The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

Summary

Inhibitors of kinesin spindle protein Eg5 are characterized by pronounced antitumor activity. Our group has recently synthesized and screened a library of 1,3,4-thiadiazoline analogues with the pharmacophoric structure of K858, an Eg5 inhibitor. We herein report the effects of K858 on four different breast cancer cell lines: MCF7 (luminal A), BT474 (luminal B), SKBR3 (HER2 like) and MDA-MB231 (basal like). We demonstrated that K858 displayed anti-proliferative activity on every analyzed breast cancer cell line by inducing apoptosis. However, at the same time, we showed that K858 up-regulated survivin, an anti-apoptotic molecule. We then performed a negative regulation of survivin expression, with the utilization of wortmannin, an AKT inhibitor, and obtained a significant increase of K858-dependent apoptosis. These data demonstrate that K858 is a potent inhibitor of replication and induces apoptosis in breast tumor cells, independently from the tumor phenotype. This anti-proliferative response of tumor cells to K858 can be limited by the contemporaneous over-expression of survivin; consequently, the reduction of survivin levels, obtained with AKT inhibitors, can sensitize tumor cells to K858-induced apoptosis.

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Erratum to: Pharmacokinetic evaluation of nanoparticle albumin-bound paclitaxel delivered via hepatic arterial infusion in patients with predominantly hepatic metastases

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Early impact of the Patient Protection and Affordable Care Act on insurance among young adults with cancer: Analysis of the dependent insurance provision

BACKGROUND

The Patient Protection and Affordable Care Act (ACA) included provisions to extend dependent health care coverage up to the age of 26 years in 2010. The authors examined the early impact of the ACA (before the implementation of insurance exchanges in 2014) on insurance rates in young adults with cancer, a historically underinsured group.

METHODS

Using National Cancer Institute Surveillance, Epidemiology, and End Results data for 18 cancer registries, the authors examined insurance rates before (pre) (January 2007-September 2010) versus after (post) (October 2010-December 2012) dependent insurance provisions among young adults aged 18 to 29 years when diagnosed with cancer during 2007 through 2012. Using multivariate generalized mixed effect models, the authors conducted difference-in-differences analysis to examine changes in overall and Medicaid insurance after the ACA among young adults who were eligible (those aged 18-25 years) and ineligible (those aged 26-29 years) for policy changes.

RESULTS

Among 39,632 young adult cancer survivors, the authors found an increase in overall insurance rates in those aged 18 to 25 years after the dependent provisions (83.5% for pre-ACA vs 85.4% for post-ACA; P<.01), but not among individuals aged 26 to 29 years (83.4% for pre-ACA vs 82.9% for post-ACA; P = .38). After adjusting for patient sociodemographics and cancer characteristics, the authors found that those aged 18 to 25 years had a 3.1% increase in being insured compared with individuals aged 26 to 29 years (P<.01); however, there were no significant changes noted in Medicaid enrollment (P = .17).

CONCLUSIONS

The findings of the current study identify an increase in insurance rates for young adults aged 18 to 25 years compared with those aged 26 to 29 years (1.9% vs -0.5%) that was not due to increases in Medicaid enrollment, thereby demonstrating a positive impact of the ACA dependent care provisions on insurance rates in this population. Cancer 2016. © 2016 American Cancer Society.

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A phase II, open-label trial of bortezomib (VELCADE ® ) in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic non-small cell lung cancer

Abstract

Background

Bortezomib is a selective reversible proteasome inhibitor with proapoptotic effects. Preclinical and phase I clinical data suggest activity of bortezomib in NSCLC, either as monotherapy or in combination with chemotherapeutic agents including gemcitabine and cisplatin.

Methods

Chemotherapy-naïve patients with inoperable stage IIIB or IV NSCLC were administered bortezomib 1 mg/m2 i.v. on days 1 and 8, and starting on day 21 (cycle 2), bortezomib (days 1 and 8) in combination with gemcitabine 1000 mg/m2, (days 1 and 8), and cisplatin 70 mg/m2 (day 1) in cycles of 21 days. Up to 8 cycles of combination therapy could be administered; single-agent bortezomib was continued until disease progression or unacceptable toxicity.

