miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma, and their effects can be efficiently counteracted by a class of tumor suppressor miRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDAC) in multiple myeloma, we investigated whether their activity could be antagonized by miR-29b, a well-established epi-miRNA. We demonstrated here that miR-29b specifically targets HDAC4 and highlighted that both molecules are involved in a functional loop. In fact, silencing of HDAC4 by shRNAs inhibited multiple myeloma cell survival and migration and triggered apoptosis and autophagy, along with the induction of miR-29b expression by promoter hyperacetylation, leading to the downregulation of prosurvival miR-29b targets (SP1, MCL-1). Moreover, treatment with the pan-HDAC inhibitor SAHA upregulated miR-29b, overcoming the negative control exerted by HDAC4. Importantly, overexpression or inhibition of miR-29b, respectively, potentiated or antagonized SAHA activity on multiple myeloma cells, as also shown in vivo by a strong synergism between miR-29b synthetic mimics and SAHA in a murine xenograft model of human multiple myeloma. Altogether, our results shed light on a novel epigenetic circuitry regulating multiple myeloma cell growth and survival and open new avenues for miR-29b–based epi-therapeutic approaches in the treatment of this malignancy. Mol Cancer Ther; 15(6); 1–12. ©2016 AACR.

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Reversal of MDR by osimertinib

The overexpression of ATP-binding cassette (ABC) transporters has been proved to be a major trigger for multidrug resistance (MDR) in certain types of cancer. In our study, we investigated whether osimertinib (AZD9291), a third generation irreversible tyrosine kinase inhibitor of both activating EGFR mutations and resistance-associated T790M point mutation, could reverse MDR induced by ABCB1 and ABCG2 in vitro, in vivo and ex vivo. Our results showed that osimertinib significantly increased the sensitivity of ABCB1- and ABCG2-overexpressing cells to their substrate chemotherapeutic agents in vitro and in the model of ABCB1-overexpressing KBv200 cell xenograft in nude mice. Mechanistically, osimertinib increased the intracellular accumulations of doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1 or ABCG2 overexpressing cells but not in their parental sensitive cells. Furthermore, osimertinib stimulated the ATPase activity of both ABCB1 and ABCG2 and competed with the [125I] Iodoarylazidoprazosin (IAAP) photolabelling bound to ABCB1 or ABCG2 but did not alter the localization and expression of ABCB1 or ABCG2 in mRNA and protein levels nor the phospharylations of EGFR, AKT and ERK. Importantly, osimertinib also enhanced the cytotoxicity of doxorubicin (DOX) and intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukaemia cells. Overall, these findings suggest osimertinib reverses ABCB1- and ABCG2-mediated MDR via inhibiting ABCB1 and ABCG2 from pumping out chemotherapeutic agents and provide possibility for cancer combinational therapy with osimertinib in the clinic.

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Emodin blocks cancer cell-macrophage interaction

Macrophage infiltration correlates with severity in many types of cancer. Tumor cells recruit macrophages and educate them to adopt an M2-like phenotype through the secretion of chemokines and growth factors, such as MCP1 and CSF1. Macrophages in turn promote tumor growth through supporting angiogenesis, suppressing anti-tumor immunity, modulating extracellular matrix remodeling, and promoting tumor cell migration. Thus tumor cells and macrophages interact to create a feedforward loop supporting tumor growth and metastasis. In this study, we tested the ability of emodin, a Chinese herb-derived compound, to inhibit breast cancer growth in mice and examined the underlying mechanisms. Emodin was used to treat mice bearing EO771 or 4T1 breast tumors. It was shown that emodin attenuated tumor growth by inhibiting macrophage infiltration and M2-like polarization, accompanied by increased T cell activation and reduced angiogenesis in tumors. The tumor inhibitory effects of emodin were lost in tumor-bearing mice with macrophage depletion. Emodin inhibited IRF4, STAT6, and C/EBPβ signaling and increased inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on the promoters of M2 related genes in tumor-associated macrophages. In addition, emodin inhibited tumor cell secretion of MCP1and CSF1, as well as expression of surface anchoring molecule Thy-1, thus suppressing macrophage migration towards and adhesion to tumor cells. These results suggest that emodin acts on both breast cancer cells and macrophages and effectively blocks the tumor-promoting feedforward loop between the two cell types, thereby inhibiting breast cancer growth and metastasis.

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Low MSLN shedding enhances efficacy of anticancer agents

Mesothelin (MSLN) is a differentiation antigen that is highly expressed in many epithelial cancers. MSLN is an important therapeutic target due to its high expression in cancers and limited expression in normal human tissues. Although it has been assumed that shed antigen is a barrier to immunotoxin action, a modeling study predicted that shed MSLN may enhance the action of MSLN targeting recombinant immunotoxins such as SS1P and similar therapeutics by facilitating their redistribution within tumors. We aimed to determine if shed MSLN enhances or reduces the anti-tumor effect of MSLN targeting immunotoxins SS1P and RG7787. We engineered a cell line, A431/G9 (TACE mutant) that expresses a mutant form of MSLN in which the tumor necrosis factor converting enzyme protease site is replaced with GGGS. We compared the response of the TACE mutant cells to immunotoxins SS1P and RG7787 with that of the parental A431/H9 cell line. We show that TACE mutant cells shed 80% less MSLN than A431/H9 cells, that TACE mutant cells show a 2-3-fold increase in MSLN targeted immunotoxin uptake, and that they are about 5-fold more sensitive to SS1P killing in cell culture. Tumors with reduced shedding respond significantly better to treatment with SS1P and RG7787. Our data show that MSLN shedding is an impediment to the anti-tumor activity of SS1P and RG7787. Approaches that decrease MSLN shedding could enhance the efficacy of immunotoxins and immuno-conjugates targeting MSLN-expressing tumors.

