitors have received approval for treating hormone-positive breast tumors, but whether other aggressive cancers respond to these molecules is not yet clear. In this issue of Cancer Cell, Goel et al. (2016) report an unexpected activity of CDK4/6 inhibitors in reducing mTOR function and re-sensitizing HER2-positive cancers to EGFR/HER2 blockade.


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Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Michael P. Smith, Holly Brunton, Emily J. Rowling, Jennifer Ferguson, Imanol Arozarena, Zsofia Miskolczi, Jessica L. Lee, Maria R. Girotti, Richard Marais, Mitchell P. Levesque, Reinhard Dummer, Dennie T. Frederick, Keith T. Flaherty, Zachary A. Cooper, Jennifer A. Wargo, Claudia Wellbrock
Once melanomas have progressed with acquired resistance to mitogen-activated protein kinase (MAPK)-targeted therapy, mutational heterogeneity presents a major challenge. We therefore examined the therapy phase before acquired resistance had developed and discovered the melanoma survival oncogene MITF as a driver of an early non-mutational and reversible drug-tolerance state, which is induced by PAX3-mediated upregulation of MITF. A drug-repositioning screen identified the HIV1-protease inhibitor nelfinavir as potent suppressor of PAX3 and MITF expression. Nelfinavir profoundly sensitizes BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors. Moreover, nelfinavir is effective in BRAF and NRAS mutant melanoma cells isolated from patients progressed on MAPK inhibitor (MAPKi) therapy and in BRAF/NRAS/PTEN mutant tumors. We demonstrate that inhibiting a driver of MAPKi-induced drug tolerance could improve current approaches of targeted melanoma therapy.

Graphical abstract

Teaser

Smith et al. discover PAX3-mediated overexpression of MITF as a reversible resistance mechanism to MAPK-pathway inhibition in BRAF mutant melanomas and identify nelfinavir, which inhibits this mechanism and sensitizes not only BRAF mutant but also BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors.


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Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Haidong Tang, Yang Wang, Lukasz K. Chlewicki, Yuan Zhang, Jingya Guo, Wei Liang, Jieyi Wang, Xiaoxiao Wang, Yang-Xin Fu
Immune checkpoint blockade therapies fail to induce responses in the majority of cancer patients, so how to increase the objective response rate becomes an urgent challenge. Here, we demonstrate that sufficient T cell infiltration in tumor tissues is a prerequisite for response to PD-L1 blockade. Targeting tumors with tumor necrosis factor superfamily member LIGHT activates lymphotoxin β-receptor signaling, leading to the production of chemokines that recruit massive numbers of T cells. Furthermore, targeting non-T cell-inflamed tumor tissues by antibody-guided LIGHT creates a T cell-inflamed microenvironment and overcomes tumor resistance to checkpoint blockade. Our data indicate that targeting LIGHT might be a potent strategy to increase the responses to checkpoint blockades and other immunotherapies in non-T cell-inflamed tumors.

Graphical abstract

Teaser

Tang et al. show that sufficient T cell infiltration in tumors is critical for the response to PD-L1 blockade and that treating EGFR⁺ resistant tumors with a fusion protein containing TNF superfamily member LIGHT with anti-EGFR antibody can increase tumor infiltrating T cells and overcome the resistance to checkpoint therapy.


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A SIRT2-Selective Inhibitor Promotes c-Myc Oncoprotein Degradation and Exhibits Broad Anticancer Activity

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Hui Jing, Jing Hu, Bin He, Yashira L. Negrón Abril, Jack Stupinski, Keren Weiser, Marisa Carbonaro, Ying-Ling Chiang, Teresa Southard, Paraszkevi Giannakakou, Robert S. Weiss, Hening Lin
Targeting sirtuins for cancer treatment has been a topic of debate due to conflicting reports and lack of potent and specific inhibitors. We have developed a thiomyristoyl lysine compound, TM, as a potent SIRT2-specific inhibitor with a broad anticancer effect in various human cancer cells and mouse models of breast cancer. Mechanistically, SIRT2 inhibition promotes c-Myc ubiquitination and degradation. The anticancer effect of TM correlates with its ability to decrease c-Myc level. TM had limited effects on non-cancerous cells and tumor-free mice, suggesting that cancer cells have an increased dependency on SIRT2 that can be exploited for therapeutic benefit. Our studies demonstrate that SIRT2-selective inhibitors are promising anticancer agents and may represent a general strategy to target certain c-Myc-driven cancers.

Teaser

Jing et al. develop a thiomyristoyl lysine compound, TM, as a potent SIRT2-specific inhibitor with broad anticancer activity but little effect on non-cancerous cells. SIRT2 inhibition promotes c-Myc ubiquitination and degradation, suggesting the therapeutic potential of TM to target certain c-Myc-driven cancers.