Results

Fifty-three patients [median age 66 years; 79.2 % male; 96.2 % stage IV; performance status (ECOG) 0/1 73.6/26.4 %; adenocarcinoma 45.3 %, squamous cell carcinoma 41.5 %] were enrolled. All patients were evaluable for toxicity and 43 for efficacy. Grade 3–4 hematologic toxicity consisted of neutropenia (22.6 %) and thrombocytopenia (17 %). Grade 2–4 non-hematologic adverse events were fever (9.4 %), fatigue (20.8 %), infection (18.9 %), and dyspnea (15.1 %). There was no >grade 2 neurotoxicity. Febrile neutropenia occurred in two (1.9 %) patients, and there were three possibly treatment-related deaths (5.4 %). In the intention-to-treat population, the objective response rate was 17 % (95 % CI 6.9–27.1 %). No difference in response rate was observed for squamous versus other histology (18.2 vs. 16.1 %, p = 0.845). The median progression-free survival was 2.5 months, the median overall survival 10.6 months and the 1-year survival rate 38.1 %.

Conclusion

The incorporation of bortezomib into the gemcitabine/cisplatin regimen, in the dose and schedule used in this study, could not improve the efficacy of the chemotherapy regimen and has not to be further investigated.

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The IL-1 cytokine family and its role in inflammation and fibrosis in the lung

Abstract

The IL-1 cytokine family comprises 11 members (7 ligands with agonist activity, 3 receptor antagonists and 1 anti-inflammatory cytokine) and is recognised as a key mediator of inflammation and fibrosis in multiple tissues including the lung. IL-1 targeted therapies have been successfully employed to treat a range of inflammatory conditions such as rheumatoid arthritis and gouty arthritis. This review will introduce the members of the IL-1 cytokine family, briefly discuss the cellular origins and cellular targets and provide an overview of the role of these molecules in inflammation and fibrosis in the lung.

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Higher EZH2 expression is associated with extramedullary infiltration in acute myeloid leukemia

Abstract

Accumulating evidence indicates that enhancer of zeste homolog 2 (EZH2) promotes the metastatic ability of solid tumors, but the role of EZH2 in extramedullary infiltration (EMI) in acute myeloid leukemia (AML) has not been thoroughly explored. In the present study, we investigated the possible association between EZH2 and EMI. We found that the messenger RNA (mRNA) and protein expression levels of EZH2 in AML patients were both significantly higher than in idiopathic thrombocytopenic purpura (ITP) patients. Furthermore, a positive correlation between EZH2 mRNA expression and percentage of peripheral blood blasts wa s found in AML patients (r = 0.404, p = 0.009). The migratory capacities of Kasumi-1 and HL-60, which both show a high level of EZH2 expression, were markedly higher than those of U937 and KG-1α. In contrast, silencing of EZH2 resulted in reduction in proliferation and migration ability and an increase in apoptosis. The latter observation was accompanied by reduced expression of associated proteins p-ERK, p-cmyc, and matrix metalloproteinase 2 (MMP-2) and an increase in epithelial cadherin (E-cadherin). These data suggest that higher expression of EZH2 may be associated with extramedullary infiltration in acute myeloid leukemia and affect pathogenesis via activation of the p-ERK/p-cmyc/MMP-2 and E-cadherin signaling pathways.

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Pearls & Oy-sters: Symptomatic innominate artery disease

A 64-year-old man presented to the emergency department with left-sided weakness and speech impairment upon awakening. He had a history of multiple myocardial infarctions and had undergone coronary angioplasty and coronary artery bypass graft surgery 1 year previously. He was a heavy smoker and had arterial hypertension. He was taking aspirin 100 mg QD, clopidogrel 75 mg QD, simvastatin 40 mg QD, and enalapril 5 mg BID.

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Hair dye use, regular exercise, and the risk and prognosis of prostate cancer: multicenter case–control and case-only studies

This study investigated the effects that hair dye use and regular exercise exert on the risk and prognosis of prostate cancer.

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Teaching NeuroImages: Severe vasospasm in traumatic brain injury

A 45-year-old man had a severe traumatic brain injury (TBI) with multicompartmental hemorrhages (figure 1). He was initially noted to be awake and following commands with his right side. Two weeks later, his examination deteriorated to coma with flaccid quadriplegia. Initial workup, including EEG, was unrevealing. MRI brain showed new multiterritorial infarcts (figure 1); a catheter-based angiogram confirmed severe vasospasm in several large vessels (figure 2).