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Interfering lncRNA consumes OncomiRs to inhibit HCC

The endogenous microRNAs (miRNAs), especially the oncogenic miRNAs (OncomiRs), have been molecular targets for cancer therapy. We generated an artificially-designed interfering long non-coding RNA (lncRNAi), which contains the sequences that can complementarily bind to multiple OncomiRs and is expressed by cancer-selectively replicating adenovirus. The adenovirus-expressed lncRNAi with high level in hepatocellular carcinoma (HCC) cells competes with OncomiR target genes to bind to and consume OncomiRs, thereby achieving the targeted anti-HCC efficacy. With the targeting replication of adenovirus in HCC cells, lncRNAi was highly expressed and resulted in decreased abilities of proliferation, migration and invasion, induced cell cycle changes and apoptosis, and markedly changed the cellular mRNA and miRNA expression profiles in HCC cells. The effective antitumor effect was also demonstrated on HCC cell line xenograft models and HCC patient-derived xenograft (PDX) tumor models in nude mice. This strategy has established a technology platform with a reliable therapeutic effect for HCC therapy.

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Unblocking the cancer drug development bottleneck via innovative partnering

Future Oncology Ahead of Print.


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Sonidegib for the treatment of advanced basal cell carcinoma: a comprehensive review of sonidegib and the BOLT trial with 12-month update

Future Oncology Ahead of Print.


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Reply to "Safety profile of capecitabine as maintenance treatment after XELOX or FOLFOX in metastatic colorectal cancer patients" by C. Cremolini et al.

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A prognostic regulatory pathway in stage I Epithelial Ovarian Cancer: new hints for the poor prognosis assessment

Currently, the therapies in stage I EOC are assigned following the clinical and histopathological risk factors. Although helpful, their sensitivity and specificity in the risk definition are completely unsatisfactory. We propose a prognostic pathway of 26 miRNAs and genes. The expressions of these elements can be used to define a patient-specific index able to improve the risk prediction at the time of diagnosis.

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Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests one third of mutations are somatic

We performed targeted sequencing of BRCA1/2 in an unselected cohort of patients diagnosed with primary breast cancer within a population without strong founder mutations. 11% of cases harbored a germline or somatic BRCA1/2 mutation, and the ratio of germline versus somatic mutation was 2:1. This has implications for treatment, genetic counseling, and interpretation of tumor-only testing.

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Percutaneous Radiofrequency Ablation of Unresectable Locally Advanced Pancreatic Cancer: Preliminary Results

Aim:

The objective of this study was to evaluate the efficacy of percutaneous radiofrequency ablation of locally advanced pancreatic cancer located in the pancreatic body.

Materials and Methods:

Patients with biopsy-proven locally advanced pancreatic adenocarcinoma were considered for percutaneous radiofrequency ablation. Postprocedural computed tomography studies and Ca19.9 tumor marker evaluation were performed at 24 hours and 1 month. At computed tomography, treatment effect was evaluated by excluding the presence of complications. The technical success of the procedure is defined at computed tomography as the achievement of tumoral ablated area.

Results:

Twenty-three patients have been included in the study. Five of the 23 patients were excluded. At computed tomography, the mean size of the intralesional postablation necrotic area was 32 mm (range: 15-65 mm). Technical success of the procedure has been obtained in 16 (93%) of the 18 cases. None of the patients developed postprocedural complications. Mean Ca19.9 serum levels 1 day before, 1 day after, and 1 month after the procedure were 285.8 U/mL (range: 16.6-942.0 U/mL), 635.2 U/mL (range: 17.9-3368.0 U/mL), and 336.0 U/mL (range: 7.0-1400.0 U/mL), respectively. Follow-up duration was less than 6 months for 11 patients and more than 6 months for 7 patients. At the time of the draft of this article, the mean survival of the patients included in the study was 185 days (range: 62-398 days).

Conclusion:

Percutaneous radiofrequency ablation of locally advanced adenocarcinoma has a high technical success rate and is effective in cytoreduction both at imaging and laboratory controls.

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Evaluating Markers for Guiding Treatment

Background: The subpopulation treatment effect pattern plot (STEPP) is an appealing method for assessing the clinical impact of a predictive marker on patient outcomes and identifying a promising subgroup for further study. However, its original formulation lacked a decision analytic justification and applied only to a single marker.

Methods: We derive a decision-analytic result that motivates STEPP. We discuss the incorporation of multiple predictive markers into STEPP using risk difference, cadit, and responders-only benefit functions.

Results: Applying STEPP to data from a breast cancer treatment trial with multiple markers, we found that none of the three benefit functions identified a promising subgroup for further study. Applying STEPP to hypothetical data from a trial with 100 markers, we found that all three benefit functions identified promising subgroups as evidenced by the large statistically significant treatment effect in these subgroups.

Conclusions: Because the method has desirable decision-analytic properties and yields an informative plot, it is worth applying to randomized trials on the chance there is a large treatment effect in a subgroup determined by the predictive markers.

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Endogenous Estrogens, Estrogen Metabolites, and Breast Cancer Risk in Postmenopausal Chinese Women

Background: The role of estrogen metabolism in determining breast cancer risk and differences in breast cancer rates between high-incidence and low-incidence nations is poorly understood.

Methods: We measured urinary concentrations of estradiol and estrone (parent estrogens) and 13 estrogen metabolites formed by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring in a nested case-control study of 399 postmenopausal invasive breast cancer case participants and 399 matched control participants from the population-based Shanghai Women's Health Study cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer by quartiles of metabolic pathway groups, pathway ratios, and individual estrogens/estrogen metabolites were estimated by multivariable conditional logistic regression. Urinary estrogen/estrogen metabolite measures were compared with those of postmenopausal non-hormone-using Asian Americans, a population with three-fold higher breast cancer incidence rates. All statistical tests were two-sided.

Results: Urinary concentrations of parent estrogens were strongly associated with breast cancer risk (OR_Q4vsQ1 = 1.94, 95% CI = 1.21 to 3.12, P_trend = .01). Of the pathway ratios, the 2-pathway:total estrogens/estrogen metabolites and 2-pathway:parent estrogens were inversely associated with risk (OR_Q4vsQ1 = 0.57, 95% CI = 0.35 to 0.91, P_trend = .03, and OR_Q4vsQ1 = 0.61, 95% CI = 0.37 to 0.99, P_trend = .04, respectively). After adjusting for parent estrogens, these associations remained clearly inverse but lost statistical significance (OR_Q4vsQ1 = 0.65, 95% CI = 0.39 to 1.06, P_trend = .12 and OR_Q4vsQ1 = 0.76, 95% CI = 0.44 to 1.32, P_trend = .28). The urinary concentration of all estrogens/estrogen metabolites combined in Asian American women was triple that in Shanghai women.