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HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Yanxin Pei, Kun-Wei Liu, Jun Wang, Alexandra Garancher, Ran Tao, Lourdes A. Esparza, Donna L. Maier, Yoko T. Udaka, Najiba Murad, Sorana Morrissy, Huriye Seker-Cin, Sebastian Brabetz, Lin Qi, Mari Kogiso, Simone Schubert, James M. Olson, Yoon-Jae Cho, Xiao-Nan Li, John R. Crawford, Michael L. Levy, Marcel Kool, Stefan M. Pfister, Michael D. Taylor, Robert J. Wechsler-Reya
Medulloblastoma (MB) is a highly malignant pediatric brain tumor. Despite aggressive therapy, many patients succumb to the disease, and survivors experience severe side effects from treatment. MYC-driven MB has a particularly poor prognosis and would greatly benefit from more effective therapies. We used an animal model of MYC-driven MB to screen for drugs that decrease viability of tumor cells. Among the most effective compounds were histone deacetylase inhibitors (HDACIs). HDACIs potently inhibit survival of MYC-driven MB cells in vitro, in part by inducing expression of the FOXO1 tumor suppressor gene. HDACIs also synergize with phosphatidylinositol 3-kinase inhibitors to inhibit tumor growth in vivo. These studies identify an effective combination therapy for the most aggressive form of MB.

Graphical abstract

Teaser

MYC-driven medulloblastoma (MB) has a poor prognosis. Pei et al. report that HDAC inhibitors potently inhibit MYC-driven MB cell growth in vitro, in part by inducing the expression of FOXO1, and synergize with PI3K inhibitors to inhibit tumor growth in vivo.


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KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Daoyan Wei, Liang Wang, Yongmin Yan, Zhiliang Jia, Mihai Gagea, Zhiwei Li, Xiangsheng Zuo, Xiangyu Kong, Suyun Huang, Keping Xie
Understanding the molecular mechanisms of tumor initiation has significant impact on early cancer detection and intervention. To define the role of KLF4 in pancreatic ductal adenocarcinoma (PDA) initiation, we used molecular biological analyses and mouse models of klf4 gain- and loss-of-function and mutant Kras. KLF4 is upregulated in and required for acinar-to-ductal metaplasia. Klf4 ablation drastically attenuates the formation of pancreatic intraepithelial neoplasia induced by mutant Kras^G12D, whereas upregulation of KLF4 does the opposite. Mutant KRAS and cellular injuries induce KLF4 expression, and ectopic expression of KLF4 in acinar cells reduces acinar lineage- and induces ductal lineage-related marker expression. These results demonstrate that KLF4 induces ductal identity in PanIN initiation and may be a potential target for prevention of PDA initiation.

Graphical abstract

Teaser

Wei et al. show that KLF4 is a pancreatic ductal fate determinant and is critical for acinar-to-ductal cell reprogramming. Injury and stress signaling can converge to induce KLF4 expression in acinar cells, potentiating the initiation of premalignant pancreatic intraepithelial neoplasia induced by mutant Kras.


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PITPNC1 Recruits RAB1B to the Golgi Network to Drive Malignant Secretion

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Nils Halberg, Caitlin A. Sengelaub, Kristina Navrazhina, Henrik Molina, Kunihiro Uryu, Sohail F. Tavazoie
Enhanced secretion of tumorigenic effector proteins is a feature of malignant cells. The molecular mechanisms underlying this feature are poorly defined. We identify PITPNC1 as a gene amplified in a large fraction of human breast cancer and overexpressed in metastatic breast, melanoma, and colon cancers. Biochemical, molecular, and cell-biological studies reveal that PITPNC1 promotes malignant secretion by binding Golgi-resident PI4P and localizing RAB1B to the Golgi. RAB1B localization to the Golgi allows for the recruitment of GOLPH3, which facilitates Golgi extension and enhanced vesicular release. PITPNC1-mediated vesicular release drives metastasis by increasing the secretion of pro-invasive and pro-angiogenic mediators HTRA1, MMP1, FAM3C, PDGFA, and ADAM10. We establish PITPNC1 as a PI4P-binding protein that enhances vesicular secretion capacity in malignancy.

Teaser

Halberg et al. identify PITPNC1 as a gene amplified in a large fraction of human breast cancer and overexpressed in multiple cancer types. PITPNC1 drives malignancy and metastasis by binding Golgi-resident PI4P and localizing RAB1B to the Golgi, facilitating GOLPH3 recruitment and secretion of pro-tumor factors.


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Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Syed A. Ali, Verline Justilien, Lee Jamieson, Nicole R. Murray, Alan P. Fields
We report that the protein kinase Cι (PKCι) oncogene controls expression of NOTCH3, a key driver of stemness, in KRAS-mediated lung adenocarcinoma (LADC). PKCι activates NOTCH3 expression by phosphorylating the ELF3 transcription factor and driving ELF3 occupancy on the NOTCH3 promoter. PKCι-ELF3-NOTCH3 signaling controls the tumor-initiating cell phenotype by regulating asymmetric cell division, a process necessary for tumor initiation and maintenance. Primary LADC tumors exhibit PKCι-ELF3-NOTCH3 signaling, and combined pharmacologic blockade of PKCι and NOTCH synergistically inhibits tumorigenic behavior in vitro and LADC growth in vivo demonstrating the therapeutic potential of PKCι-ELF3-NOTCH3 signal inhibition to more effectively treat KRAS LADC.

Graphical abstract

Teaser

Ali et al. show that in KRAS-mediated lung adenocarcinoma, PKCι controls NOTCH3 expression by phosphorylating ELF3 and driving occupancy at the NOTCH3 promoter. PKCι-ELF3-NOTCH3 signaling controls the TIC phenotype and combined blockade of PKCι and NOTCH has a synergistic antitumor effect in vitro and in vivo.