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Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis and the pentose phosphate pathway

Abstract

Metabolic adaptations are intimately associated with changes in cell behavior. Cancers are characterized by a high metabolic plasticity resulting from mutations and the selection of metabolic phenotypes conferring growth and invasive advantages. While metabolic plasticity allows cancer cells to cope with various microenvironmental situations that can be encountered in a primary tumor, there is increasing evidence that metabolism is also a major driver of cancer metastasis. Rather than a general switch promoting metastasis as a whole, a succession of metabolic adaptations is more likely needed to promote different steps of the metastatic process. This review addresses the contribution of pH, glycolysis and the pentose phosphate pathway, and a companion paper summarizes current knowledge regarding the contribution of mitochondria, lipids and amino acid metabolism. Extracellular acidification, intracellular alkalinization, the glycolytic enzyme phosphoglucose isomerase acting as an autocrine cytokine, lactate and the pentose phosphate pathway are emerging as important factors controlling cancer metastasis.

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Adjuvant and Novel Treatment of Recurrent Respiratory Papillomatosis

Abstract

Recurrent respiratory papillomatosis (RRP) is a rare benign neoplasm of the respiratory tract caused by human papillomavirus types 6 and 11. Surgical removal of the papilloma by microdebridement or laser is the current standard of care, but in most cases the disease recurs and patients require repeated surgical intervention. Over time, repeated procedures can lead to complications such as significant vocal cord scarring and laryngeal stenosis. There is therefore an urgent need for adjuvant treatments or alternative therapies that can control the disease or prevent recurrence, but unfortunately there is currently no known universally effective adjuvant therapy. Challenges for evaluating the effectiveness of adjuvant treatment in RRP include variable success rates in patients, the highly unpredictable underlying disease process, and potential for side effects. The current adjuvant treatment and novel approaches for RRP are presented.

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Dengue virus infection in a French traveller to the hilly region of Nepal in 2015: a case report

Dengue viral infections are known to pose a significant risk during travel to tropical regions, but it is surprising to find dengue transmission in the hilly region of Nepal, which is over 1800mtr above sea le...

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Volume matters in the systemic treatment of metastatic pancreatic cancer: a population-based study in the Netherlands

Abstract

Purpose

In pancreatic surgery, a relation between surgical volume and postoperative mortality and overall survival (OS) has been recognized, with high-volume centers reporting significantly better survival rates. We aimed to explore the influence of hospital volume on administration of palliative chemotherapy and OS in the Netherlands.

Methods

Patients diagnosed between 2007 and 2011 with metastatic pancreatic cancer were identified in the Netherlands Cancer Registry. Three types of high-volume centers were defined: high-volume (1) incidence center, based on the number of patients diagnosed with metastatic pancreatic cancer, (2) treatment center based on number of patients with metastatic pancreatic cancer who started treatment with palliative chemotherapy and (3) surgical center based on the number of resections with curative intent for pancreatic cancer. Independent predictors of administration of palliative chemotherapy were evaluated by means of logistic regression analysis. The multivariable Cox proportional hazard model was used to assess the impact of being diagnosed or treated in high-volume centers on survival.

Results

A total of 5385 patients presented with metastatic pancreatic cancer of which 24 % received palliative chemotherapy. Being treated with chemotherapy in a high-volume chemotherapy treatment center was associated with improved survival (HR 0.76, 95 % CI 0.67–0.87). Also, in all patients with metastatic pancreatic cancer, being diagnosed in a high-volume surgical center was associated with improved survival (HR 0.74, 95 % CI 0.66–0.83).

Conclusions

Hospital volume of palliative chemotherapy for metastatic pancreatic cancer was associated with improved survival, demonstrating that a volume–outcome relationship, as described for pancreatic surgery, may also exist for pancreatic medical oncology.

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Update on parathyroid carcinoma

Abstract

Introduction

Parathyroid carcinoma (PC) is a rare endocrine disorder, commonly causing severe primary hyperparathyroidism (PHPT). PC is mainly a sporadic disease, but it may occur in familial PHPT. Patients with PC usually present markedly elevated serum calcium and PTH. The clinical features are mostly due to the effects of the excessive secretion of PTH rather than to the spread of tumor. At times, the diagnosis can be difficult.

Purpose

The aim of this work is to review the available data on PC, and focus its molecular pathogenesis and the clinical utility of CDC73 genetic testing and immunostaining of its product, parafibromin. The pathological diagnosis of PC is restricted to lesions showing unequivocal growth into adjacent tissues or metastasis. Inactivating mutations of the cell division cycle 73 (CDC73) gene have been identified in up to 70 % of apparently sporadic PC and in one-third are germline. Loss of parafibromin immunostaining has been shown in most PC. The association of CDC73 mutations and loss of parafibromin predicts a worse clinical outcome and a lower overall 5- and 10-year survival.