Conclusions: Lower urinary parent estrogen concentrations and more extensive 2-hydroxylation were each associated with reduced postmenopausal breast cancer risk in a low-risk nation. Markedly higher total estrogen/estrogen metabolite concentrations in postmenopausal United States women (Asian Americans) than in Shanghai women may partly explain higher breast cancer rates in the United States.

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RE: Serum Lipids, Lipoproteins, and Risk of Breast Cancer: A Nested Case-Control Study Using Multiple Time Points

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Unblocking the cancer drug development bottleneck via innovative partnering

Future Oncology Ahead of Print.


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Sonidegib for the treatment of advanced basal cell carcinoma: a comprehensive review of sonidegib and the BOLT trial with 12-month update

Future Oncology Ahead of Print.


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Checkpoint Inhibitors and Other Immune Therapies for Hodgkin and Non-Hodgkin Lymphoma

Opinion statement

Treatment for relapsed/refractory (R/R) Hodgkin and non-Hodgkin lymphoma remains challenging. The introduction of rituximab to B cell non-Hodgkin lymphoma (B-NHL) treatment significantly improved patients' response rate and survival; however, approximately one third of patients with diffuse large B cell lymphoma, the most common B-NHL subtype, still have a relapse or become refractory after first-line therapy. More recently, antibody therapies and small-molecule inhibitors were approved for treating R/R lymphomas; these agents include brentuximab vedotin, ibrutinib, and idelalisib. Immune checkpoint inhibitors and other immune therapies are emerging treatments currently being evaluated in various clinical trials for their efficacy against lymphoid malignancies. Striking results from these treatment modalities have been observed in solid tumors, and evidence is accumulating to support their use in various lymphomas. The most exciting results from immune checkpoint inhibitor therapy have been seen in patients with R/R Hodgkin lymphoma, in whom the overall response rate has reached 60–80 %. Results in NHL are more similar to those seen in other solid malignancies, ranging between 20 and 40 %, depending on the histology. Formal approval of these drugs is being awaited, as are the results of combination therapy with checkpoint inhibitors and other treatment modalities, including conventional chemotherapy, small-molecule inhibitors, and other immune therapies. Although response rates have been promising, attention must be paid to the management of unique immune-related adverse events, which warrant close monitoring in some cases. Identification of biomarkers that predict response or severe adverse events using either the tumor specimen or peripheral blood would aid in selecting patients suited for these types of treatment as well as determining the ideal sequence of treatment within the realm of immune therapies.

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Checkpoint Inhibitors and Other Immune Therapies for Hodgkin and Non-Hodgkin Lymphoma

Opinion statement

Treatment for relapsed/refractory (R/R) Hodgkin and non-Hodgkin lymphoma remains challenging. The introduction of rituximab to B cell non-Hodgkin lymphoma (B-NHL) treatment significantly improved patients' response rate and survival; however, approximately one third of patients with diffuse large B cell lymphoma, the most common B-NHL subtype, still have a relapse or become refractory after first-line therapy. More recently, antibody therapies and small-molecule inhibitors were approved for treating R/R lymphomas; these agents include brentuximab vedotin, ibrutinib, and idelalisib. Immune checkpoint inhibitors and other immune therapies are emerging treatments currently being evaluated in various clinical trials for their efficacy against lymphoid malignancies. Striking results from these treatment modalities have been observed in solid tumors, and evidence is accumulating to support their use in various lymphomas. The most exciting results from immune checkpoint inhibitor therapy have been seen in patients with R/R Hodgkin lymphoma, in whom the overall response rate has reached 60–80 %. Results in NHL are more similar to those seen in other solid malignancies, ranging between 20 and 40 %, depending on the histology. Formal approval of these drugs is being awaited, as are the results of combination therapy with checkpoint inhibitors and other treatment modalities, including conventional chemotherapy, small-molecule inhibitors, and other immune therapies. Although response rates have been promising, attention must be paid to the management of unique immune-related adverse events, which warrant close monitoring in some cases. Identification of biomarkers that predict response or severe adverse events using either the tumor specimen or peripheral blood would aid in selecting patients suited for these types of treatment as well as determining the ideal sequence of treatment within the realm of immune therapies.

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Improving Cancer Control in Rural Communities: An Interview with Dr. Robert Croyle

Researchers from several NCI-Designated Cancer Centers and NCI Community Oncology Research Program (NCORP) sites that serve rural parts of the United States recently met with NCI leaders to discuss the disparities in cancer outcomes in many rural areas of the country. The meeting was part of NCI's efforts to prioritize its research activities to improve cancer control in rural areas.

In this interview, Robert Croyle, Ph.D., director of NCI's Division of Cancer Control and Population Sciences, discusses some of the issues faced by rural communities and how NCI is approaching this important problem.

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Randomized-controlled trial of mindfulness-based cancer recovery versus supportive expressive group therapy among distressed breast cancer survivors (MINDSET): long-term follow-up results

Abstract

Background

Mindfulness-based cancer recovery (MBCR) and supportive expressive group therapy (SET) are two well-validated psychosocial interventions, but they have not been directly compared, and little is known about long-term outcomes. This comparative effectiveness study measured the effects of these two interventions immediately following the groups and for 1 year thereafter in distressed breast cancer survivors.

Methods

Two hundred fifty-two distressed Stage I–III breast cancer survivors were randomized into either MBCR or SET. Women completed questionnaires addressing mood, stress symptoms, quality of life, social support, spirituality and post-traumatic growth before and after the interventions, and 6 and 12 months later.