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Genome-Wide Profiles of Extra-cranial Malignant Rhabdoid Tumors Reveal Heterogeneity and Dysregulated Developmental Pathways

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Hye-Jung E. Chun, Emilia L. Lim, Alireza Heravi-Moussavi, Saeed Saberi, Karen L. Mungall, Mikhail Bilenky, Annaick Carles, Kane Tse, Inna Shlafman, Kelsey Zhu, Jenny Q. Qian, Diana L. Palmquist, An He, William Long, Rodrigo Goya, Michelle Ng, Veronique G. LeBlanc, Erin Pleasance, Nina Thiessen, Tina Wong, Eric Chuah, Yong-Jun Zhao, Jacquie E. Schein, Daniela S. Gerhard, Michael D. Taylor, Andrew J. Mungall, Richard A. Moore, Yussanne Ma, Steven J.M. Jones, Elizabeth J. Perlman, Martin Hirst, Marco A. Marra
Malignant rhabdoid tumors (MRTs) are rare lethal tumors of childhood that most commonly occur in the kidney and brain. MRTs are driven by SMARCB1 loss, but the molecular consequences of SMARCB1 loss in extra-cranial tumors have not been comprehensively described and genomic resources for analyses of extra-cranial MRT are limited. To provide such data, we used whole-genome sequencing, whole-genome bisulfite sequencing, whole transcriptome (RNA-seq) and microRNA sequencing (miRNA-seq), and histone modification profiling to characterize extra-cranial MRTs. Our analyses revealed gene expression and methylation subgroups and focused on dysregulated pathways, including those involved in neural crest development.

Teaser

Chun et al. perform integrated molecular analyses of extra-cranial malignant rhabdoid tumors (MRTs) and show that, although SMARCB1 loss drives nearly all MRTs, there are two subgroups of MRTs that are associated with patient age and differentially expressed genes.


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A porcine model of osteosarcoma

A porcine model of osteosarcoma

Oncogenesis 5, e210 (March 2016). doi:10.1038/oncsis.2016.19

Authors: A Saalfrank, K-P Janssen, M Ravon, K Flisikowski, S Eser, K Steiger, T Flisikowska, P Müller-Fliedner, É Schulze, C Brönner, A Gnann, E Kappe, B Böhm, B Schade, U Certa, D Saur, I Esposito, A Kind & A Schnieke

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Radiotherapy plus EGFR TKIs in non-small cell lung cancer patients with brain metastases: an update meta-analysis

Abstract

Brain metastasis (BM) is the common complication of non-small cell lung cancer (NSCLC) with a poor prognosis and dismal survival rate. This update meta-analysis aimed to derive a more precise estimation of radiotherapy plus epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC patients with BM. PubMed, EMBASE, Web of Science, Google Scholar, and Cochrane Library were searched to identify any relevant publications. After screening the literature and undertaking quality assessment and data extraction, the meta-analysis was performed using STATA Version 12.0. In total, 15 studies involving 1552 participants were included. The results indicated that radiotherapy plus EGFR TKIs was more effective at improving response rate and disease control rate (DCR) (risk ratio (RR) = 1.48, 95% confidence interval [CI]: 1.12–1.96, P = 0.005; RR = 1.29, 95% CI: 1.02–1.60, P = 0.035; respectively) than radiotherapy alone or plus chemotherapy. Moreover, radiotherapy plus EGFR TKIs significantly prolonged the time to central nervous system progression (CNS-TTP) (HR = 0.56, 95% CI [0.33, 0.80]; P = 0.000) and median overall survival (OS) (HR = 0.58, 95% CI [0.42, 0.74]; P = 0.000) but significantly increased adverse events (any grade) (RR = 1.25, 95% CI [1.01, 1.57]; P = 0.009), especially rash and dry skin. These results suggested that radiotherapy plus EGFR TKIs produced superior response rate and DCR and markedly prolonged the CNS-TTP and OS of NSCLC patients with BM. However, combined groups had the higher rate of incidence of overall adverse effects, especially rash and dry skin.

Radiotherapy plus epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) produced superior risk ratio and disease control rate, and markedly prolonged the central nervous system (CNS)-TTP and overall survival of non-small cell lung cancer (NSCLC) patients with brain metastasis (BM). Meanwhile, combined group increased the incidence of overall adverse effects, especially rash and dry skin. In future, more high-quality and large-scale clinical trials are necessary to confirm the efficacy and safety of radiotherapy plus EGFR TKIs and select the most benefit population in NSCLC patients with BM.

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The local treatment modalities in FIGO stage I-II small-cell carcinoma of the cervix are determined by disease stage and lymph node status

Abstract

The purpose of this study was to identify the optimal local treatment modalities for International Federation of Gynecology and Obstetrics (FIGO) stage I-II small-cell carcinoma of the cervix (SCCC), including cancer-directed surgery (CDS) and/or radiotherapy (RT). The Surveillance Epidemiology and End Results (SEER) database was used to identify SCCC patients from 1988 to 2012, and analyzed using Kaplan–Meier survival and Cox regression proportional hazard methods to determine factors significant for cause-specific survival (CSS) and overall (OS). A total of 208 patients of SCCC were enrolled. The median follow-up time was 31 months. Fifty-eight (27.9%) patients were treated with primary CDS, 88 (42.3%) patients underwent CDS combined with RT, and 62 (29.8%) patients were treated with primary RT. Univariate and multivariate analyses showed that local treatment modalities were independent prognostic factors for CSS and OS. Patients who had undergone CDS had better CSS and OS, compared with patients who had been treated with combined CDS and RT or RT alone. The 5-year CSS and OS of entire group was 49.8% and 46.4%, respectively. The 5-year CSS in the groups of patients receiving CDS, CDS combined with RT, and RT alone were 67.9%, 49.7%, and 32.6%, respectively (P < 0.001). The 5-year OS in patients treated with CDS, CDS combined with RT, and RT alone were 64.9%, 46.2%, and 28.8% (P < 0.001). Primary surgery was associated with improved CSS and OS for FIGO stage I and lymph node negative disease. Primary surgery is the most effective local treatment for FIGO stage I-II SCCC, as adjuvant RT or radical RT does not improve survival compared to radical surgery, especially in patients with FIGO stage I and lymph node negative disease.