Results

Immediately following the intervention, women in MBCR reported greater reduction in mood disturbance (primarily fatigue, anxiety and confusion) and stress symptoms including tension, sympathetic arousal and cognitive symptoms than those in SET. They also reported increased emotional and functional quality of life, emotional, affective and positive social support, spirituality (feelings of peace and meaning in life) and post-traumatic growth (appreciation for life and ability to see new possibilities) relative to those in SET, who also improved to a lesser degree on many outcomes. Effect sizes of the time × group interactions were small to medium, and most benefits were maintained over 12 months of follow-up.

Conclusions

This study is the first and largest to demonstrate sustained benefits of MBCR in distressed breast cancer survivors relative to an active control. MBCR was superior to SET for improving psychological well-being with lasting benefits over 1 year, suggesting these women gained long-lasting and efficacious tools to cope with cancer.

Trial Registration

Registered on clinicaltrials.gov number NCT00390169, October 2006. Copyright © 2016 John Wiley & Sons, Ltd.

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Overexpression of CTNND1 in hepatocellular carcinoma promotes carcinous characters through activation of Wnt/β-catenin signaling

Abstract

Background

Increasing evidence supports the association of CTNND1 with tumor development and progression. However, the mechanism and clinical significance of CTNND1 deregulation in hepatocellular carcinoma (HCC) remains unknown. In this study, we aim to investigate the role of CTNND1 in HCC.

Methods

qRT-PCR and immunohistochemical analyses were used to measure the levels of CTNND1 in HCC specimens and HCC cell lines. CTNND1 and shCTNND1 were transfected into HCC cell lines to investigate its role in HCC. Cell migration and invasion were measured by Transwell and Matrigel analyses in vitro. In vivo metastasis assays were performed in SCID mice.

Results

In clinical HCC samples, we found that CTNND1 expression was significantly up-regulated in cancer lesions compared with paired normal liver tissues. By silencing or overexpressing CTNND1 in HCC cells, we found that CTNND1 could promote cell proliferation, migration, and invasion in vitro. An in-vivo assay showed that CTNND1 dramatically promoted HCC cell tumor formation and metastasis. Moreover, CTNND1 promoted HCC metastasis, at least in part, by indirectly enhancing Wnt/β-catenin signaling. Consistent with these results, the expression of CTNND1 was positively correlated with β-catenin, WNT11, Cyclin D1, and BMP7 expression in human HCC specimens.

Conclusions

Our study provides evidence that CTNND1 functions as a novel tumor oncogene in HCC, and may be a potential therapeutic target for HCC management.

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Diagnostic efficacy of abattoir meat inspection for detecting bovine tuberculosis at Adama municipal abattoir, Ethiopia

Abstract

Bovine tuberculosis (BTB) is endemic in Ethiopia and like other developing countries in Africa. Ethiopia has limited laboratory and other diagnostic facilities. Therefore, abattoir inspection still remains the only option for monitoring BTB prevalence in domestic animals. However, information regarding the efficacy of such routine abattoir (RA) inspection is limited. The present study was conducted on 500 slaughtered cattle heads, slaughtered at the Adama municipal abattoir, Ethiopia from December 2009 to April 2010 to elucidate the efficacy of RA inspection with respect to the detailed abattoir (DA) inspection, bacteriological isolation, and PCR. Diagnostic accuracy of the RA inspection was determined by calculating sensitivity and specificity. The agreement between both the inspection protocols was determined by using kappa statistics. Results showed that there was a moderate agreement between the two inspection protocols (kappa = 0.43) conducted at Adama municipal abattoir, Ethiopia. The sensitivity and specificity of RA were 57.14 [CI 28.92–82.24] and 71.79 % [CI 55.12–84.98] when isolation was considered as reference test and 33.33 [CI 5.33–77.32] and 75.00 % [CI 35.05–96.07] when PCR was considered as reference test. However, DA inspection showed higher sensitivity, when isolation {82.35 % (14/17) [95 % CI 56.55–95.99]} and PCR {75 % (6/8) [95 % CI 35.05–96.07]} were considered as reference tests. The RA inspection failed to detect 69.81 %TB-infected carcasses which increased the chances of BTB-infected carcasses being released into the food chain. Based on our study, it is recommended that integrated preventive approaches involving enhanced surveillance of the disease through establishment of standardized abattoirs well-equipped with laboratory facilities. Also, adequate training to meat inspectors is essential to prevent the spread of the disease.

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The Syrian refugees crisis brings challenges to the health authorities in Europe: hepatitis A virus is a case in point

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Is radioiodine administration in patients with papillary thyroid multifocal microcarcinoma unnecessary?

Summary

Radioiodine (RAI) has played a crucial role in differentiated thyroid cancer treatment for more than 60years. However, the use of RAI administration in patients with papillary thyroid microcarcinoma (even multifocal) is now being widely discussed and often not recommended. In accordance with European consensus, and contrary to the American Thyroid Association (ATA) guidelines, we recently performed RAI thyroid remnant ablation in a patient with differentiated papillary multifocal microcarcinoma. The post-therapeutic whole-body scan and SPECT/CT revealed the real and unexpected extent of disease, with metastases to upper mediastinal lymph nodes. This finding led to the patient's upstaging from stage I to stage IVa according to the American Joint Committee on Cancer/International Union Against Cancer criteria.

Learning points

¹³¹I is a combined beta–gamma emitter, thus allowing not only residual thyroid tissue ablation but also metastatic tissue imaging.

RAI remnant ablation omission also means post-treatment whole-body scan omission, which may lead to disease underestimation, due to incorrect nodal and metastatic staging.

RAI should be considered also in "low-risk" patients, especially when the lymph node involvement is not reliably documented.

Lower administered RAI activity (30mCi, 1.1GBq) may be a workable compromise in low-risk patients, not indicated for RAI remnant ablation according to ATA guidelines.

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Cost-effectiveness of sorafenib versus SBRT for unresectable advanced hepatocellular carcinoma

Abstract

Objective

Stereotactic body radiotherapy (SBRT) has been shown to improve overall survival in patients with advanced hepatocellular carcinoma. This study aimed to assess the cost-effectiveness of SBRT compared to sorafenib which is the only drug for advanced hepatocellular carcinoma.

Methods

A Markov decision-analytic model was performed to compare the cost-effectiveness of SBRT and sorafenib for unresectable advanced hepatocellular carcinoma. Patients transitioned between three health states: stable disease, progression disease and death. We calculated the data on cost from the perspective of our National Health Insurance Bureau. Sensitivity analyses were conducted to determine the impact of several variables.

Results

The incremental cost effectiveness ratio (ICER) for sorafenib compared to SBRT was NT$3,788,238 per quality-adjusted life year gained (cost/QALY), which was higher than the willingness to pay threshold of Taiwan according to WHO's guideline. One-way sensitivity analysis revealed that the utility of progression disease for the sorafenib treatment, utility of progression free survival for SBRT, utility of progression free survival for sorafenib, utility of PFS to progression disease for SBRT and transition probability of progression disease to dead for SBRT were the most sensitive parameters in all cost scenarios. The Monte-Carlo simulation demonstrated that the probability of cost-effectiveness at a willingness to pay threshold of NT$ 2,213,145 per QALY was 100 % and 0 % chance for SBRT and sorafenib.

Conclusion

This study indicated that SBRT for advanced hepatocellular carcinoma is cost-effective at a willingness to pay threshold as defined by WHO guideline in Taiwan.

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Erratum.

Related Articles

Erratum.

Cancer Biol Ther. 2016 May 3;17(5):577

Authors:

PMID: 27184038 [PubMed - in process]

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Erratum.

Related Articles

Erratum.

Cancer Biol Ther. 2016 May 3;17(5):577

Authors:

PMID: 27184038 [PubMed - in process]

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Prognostic factors in recurrent glioblastoma patients treated with bevacizumab

Abstract

The value of bevacizumab (BEV) in recurrent glioblastoma is unclear. Imaging parameters and progression-free survival (PFS) are problematic endpoints. Few data exist on clinical factors influencing overall survival (OS) in unselected patients with recurrent glioblastoma exposed to BEV. We retrospectively analyzed 174 patients with recurrent glioblastoma treated with BEV at two German brain tumor centers. We evaluated general patient characteristics, MGMT status, pretreatment, concomitant oncologic treatment and overall survival. Karnofsky performance score, number of prior chemotherapies, number of prior recurrences and combined treatment with irinotecan (IRI) were significantly associated with OS in univariate analysis. We did not find differences in OS related to sex, age, histology, MGMT status, prior surgical treatment or number of prior radiotherapies. Combined treatment with IRI and higher KPS both remained significantly associated with prolonged survival in multivariate analysis, but patients receiving IRI co-treatment had less advanced disease. Grouping into clinically relevant categories revealed an OS of 16.9 months from start of BEV in patients with first recurrence and KPS ≥ 80 % (n = 25). In contrast, in patients with second recurrence and KPS < 80 %, OS was 3.6 months (n = 27). Our observational data support an early use of BEV in patients with good performance status. The benefit of co-treatment with IRI in our cohort seems to be the result of biased patient recruitment.

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Transforming growth factor-β and stem cell markers are highly expressed around necrotic areas in glioblastoma

Abstract

Invasion into surrounding normal brain and resistance to genotoxic therapies are the main devastating aspects of glioblastoma (GBM). These biological features may be associated with the stem cell phenotype, which can be induced through a dedifferentiation process known as epithelial-mesenchymal transition (EMT). We show here that tumor cells around pseudopalisading necrotic areas in human GBM tissues highly express the most important EMT inducer, transforming growth factor (TGF-β), concurrently with the EMT-related transcriptional factor, TWIST. In addition, the stem cell markers CD133 and alkaline phosphatase (ALPL) were also highly expressed around necrotic foci in GBM tissues. The high expression of TGF-β around necrotic regions was significantly correlated with shorter progression-free survival and overall survival in patients with GBM. High expression of stem cell markers, ALPL, CD133, and CD44 was also correlated with poor outcomes. These results collectively support the hypothesis that tissue hypoxia induces the stem cell phenotype through TGF-β-related EMT and contributes to the poor outcome of GBM patients.

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[The surrogate: Partner in the shared decision-making].

Related Articles

[The surrogate: Partner in the shared decision-making].

Bull Cancer. 2016 May 12;

Authors: Sarradon-Eck A, Capodano G, Bureau E, Julian-Reynier C

Abstract
The legislative process of the surrogate appears to be unclear to health professionals and to patients and next of kin. To better adapt this process to the clinical practice our objective was here to document how the persons designated as surrogate perceived their role and how they described the difficulties encountered in oncology.
METHODS: Qualitative survey with an ethnographic approach carried out in 2014-2015, fieldwork, face-to-face interviews (n=26 including 20 surrogates and 6 patients) in a mobile palliative care unit located at a Regional Comprehensive Cancer Centre.
RESULTS: Close relationship, psychological and cognitive competences were the main attribute to designate a surrogate. Perceived roles included the fact to be involved in decisions, to protect the patient, to be present, and to be a messenger. This process gives the next of kin the feeling to be part of the patient management. In the context of divorced families, it sometimes allows to rehabilitate and to reinforce the affective links. Our data highlight the confusion between the designation of the 'person to call' and 'the surrogate'.
DISCUSSION: Our results highlight the 'surrogate' protective role of the patient, and the positive sides of the process, in particular in the context of divorced/rebuilt families. We recommend splitting the process to designate the 'person to call' and the 'surrogate', as administrative and medical duties, respectively.

PMID: 27181760 [PubMed - as supplied by publisher]

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[Prognosis prediction of febrile neutropenia by MASCC score: A retrospective study].

Related Articles

[Prognosis prediction of febrile neutropenia by MASCC score: A retrospective study].