Primary surgery is the most effective local treatment for Federation of Gynecology and Obstetrics (FIGO) stage I–II small-cell carcinoma of the cervix, as adjuvant radiotherapy or radical radiotherapy does not improve survival compared to radical surgery, especially in patients with FIGO stage I and lymph node negative disease.

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Hypoxia-responsive miR-124 and miR-144 reduce hypoxia-induced autophagy and enhance radiosensitivity of prostate cancer cells via suppressing PIM1

Abstract

Cancer cells in hypoxia usually make adaptive changes in cellular metabolism, such as altered autophagy. This might be a cause of enhanced radioresistance in some types of cancer. In this study, we investigated hypoxia-responsive miRNAs in two prostate cancer cell lines (DU145 and PC3). This study firstly reported that hypoxia induces further downregulation of miR-124 and miR-144, which might be a result of impaired dicer expression. These two miRNAs can simultaneously target 3′UTR of PIM1. Functional study showed that miR-124 or miR-144 overexpression can inhibit hypoxia-induced autophagy and enhance radiosensitivity at least via downregulating PIM1. Therefore, hypoxia induced miR-124 and miR-144 downregulation may contribute to a prosurvival mechanism of prostate cancer cells to hypoxia and irradiation at least through attenuated suppressing of PIM1. This finding presents a potential therapeutic target for prostate cancer.

Hypoxia induced miR-124 and miR-144 downregulation may contribute to a prosurvival mechanism of prostate cancer cells to hypoxia and irradiation at least through attenuated suppressing of PIM1. This presents a potential therapeutic target for the treatment of prostate cancer.

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Role of cancer stem cells in racial disparity in colorectal cancer

Abstract

Although African-Americans (AAs) have a higher incidence of colorectal cancer (CRC) than White people, the underlying biochemical mechanisms for this increase are poorly understood. The current investigation was undertaken to examine whether differences in self-renewing cancer stem/stem-like cells (CSCs) in the colonic mucosa, whose stemness is regulated by certain microRNAs (miRs), could partly be responsible for the racial disparity in CRC. The study contains 53 AAs and 47 White people. We found the number of adenomas and the proportion of CD44⁺CD166⁻  CSC phenotype in the colon to be significantly higher in AAs than White people. MicroRNAs profile in CSC-enriched colonic mucosal cells, expressed as ratio of high-risk (≥3 adenomas) to low-risk (no adenoma) CRC patients revealed an 8-fold increase in miR-1207-5p in AAs, compared to a 1.2-fold increase of the same in White people. This increase in AA was associated with a marked rise in lncRNA PVT1 (plasmacytoma variant translocation 1), a host gene of miR-1207-5p. Forced expression of miR-1207-5p in normal human colonic epithelial cells HCoEpiC and CCD841 produced an increase in stemness, as evidenced by morphologically elongated epithelial mesenchymal transition( EMT) phenotype and significant increases in CSC markers (CD44, CD166, and CD133) as well as TGF-β, CTNNB1, MMP2, Slug, Snail, and Vimentin, and reduction in Twist and N-Cadherin. Our findings suggest that an increase in CSCs, specifically the CD44⁺CD166⁻ phenotype in the colon could be a predisposing factor for the increased incidence of CRC among AAs. MicroRNA 1207-5p appears to play a crucial role in regulating stemness in colonic epithelial cells in AAs.

Although the incidence of and mortality from colorectal cancer (CRC) is higher among the African Americans (AAs) than White people, the underlying biochemical mechanism(s) for this racial disparity are poorly understood. The present investigation is aimed at elucidating the regulatory mechanisms for differences in cancer stem/stem-like cells (CSCs) in colonic neoplasia between AAs and White people by evaluating the role of microRNAs, specifically the microRNA-1207-5p, which is shown to be upregulated in CRC. microRNA (miR)-1207-5p plays a critical role in regulating stemness in colon CSCs and suggests a potential molecular mechanism for the increased risk of CRC among AAs.

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90-yttrium-ibritumomab tiuxetan consolidation of fludarabine, mitoxantrone, rituximab in intermediate/high-risk follicular lymphoma: updated long-term results after a median follow-up of 7 years

Abstract

Radioimmunotherapy (RIT) after an induction phase with conventional chemoimmunotherapy became an attractive strategy of consolidation for patients with advanced follicular lymphoma: in particular, in many studies RIT was represented by yttrium-90-ibritumomab tiuxetan (⁹⁰Y-IT). Independently by the different front-line treatment, updates on the long-term follow-up of these studies are needed because the disease course of follicular lymphoma is characterised by multiple relapses and progressively shorter durations of response. We report updated long-term efficacy and toxicity results of a multicenter phase II study on sequential treatment with four cycles of fludarabine, mitoxantrone, and rituximab followed by ⁹⁰Y-IT as front-line therapy for untreated patients with intermediate/high-risk follicular lymphoma. With a median follow-up of 84 months, only 19/49 (38.8%) complete response patients relapsed, yielding an estimated long-term disease-free survival of 62.6%. The 7-year overall survival was 72.7%. Four (7.3%) second acute myeloid leukemia occurred, with a median time following RIT of 42 months. A relevant patients' responsiveness to subsequent therapies occurred: approximately 65% of relapsed patients obtained a good clinical response after the second-line treatment. These data represented the first evidence of a real role even in the long period of 90Y-IT after a fludarabine-containing regimen plus rituximab in the treatment of high-risk follicular lymphoma.

Consolidation with radioimmunotherapy (RIT) after the induction phase including conventional chemoimmunotherapy became an attractive strategy for patients with advanced follicular lymphoma but updates of the long-term outcomes of this approach are lacking. For this reason, we report updated long-term efficacy and toxicity results of a sequential treatment with four cycles of fludarabine, mitoxantrone, and rituximab followed by ⁹⁰Y-IT as a front-line therapy for untreated patients with intermediate/high-risk follicular lymphoma. These data represented the first evidence of a real role even in the long period of RIT after a fludarabine-containing regimen plus rituximab in the treatment of high-risk follicular lymphoma: a long-term of disease-free survival (63%) and a relevant patients' responsiveness to subsequent therapies.

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Table of Content Volume 55, Number 5, May 2016

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Persistent Multiyear Control of Relapsed T-Cell Acute Lymphoblastic Leukemia With Successive Donor Lymphocyte Infusions: A Case Report

There are few therapeutic options for patients with T-cell acute lymphoblastic leukemia (T-ALL) who have recurrent disease after initial matched sibling hematopoietic stem cell transplantation. While a second hematopoietic stem cell transplant (HSCT) from a haploidentical donor offers the conceptual possibility of greater graft versus leukemia effect, there is minimal literature to describe the efficacy of this approach in recurrent pediatric T-ALL. We present the case of a now 9-year-old female in whom second haploidentical HSCT, followed by successive donor lymphocyte infusions in response to minimal residual disease reemergence, has led to 3+ years of ongoing disease control without graft versus host disease and excellent quality of life.

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Fibrolamellar Hepatocellular Carcinoma: Mechanistic Distinction From Adult Hepatocellular Carcinoma

Fibrolamellar hepatocellular carcinoma (FL-HCC) has historically been classified as a rare subtype of HCC. However, unlike "classic" HCC, it occurs in children and young adults without underlying liver disease. The recent discovery of a deletion mutation in all FL-HCCs represented a major advancement in understanding the pathogenesis of this disease. This deletion results in the fusion of the genes encoding a heat shock protein (DNAJB1) and the catalytic subunit of protein kinase A (PKA, PRKACA), and overexpression of PRKACA and enhanced cAMP-dependent PKA activity. This review summarizes recent advancements in FL-HCC pathogenesis and characteristics of the HSP40-PKA C protein.

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Prognostic and predictive effects of diabetes, hypertension, and coronary artery disease among women on extended adjuvant letrozole: NCIC CTG MA.17

Publication date: May 2016
Source:European Journal of Cancer, Volume 58
Author(s): Rachel A. Goodwin, Rahima Jamal, Christopher M. Booth, Paul E. Goss, Elizabeth A. Eisenhauer, Dongsheng Tu, Lois E. Shepherd
BackgroundWomen with breast cancer and diabetes mellitus (DM) have poorer survival. Mechanisms include insulin dysregulation and/or DM related co-morbidities (CM). In MA.17 adjuvant letrozole (LET) after 5 years of tamoxifen (TAM) reduced the risk of recurrence and improved survival. We evaluated DM, hypertension (HTN), and coronary artery disease (CAD) as prognostic and predictive factors in MA.17.Patients and methodsDisease free survival, distant disease free survival (DDFS) and overall survival (OS) were compared using Cox regression model adjusting for other prognostic factors: in women treated by placebo (PLAC) based on the presence or absence of baseline DM (n = 462), HTN (n = 1627), CAD (n = 604) or any one of these CM (n = 2049), and between LET and PLAC groups in each CM. Analyses based on nodal status were performed.ResultsDM was neither prognostic nor predictive for women on extended LET. Women with one CM had similar outcomes on LET compared to women free of CM. For node positive women, the difference between LET and PLAC in DDFS was greater among women with one CM (hazard ratio [HR] = 0.30 [0.15–0.60], p = 0.001) compared to those without CM (HR = 0.72 [0.45–1.16], p = 0.17, p interaction = 0.04). Women on PLAC with HTN trended towards lower DDFS (HR = 1.50 [0.98–2.3], p = 0.06) and OS (HR = 1.61 [0.95–2.72], p = 0.08) than non-HTN women. HTN women had better DDFS on LET than non-HTN women. Women with one CM on PLAC had lower OS (HR = 2.10 [1.26–3.51], p = 0.004) than those free of CM.ConclusionsDM was not prognostic or predictive of outcomes. Women with CM who remain disease free after 5 years of TAM should be offered LET. HTN trended towards a negative prognosticator and outcomes among this group were improved on LET. More studies are needed to assess impact of adrenergic stimulation as a possible link to poorer breast cancer outcomes.