Bull Cancer. 2016 May 12;

Authors: Cervetti L, Vallard A, Le Moulec S, Espenel S, Falk AT, Ben Mrad M, Guy JB, Diao P, Méry B, Langrand-Escure J, Ferrand FR, Rivoirard R, Ceccaldi B, Védrine L, Magné N, Chargari C

Abstract
INTRODUCTION: The score of the MASCC, by means of clinical criteria, estimates the risk of serious complications in patients with neutropenic fever induced by chemotherapy.
METHODS: We retrospectively studied a cohort of patients hospitalized for a neutropenic fever and analyzed complications according to the criteria defined by the MASCC.
RESULTS: Eighty-one neutropenic fevers in 71 patients were identified. Microbiological documentation was obtained in 33% of cases only. Fifty-eight patients (72%) presented with a MASCC score≥21 and were considered as low risk of complications. In the total population, 10 patients died during their hospitalizations for neutropenic fever, 7 in the high-risk group versus 3 in the low risk group, including 2 patients suffering from significant comorbidities not taken into account by MASCC score. Within the low risk group, presence of a metastatic disease and existence of 2 or more comorbidities were associated with a longer duration of hospitalization.
CONCLUSION: This analysis suggests that the criteria of the MASCC are not always enough to thoroughly identify which patients were at risk of complications or could be treated through outpatient management. By better taking into account the comorbidities and tumoral stage, a better selection of the patients who are likely to receive an ambulatory treatment could be made. To date, hospitalization remains frequently necessary in neutropenic fevers, at least in its initial steps, and the place of the general practitioner remains to be better defined.

PMID: 27181759 [PubMed - as supplied by publisher]

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American Journal of Cancer Research; +47 new citations

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American Journal of Cancer Research

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Erratum.

Related Articles

Erratum.

Cancer Biol Ther. 2016 May 3;17(5):577

Authors:

PMID: 27184038 [PubMed - in process]

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Microbial translocation and skeletal muscle in young and old vervet monkeys

Abstract

Intestinal barrier dysfunction leads to microbial translocation (MT) and inflammation in vertebrate and invertebrate animal models. Age is recently recognized as a factor leading to MT, and in some human and animal model studies, MT was associated with physical function. We evaluated sarcopenia, inflammation, MT biomarkers, and muscle insulin sensitivity in healthy female vervet monkeys (6–27 years old). Monkeys were fed consistent diets and had large and varied environments to facilitate physical activity, and stable social conditions. Aging led to sarcopenia as indicated by reduced walking speeds and muscle mass, but general metabolic health was similar in older monkeys (n = 25) as compared to younger ones (n = 26). When older monkeys were physically active, their MT burden approximated that in young monkeys; however, when older monkeys were sedentary, MT burden was dramatically increased. MT levels were positively associated with inflammatory burden and negatively associated with skeletal muscle insulin sensitivity. Time spent being active was positively associated with insulin sensitivity as expected, but this relationship was specifically modified by the individual monkey's MT, not inflammatory burden. Our data supports clinical observations that MT interacts with physical function as a factor in healthy aging.

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Clinical and pathologic features of patients with non-epithelial ovarian cancer: retrospective analysis of a single institution 15-year experience

Abstract

Purpose

Non-epithelial ovarian cancers (NEOCs) are rare diseases. Despite their overall good prognosis, the best management and current prognostic factors remain unclear. The objective of our study was to assess the clinical and pathological features of NEOC patients treated in our institution in the last 15 years and to explore risk factors for relapse and survival.

Methods/patients

All patients with a pathological diagnosis of NEOC referred to the medical oncology department at Hospital Universitario Virgen del Rocio between 1999 and 2014 were included. Demographics, tumor characteristics, treatment procedures, and clinical follow-up were retrospectively collected. Risk factors for disease-free survival (DFS) and overall survival (OS) were assessed.

Results

Fifty-seven patients were included, 33 (58 %) had a sex cord-stromal tumor (SCST) and 24 (42 %) had a germ-cell tumor (GCT). Median age, non-conservative surgery rates and DFS were lower in the GCT cohort; however, salvage chemotherapy led to a high proportion of complete responses in this group translating into a 90 % 3-year OS rate in both NEOC subtypes. The only identified risk factors statistically significant were stage and tumour relapse that associated, respectively, with DFS (HR = 8.84; 95 % CI 1.85–42) and OS (HR = 11.02; 95 % CI 1.76–68.7).

Conclusions

Despite their rarity, NEOCs remain a highly curable group of neoplasm. In our series, a more conservative treatment approach in ovarian GCTs revealed comparable OS outcomes to SCST. No new risk factors that would help in patient stratification were identified.

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Improved Minimal Residual Disease Detection by Targeted Quantitative Polymerase Chain Reaction in Nucleophosmin 1 Type A Mutated Acute Myeloid Leukemia

Abstract

Multicolor flow cytometry (MFC) and real-time quantitative PCR (RQ-PCR) are important independent techniques to determine minimal residual disease (MRD) in acute myeloid leukemia (AML). MFC is the standard method, but may be unreliable. Therefore, we set out to compare MFC-based determination of MRD with an RQ-PCR-based approach targeting the nucleophosmin 1 (NPM1) type A mutation. Since most current NPM1 RQ-PCR MRD protocols suffer from clear definitions of quantifiability, we sought to define quantifiability in a reproducible and standardized manner.

The limit of quantifiability of our RQ-PCR protocol for the NPM1 type A mutation varied between 0.002% and 0.04% residual leukemic cells depending on the features of the standard curve for each PCR experiment. The limit of detection was close to 0.001% leukemic cells. The limit of detection by MFC ranged from 0.01% to 1% depending on the phenotype of the leukemic cells as compared to non-leukemic bone marrow cells. We analyzed 45 MRD samples from 15 patients using both NPM1 mutation specific RQ-PCR and MFC. In 32 of the 45 samples (71%), an MRD-signal could be detected with RQ-PCR. A quantifiable NPM1 mutation signal was found in 15 samples (33%) (range 0.003% to 2.6% leukemic cells). By contrast, only two follow-up samples (4%) showed residual leukemic cells (0.04% and 0.3%, respectively) by MFC. Thus, RQ-PCR of the NPM1 type A mutation was more sensitive and reliable than MFC for determination of MRD, which might have clinical implications. This article is protected by copyright. All rights reserved.