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Self-reported financial burden of cancer care and its effect on physical and mental health-related quality of life among US cancer survivors

BACKGROUND

Cancer-related financial burden has been linked to cancer survivors (CS) forgoing/delaying medical care, skipping follow-up visits, and discontinuing medications. To the authors' knowledge, little is known regarding the effect of financial burden on the health-related quality of life of CS.

METHODS

The authors analyzed 2011 Medical Expenditure Panel Survey data. Financial burden was present if one of the following problems was reported: borrowed money/declared bankruptcy, worried about paying large medical bills, unable to cover the cost of medical care visits, or other financial sacrifices. The following outcomes were evaluated: Physical Component Score (PCS) and Mental Component Score (MCS) of the 12-Item Short-Form Health Survey (SF-12), depressed mood, psychological distress, and worry related to cancer recurrence. The authors also assessed the effect of the number of financial problems on these outcomes.

RESULTS

Of the 19.6 million CS analyzed, 28.7% reported financial burden. Among them, the average PCS (42.3 vs 44.9) and MCS (48.1 vs 52.1) were lower for those with financial burden versus those without. In adjusted analyses, CS with financial burden had significantly lower PCS (β = -2.45), and MCS (β = -3.05), had increased odds of depressed mood (odds ratio, 1.95), and were more likely to worry about cancer recurrence (odds ratio, 3.54). Survivors reporting ≥ 3 financial problems reported statistically significant and clinically meaningful differences (≥3 points) in the mean PCS and MCS compared with survivors without financial problems.

CONCLUSIONS

Cancer-related financial burden was associated with lower health-related quality of life, increased risk of depressed mood, and a higher frequency of worrying about cancer recurrence among CS. Cancer 2015. © 2015 American Cancer Society.

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Enhanced Efficacy against Cervical Carcinomas through Polymeric Micelles Physically Incorporating the Proteasome Inhibitor MG132

Abstract

Treatment of recurrent or advanced cervical cancer is still limited, and new therapeutic choices are needed for improving prognosis and quality of life of patients. Because human papilloma virus (HPV) infection is critical in cervical carcinogenesis, with E6 and E7 oncogenes of HPV degrading tumor suppressor proteins through ubiquitin proteasome system (UPS), the inhibition of the UPS appears as an ideal target to suppress the growth of cervical tumors. Herein, we focused on the ubiquitin proteasome inhibitor MG132 (carbobenzoxy-Leu-Leu-leucinal) as the anticancer agent against cervical cancer cells, and physically incorporated it into micellar nanomedicines for achieving selective delivery to solid tumors and improving its in vivo efficacy. These MG132-loaded polymeric micelles (MG132/m) showed strong tumor inhibitory in vivo effect against HPV-positive tumors from HeLa and CaSki cells, and even in HPV-negative tumors from C33A cells. Repeated injection of MG132/m showed no significant toxicity to mice under analysis by mice weight change and histopathology. Moreover, the tumors treated with MG132/m showed higher levels of tumor suppressing proteins, hScrib and p53, as well as apoptotic degree, than tumors treated with free MG132. This enhanced efficacy of MG132/m was attributed to their prolonged circulation in the bloodstream, which allowed their gradual extravasation and penetration within the tumor tissue, as determined by intravital microscopy. These results support the use of MG132 incorporated into polymeric micelles as a safe and effective therapeutic strategy against cervical tumors.

This article is protected by copyright. All rights reserved.

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Combined detection of serum Dickkopf-1 and its autoantibodies to diagnose esophageal squamous cell carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) can be treated effectively if diagnosed at an early stage. We evaluated whether measurement of Dickkopf-1 (DKK-1) in combination of DKK-1 autoantibodies in serum may benefit early diagnosis of ESCC. Serum DKK-1 and DKK-1 autoantibodies were measured by enzyme-linked immunosorbent assay in a training cohort (185 ESCC samples vs. 97 normal controls) and validated in a validation cohort (104 ESCC samples vs. 53 normal controls). Receiver operating characteristic (ROC) was applied to calculate diagnostic accuracy. Testing of DKK-1 and DKK-1 autoantibodies together could differentiate ESCC from normal controls (area under the ROC curve [AUC] 0.769, 95% confidence interval (CI), 0.715–0.823, 50.3% sensitivity, and 90.7% specificity in the training cohort; AUC 0.752, 95% CI, 0.675–0.829, 50.0% sensitivity, and 84.9% specificity in the validation cohort). Importantly, the diagnostic performance of the combination of DKK-1 and DKK-1 autoantibodies persisted in early ESCC patients (AUC 0.780, 95% CI, 0.699–0.862, 50.0% sensitivity, and 90.7% specificity in the training cohort; AUC 0.745, 95% CI, 0.626–0.865, 53.8% sensitivity, and 84.9% specificity in the validation cohort). Furthermore, the levels of serum DKK-1 or DKK-1 autoantibody after surgical resection were lower, respectively, compared with the corresponding preoperative samples (P < 0.05). Our results suggest that measurement of DKK-1 combined with DKK-1 autoantibodies is a potentially valuable tool for the early detection of ESCC.

Detection of serum/plasma biomarker may benefit early diagnosis of esophageal squamous cell carcinoma (ESCC). We evaluate the diagnostic value of serum Dickkopf-1 (DKK-1) combined with DKK-1 autoantibodies in a training cohort and a validation cohort. Our findings offers evidence that combined detection of serum DKK1 and DKK1 autoantibodies has the power of discrimination between early ESCC patients and normal controls. Moreover, serum DKK-1 and DKK-1 autoantibody may be potential markers of therapeutic surveillance for ESCC.

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Short-term effectiveness of a web-based tailored intervention for cancer survivors on quality of life, anxiety, depression, and fatigue: randomized controlled trial

Abstract

Background

The aim of this study was to evaluate the short-term effectiveness of the web-based computer-tailored intervention Kanker Nazorg Wijzer (Cancer Aftercare Guide). The intervention aims to support cancer survivors with managing psychosocial and lifestyle-related issues. In this study, the impact on quality of life, anxiety, depression, and fatigue were evaluated.

Methods

Cancer survivors were recruited through 21 Dutch hospitals (November 2013–June 2014). Outcome measures included quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30), anxiety and depression (Hospital Anxiety and Depression Scale), and fatigue (Checklist Individual Strength). In a randomized controlled trial with an intervention group (n = 231) and a waiting list control group (n = 231), the short-term effectiveness was evaluated through multilevel linear regression analyses, controlling for selective dropout, baseline differences, and several demographic and disease-related characteristics.

Results

In total, 188 participants of the intervention group and 221 of the control group completed the 6-month measurement (dropout = 11.5%). The intervention was effective in reducing depression (B = −0.63, p = 0.007, f² = 0.019, d = 0.21) and fatigue (B = −4.36, p = 0.020, f² = 0.013, d = 0.21). In addition, effects were found for emotional (B = 3.47, p = 0.022, f² = 0.013, d = 0.15) and social functioning (B = 3.95, p = 0.011, f² = 0.017, d = 0.15), although this evidence was less strong. There were indications that the effects of fatigue and social functioning were influenced by module use.

Conclusions

While effect sizes were small, they can be considered as clinically relevant. With the Cancer Aftercare Guide being an effective, low-intensive, and easy accessible intervention, it could serve as a first step in stepped care for needs assessment and initial support for psychosocial problems that are present after cancer treatment. Copyright © 2016 John Wiley & Sons, Ltd.

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A systematic review of inequalities in psychosocial outcomes for women with breast cancer according to residential location and Indigenous status in Australia

Abstract

Background

The aim of this systematic review was to examine variations in psychosocial outcomes by residential location and Indigenous status in women diagnosed with breast cancer (BC) in Australia.

Methods

Systematic searches were undertaken using multiple databases covering articles between 1 January 1990 and 1 March 2015 focusing on adult women with BC in an Australian setting and measuring quality of life (QOL), psychological distress or psychosocial support.

Results

Thirteen quantitative and three qualitative articles were included. Two quantitative and one qualitative article were rated high quality, seven moderate and the remaining were low quality. No studies examining inequalities by Indigenous status were identified. Non-metropolitan women were more likely to record lower QOL relating to breast cancer-specific concerns and reported a lack of information and resources specific to their needs. Continuity of support, ongoing care and access to specialist and allied health professionals were major concerns for non-metropolitan women. Non-metropolitan women identified unmet needs in relation to travel, fear of cancer recurrence and lack of psychosocial support.

Conclusions

Overall, there was a lack of evidence relating to variations in psychosocial outcomes for women with BC according to residential status or Indigenous status. While the review identified some specific concerns for non-metropolitan women with BC, it was limited by the lack of good quality studies using standardised measures. Copyright © 2016 John Wiley & Sons, Ltd.

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Grief symptoms and difficult patient loss for oncologists in response to patient death

Abstract

Objective

The study aimed to explore oncologist's grief symptoms over patient death and to identify why and which losses are particularly challenging when patients die.

Methods

The grounded theory method was used to collect and analyze the data. Twenty-two oncologists were interviewed between March 2013 and June 2014 from three adult oncology centers in the north, center, and south of Israel. Oncologists were at different stages of their careers and varied in their sub-specialties, gender, and personal and professional backgrounds.

Results

Grief begun when the patient died, in anticipation of the patient's death, many days after the death, or when the patient received a poor prognosis. The phenomenological experience of grief for oncologists included behavioral, cognitive, physical, and emotional symptoms in response to patient death. Behavioral symptoms included crying and difficulties sleeping. Cognitive symptoms included self-doubt and rumination about the patient and the care the patient had received before death. Physical symptoms included chest pain, fatigue, and general physical discomfort. Emotional symptoms included sadness, anxiety, helplessness, guilt, relief, irritability, and loss. Difficult patient loss was caused by patient-related factors, family-related factors, and disease-related factors.

Conclusions

Patient deaths result in behavioral, cognitive, physical, and emotional symptoms of grief in oncologists. These symptoms become particularly intense in the context of patient, family, and disease-related factors. Educational and supportive interventions for managing grief related to patient death are needed in order to support oncologists in their emotionally and mentally taxing work. Copyright © 2016 John Wiley & Sons, Ltd.

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Concurrent sorafenib therapy extends the interval to subsequent TACE for patients with unresectable hepatocellular carcinoma

Background and Objectives

To compare the impact of concurrent TACE + sorafenib versus TACE alone on overall survival (OS) and time to progression (TTP) in patients with unresectable hepatocellular carcinoma (uHCC). A secondary goal was to determine if sorafenib use increases the interval between courses of TACE.

Methods

This study enrolled 150 patients with uHCC from June 2011 to June 2014, including 50 treated with TACE + sorafenib and 100 treated with TACE alone. Factors associated with OS and TTP were identified by univariate and multivariate Cox-regression model analyses. Average TACE interval was defined as TTP/TACE frequency.