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Identifying novel therapeutic agents using xenograft models of pediatric cancer

Abstract

In the USA, the overall cure rate for all childhood cancers is seventy percent, and in many patients that ultimately fail curative therapy, initial responses to current multimodality treatments (surgery, radiation therapy and chemotherapy) is good, with overall 5-year event-free survival approaching 80 %. However, current approaches to curative therapy result in significant morbidity and long-term sequelae, including cardiac dysfunction and cognitive impairment. Furthermore, dose-intensive chemotherapy with conventional agents has not significantly improved outcomes for patients that present with advanced or metastatic disease. Classical cytotoxic agents remain the backbone for curative therapy of both hematologic and solid tumors of childhood. While 'molecularly' targeted agents have shown some clinical activity, responses are often modest and of short duration; hence, there is a need to identify new classes of cytotoxic agent that are effective in patients at relapse and that have reduced or different toxicity profiles to normal tissues. Here we review the pediatric preclinical testing program experience of testing novel agents, and the value and limitations of preclinical xenograft models and genetically engineered mouse models for developing novel agents for treatment of childhood cancer.

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Associations between birth weight and colon and rectal cancer risk in adulthood

Publication date: June 2016
Source:Cancer Epidemiology, Volume 42
Author(s): Natalie R. Smith, Britt W. Jensen, Esther Zimmermann, Michael Gamborg, Thorkild I.A. Sørensen, Jennifer L. Baker
BackgroundBirth weight has inconsistent associations with colorectal cancer, possibly due to different anatomic features of the colon versus the rectum. The aim of this study was to investigate the association between birth weight and colon and rectal cancers separately.Methods193,306 children, born from 1936 to 1972, from the Copenhagen School Health Record Register were followed prospectively in Danish health registers. Colon and rectal cancer cases were defined using the International Classification of Disease version 10 (colon: C18.0–18.9, rectal: 19.9 and 20.9). Only cancers classified as adenocarcinomas were included in the analyses. Cox regressions were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Analyses were stratified by birth cohort and sex.ResultsDuring 3.8 million person-years of follow-up, 1465 colon and 961 rectal adenocarcinomas were identified. No significant sex differences were observed; therefore combined results are presented. Birth weight was positively associated with colon cancers with a HR of 1.14 (95% CI, 1.04–1.26) per kilogram of birth weight. For rectal cancer a significant association was not observed for birth weights below 3.5kg. Above 3.5kg an inverse association was observed (at 4.5kg, HR=0.77 [95% CI, 0.61–0.96]). Further, the associations between birth weight and colon and rectal cancer differed significantly from each other (p=0.006).ConclusionsBirth weight is positively associated with the risk of adult colon cancer, whereas the results for rectal cancer were inverse only above values of 3.5kg. The results underline the importance of investigating colon and rectal cancer as two different entities.



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Salvage of the proximal femur following pathological fractures involving benign bone tumors

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Response to Letter to the Editor re: Cananzi, et al.—Surgery of leiomyosarcoma of the inferior vena cava

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In-vitro and in-vivo evaluation of the anticancer activity of diruthenium-2, a new trithiolato arene ruthenium complex [([eta]6-p-MeC6H4Pri)2Ru2([mu]-S-p-C6H4OH)3]Cl.

In the present study, we investigated the anticancer action of the trithiolato arene ruthenium complex, [([eta]6-p-MeC6H4Pri)2Ru2([mu]-S-p-C6H4OH)3]Cl, named diruthenium-2, both in vitro and in vivo. The mechanism of antiproliferative, cytotoxic, and DNA-damaging activity, and the effect on expressions of cell cycle regulatory proteins were investigated using a WST-1-based proliferation assay, lactate dehydrogenase leakage assay, comet assay, flow cytometry, and western blot analysis. In-vivo anticancer activity was evaluated using Ehrlich tumor-bearing NMRI mice. Diruthenium-2 inhibited the growth of all cancer cell lines used, the most sensitive being gastric (AGS), breast cancer (BT-549, MCF-7, MDA-MB-231), and leukemic (HL-60, MOLT-4) cells. In MCF-7 cells, it caused a G1/S cell cycle arrest, along with an increase in the expression of protein p21 and cyclin B1. We also observed increased levels of MRN complex proteins, which, together with the results from the comet assay, indicate the formation of DNA double-strand breaks. In tumor-bearing mice, diruthenium-2 at doses of 3 and 5 mg/kg inhibits the growth of solid Ehrlich tumor, although weaker than cisplatin. However, it did not prolong the post-therapeutic survival. Our results suggest the in-vitro potential of diruthenium-2 should be further evaluated in studies using other in-vivo models. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Suppressive effects on cell proliferation and motility in gastric cancer SGC-7901 cells by introducing ulinastatin in vitro.

Ulinastatin (UTI) is a kind of urinary trypsin inhibitor regulating broad-spectrum proteases and is used widely in the treatment of inflammatory diseases. Some evidence has suggested that UTI has antitumor functions in human carcinomas, but its function in gastric cancer (GC) has not been discussed extensively. In this study, we investigated the effects of UTI on GC SGC-7901 cells in vitro by preincubating cells with the UTI. The expression of the related molecules, urokinase-type plasminogen activator (uPA), was investigated at both the mRNA and the protein stages. Activation of uPA was analyzed and the phosphorylation of ERK1/2 downstream uPA was detected. According to the results, UTI downregulated uPA expression and significantly suppressed the activation of uPA and the phosphorylation of ERK1/2. Furthermore, the SGC-7901 cells treated by UTI showed a significant decrease in cell proliferation and impairment of invasion and migration. However, no significant influence was observed on cell apoptosis. By ectopically expressing uPA in SGC-7901 cells, suppression effects of UTI were rescued. We suggest that UTI suppresses GC cell proliferation, motility, and at least partly conducted through uPA. Although the effects of UTI in GC cells need to be validated further, UTI represents a strong therapeutic strategy that is worth following up in GC treatment. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Targeting Wee1 in a Proneural GBM Model