Results

The median OS (21.7 vs. 11.5 months) and TTP (10.2 vs. 6.7 months) were longer in the TACE + sorafenib group compared to the TACE group. Patients receiving combination therapy had higher survival rate (P < 0.032) and longer average interval to TACE (P < 0.001), but lower progression rate (P < 0.001). TACE + sorafenib therapy was associated with improved OS (P ≤ 0.009) and TTP (P ≤ 0.021). The majority of AEs identified in patients receiving the combination therapy were classified as Grades 1 and 2, and skin-related reactions and fatigue were the most common.

Conclusion

Concurrent sorafenib with TACE provides survival benefits over TACE monotherapy, which may be related to a prolonged interval between subsequent TACE courses. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Issue Information – Table of Contents

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Issue Information – UICC

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Issue Information – Information for Authors

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68Ga-DOTATATE PET in juvenile angiofibroma

Future Oncology Ahead of Print.


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68Ga-DOTATATE PET in juvenile angiofibroma

Future Oncology Ahead of Print.


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Trends in surgery and outcomes of squamous cell vulvar cancer patients over a 16-year period (1998–2013): a population-based analysis

Abstract

Purpose

The objective was to identify trends in surgery and the outcomes of squamous cell vulvar cancer in a population-based setting.

Methods

A total of 1113 patients with squamous cell vulvar cancer diagnosed between 1998 and 2013 in the catchment area of the Munich Cancer Registry (population approximately 4.6 million) were analysed. Trends in prognostic factors and treatment were examined by comparing patients diagnosed between 1998 and 2008 with those diagnosed between 2009 and 2013. Cumulative incidence was used to calculate time to local (LR) and lymph node recurrence (LNR). Survival was analysed by the Kaplan–Meier method, calculation of relative survival (RS), and a Cox model.

Results

The high median age at diagnosis of 75 years did not change significantly over time. In addition, no changes in the subsite of tumour or grading were noted. A decrease in patients undergoing complete vulvectomy from 27.7 to 17.8 % (p < 0.001) as well as an increase in the use of sentinel lymph node biopsy from 11.4 to 39.1 % (p < 0.001) was observed. However, time to LR (from 19 to 19 %) and time to LNR (from 9 to 9 %) as well as 5-year overall survival (from 55 to 55 %) and RS (from 66 to 63 %) were not significantly altered. After adjustment for prognostic factors, less radical locoregional surgery had no influence on survival.

Conclusion

Less radical locoregional surgery in vulvar cancer is increasingly implemented. Locoregional recurrence and survival have not been affected by these changes and are likely accompanied by an improvement in quality of life.

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Mass balance, pharmacokinetics, and metabolism of linsitinib in cancer patients

Abstract

Purpose

This study characterized the pharmacokinetics, mass balance, routes and extent of elimination, metabolites, and safety of a single oral dose of ¹⁴C-linsitinib, an IGF-1R/IR inhibitor, in patients with advanced solid tumors. The tolerability of linsitinib after multiple-dose administration was assessed in those patients who wished to continue treatment beyond the single ¹⁴C-linsitinib dose.

Methods

Five patients received a single oral dose of 150 mg ¹⁴C-linsitinib, followed by collection of blood, plasma, urine, and feces for 10 days. The collected material was analyzed for total radioactivity, linsitinib, and metabolites. The safety of 150 mg of unlabeled linsitinib administered twice daily until disease progression was also assessed.

Results

The median time to reach the maximum plasma concentration of linsitinib was 3.0 h, median maximum plasma concentration was 1789 ng/mL, median terminal half-life was 2.4 h, and median apparent oral clearance was 12.45 L/h. After a single dose of ¹⁴C-linsitinib, 5.44 and 76.4 % of mean total radioactivity administered were recovered in urine and feces, respectively. Eighteen linsitinib metabolites (M1–M18) were detected in plasma, urine, and feces samples, and their structures were elucidated. The main metabolic reactions of linsitinib in humans were oxidation and sulfate conjugation. Linsitinib was well tolerated after a single dose of ¹⁴C-linsitinib, and fatigue was the most frequent adverse event following multiple doses of unlabeled linsitinib.

Conclusions

¹⁴C-linsitinib is rapidly absorbed and extensively metabolized. Linsitinib excretion via bile into feces is the predominant elimination route from plasma with minor renal elimination.

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Cancers, Vol. 8, Pages 35: Mechanisms of Nuclear Export in Cancer and Resistance to Chemotherapy

Tumour suppressor proteins, such as p53, BRCA1, and ABC, play key roles in preventing the development of a malignant phenotype, but those that function as transcriptional regulators need to enter the nucleus in order to function. The export of proteins between the nucleus and cytoplasm is complex. It occurs through nuclear pores and exported proteins need a nuclear export signal (NES) to bind to nuclear exportin proteins, including CRM1 (Chromosomal Region Maintenance protein 1), and the energy for this process is provided by the RanGTP/RanGDP gradient. Due to the loss of DNA repair and cell cycle checkpoints, drug resistance is a major problem in cancer treatment, and often an initially successful treatment will fail due to the development of resistance. An important mechanism underlying resistance is nuclear export, and a number of strategies that can prevent nuclear export may reverse resistance. Examples include inhibitors of CRM1, antibodies to the nuclear export signal, and alteration of nuclear pore structure. Each of these are considered in this review.

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