Glioblastoma (GBM) is the most common malignant primary brain cancer. With a median survival of about a year, new approaches to treating this disease are necessary. To identify signaling molecules regulating GBM progression in a genetically engineered murine model of proneural GBM, we quantified phosphotyrosine-mediated signaling using mass spectrometry. Oncogenic signals, including phosphorylated ERK MAPK, PI3K, and PDGFR, were found to be increased in the murine tumors relative to brain. Phosphorylation of CDK1 pY15, associated with the G₂ arrest checkpoint, was identified as the most differentially phosphorylated site, with a 14-fold increase in phosphorylation in the tumors. To assess the role of this checkpoint as a potential therapeutic target, syngeneic primary cell lines derived from these tumors were treated with MK-1775, an inhibitor of Wee1, the kinase responsible for CDK1 Y15 phosphorylation. MK-1775 treatment led to mitotic catastrophe, as defined by increased DNA damage and cell death by apoptosis. To assess the extensibility of targeting Wee1/CDK1 in GBM, patient-derived xenograft (PDX) cell lines were also treated with MK-1775. Although the response was more heterogeneous, on-target Wee1 inhibition led to decreased CDK1 Y15 phosphorylation and increased DNA damage and apoptosis in each line. These results were also validated in vivo, where single-agent MK-1775 demonstrated an antitumor effect on a flank PDX tumor model, increasing mouse survival by 1.74-fold. This study highlights the ability of unbiased quantitative phosphoproteomics to reveal therapeutic targets in tumor models, and the potential for Wee1 inhibition as a treatment approach in preclinical models of GBM. Mol Cancer Ther; 15(6); 1–12. ©2016 AACR.

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Effects of Fatty Acid Synthase Inhibition by Orlistat on Proliferation of Endometrial Cancer Cell Lines

Abstract

Objective

Fatty acid synthase (FAS) is a key lipogenic enzyme that is highly expressed in endometrial cancer. Orlistat is a weight loss medication that has been shown to be a potent inhibitor of FAS. The goal of this study was to evaluate the anti-tumorigenic potential of orlistat in endometrial cancer cell lines.

Methods

The endometrial cancer cell lines ECC-1 and KLE were used. Cell proliferation was assessed by MTT assay after treatment with orlistat. Cell cycle progression was evaluated by Cellometer and apoptosis was assessed using the Annexin V assay. Reactive oxygen species (ROS) was measured using the DCFH-DA assay. Western immunoblotting was performed to determine changes in FAS, cellular stress, cell cycle progression, and the AMPK/mTOR pathways.

Results

Orlistat inhibited cell proliferation by 61 % in ECC-1 cells and 57 % in KLE cells at a dose of 500 μM. Treatment with orlistat at this concentration resulted in G1 arrest (p < 0.05) but did not affect apoptosis. Orlistat increased ROS and induced the expression of BIP (1.28-fold in ECC-1 compared to control, p < 0.05; 1.92-fold in KLE, p < 0.05) and PERK (2.25-fold in ECC-1, 1.4-fold in KLE, p < 0.05). Western immunoblot analysis demonstrated that orlistat decreased expression of important proteins in fatty acid metabolism including FAS (67 % in ECC-1, 15 % in KLE), acetyl-CoA carboxylase (40 % in ECC-1, 35 % in KLE), and carnitine palmitoyltransferase 1A (CPT1A) (65 % in ECC-1, 25 % in KLE) in a dose-dependent manner. In addition, orlistat at a dose of 500 μM increased expression of phosphorylated-AMPK (1.9-fold in ECC-1, p < 0.01; 1.5-fold in KLE, p < 0.05) and decreased expression of phosphorylated-Akt (25 % in ECC-1, p < 0.05; 37 % in KLE, p < 0.05) and phosphorylated-S6 (68 % in ECC-1, 56 % in KLE).

Conclusions

Orlistat inhibits cell growth in endometrial cancer cell lines through inhibition of fatty acid metabolism, induction of cell cycle G1 arrest, activation of AMPK and inhibition of the mTOR pathway. Given that patients with endometrial cancer have high rates of obesity, orlistat should be further investigated as a novel strategy for endometrial cancer treatment.

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Assessing Colorectal Cancer Screening Adherence of Medicare Fee-for-Service Beneficiaries Age 76 to 95 Years [Care Delivery]

Introduction:

There are concerns about potential overuse of colorectal cancer (CRC) screening services among average-risk individuals older than age 75 years.

Materials and Methods:

Using a 5% random noncancer sample of Medicare beneficiaries who resided in the SEER areas, we examined rates of CRC screening adherence, defined by the Medicare coverage policy, among average-risk fee-for-service beneficiaries age 76 to 95 years from 2002 to 2010. The two outcomes are the status of overall CRC screening adherence, and the status of adherence to colonoscopy (v other modalities) conditional on patient adherence.

Results:

Overall CRC screening adherence rates of Medicare beneficiaries age 76 to 95 years increased from 13.0% to 21.4% from 2002 to 2010. In 2002, 2.2% of beneficiaries were adherent to colonoscopy, and 10.7%, by other modalities; the corresponding rates were 19.5% and 1.9%, respectively, in 2010. Specifically, rates of adherence to colonoscopy were 1.1% for those age 86 to 90 years and almost nil for those age 91 to 95 years in 2002, but the rates became 13.5% and 8.2%, respectively, in 2010. Compared with white beneficiaries, black beneficiaries age 76 to 95 years had a 7-percentage-point lower adherence rate. However, overall adherence rates among blacks increased by 168.6% from 2002 to 2010, whereas rates among whites increased by 63.0%. Logistic regressions showed that blacks age 86 to 95 years were less likely than whites to be adherent (odds ratio, 0.56; 95% CI, 0.47 to 0.59) but were more likely to be adherent to colonoscopy (odds ratio, 2.34; 95% CI, 1.47 to 3.91).

Conclusion:

High proportions of average-risk Medicare fee-for-service beneficiaries screened by colonoscopy may represent opportunities for improving appropriateness and allocative efficiency of CRC screening by Medicare.

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