Conclusions

The treatment of choice is the en bloc resection of the tumor. The course of PC is variable; most patients have local recurrences or distant metastases and die from unmanageable hypercalcemia.

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A Novel Mutation in a Patient with Hyperparathyroidism–Jaw Tumour Syndrome

Abstract

Hyperparathyroidism–jaw tumour syndrome (HPT-JT) is a rare variant of familial hyperparathyroidism, characterized by primary hyperparathyroidism (PHPT) due to one or multiple parathyroid adenomas, and benign tumours of the mandible and maxilla. It has an autosomal dominant pattern of inheritance, and is associated with mutations that deactivate the cell division cycle protein 73 homolog (CDC73) gene, also known as hyperparathyroidism 2 (HRPT2), located on the long arm of chromosome 1, that encodes for the tumour suppressor protein parafibromin. In the majority of cases, PHPT is the presenting symptom, but up to 30 % of HPT-JT cases initially present with an ossifying fibroma of the maxillofacial bones. HPT-JT may result in severe hypercalcemia-related complications and an elevated risk of parathyroid carcinoma. For this reason, early identification of the disease is important. We present the case of a 23-year-old woman who was found to have jaw tumours and was later diagnosed with PHPT. Genetic analysis revealed a novel mutation in exon 1 of CDC73. This report contributes to the understanding of the genetics of this rare syndrome. It also highlights the fact that HPT-JT should be considered and CDC73 mutation analysis should be performed in cases of early-onset PHPT associated with ossifying fibromas of the jaw.

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Viruses ‘piggyback’ on host microbes’ success

In the microscopic life that thrives around coral reefs, San Diego State University researchers have discovered an interplay between viruses and microbes that defies conventional wisdom. As the density of microbes rises in an ecosystem, the number of viruses infecting those microbes rises with i…

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Bacteria take ‘RNA mug shots’ of threatening viruses

Scientists from The University of Texas at Austin, the Stanford University School of Medicine and two other institutions have discovered that bacteria have a system that can recognize and disrupt dangerous viruses using a newly identified mechanism involving ribonucleic acid (RNA). It is similar…

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Randomized phase II trial of cyclophosphamide and the oral poly (ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer

Summary

Background In tumors carrying BRCA mutations, DNA damage caused by standard cytotoxic chemotherapy can be potentiated by poly [ADP-ribose] polymerase (PARP) inhibitors, leading to increased cell death through synthetic lethality. Individuals carrying mutations in BRCA have an increased incidence of triple negative breast cancer (TNBC). In order to assess the role of PARP inhibition in the treatment of TNBC, we conducted a randomized phase II trial of the combination of veliparib, a small molecule PARP inhibitor, with the cytotoxic agent cyclophosphamide versus cyclophosphamide alone in patients with refractory TNBC. Methods Adult patients with TNBC were randomized to receive oral cyclophosphamide 50 mg once daily with or without oral veliparib at 60 mg daily in 21-day cycles. Patients on the cyclophosphamide arm could crossover to the combination arm at disease progression. Results Forty-five patients were enrolled; 18 received cyclophosphamide alone and 21 received the combination as their initial treatment regimen. Lymphopenia was the most common grade 3/4 toxicity noted in both arms. One patient in the cyclophosphamide alone arm, and 2 in the combination arm had objective responses. Response rates and median progression free survival did not significantly differ between both treatment arms. Conclusion The addition of veliparib to cyclophosphamide, at the dose and schedule evaluated, did not improve the response rate over cyclophosphamide treatment alone in patients with heavily pre-treated triple-negative breast cancer.

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The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

Summary

Inhibitors of kinesin spindle protein Eg5 are characterized by pronounced antitumor activity. Our group has recently synthesized and screened a library of 1,3,4-thiadiazoline analogues with the pharmacophoric structure of K858, an Eg5 inhibitor. We herein report the effects of K858 on four different breast cancer cell lines: MCF7 (luminal A), BT474 (luminal B), SKBR3 (HER2 like) and MDA-MB231 (basal like). We demonstrated that K858 displayed anti-proliferative activity on every analyzed breast cancer cell line by inducing apoptosis. However, at the same time, we showed that K858 up-regulated survivin, an anti-apoptotic molecule. We then performed a negative regulation of survivin expression, with the utilization of wortmannin, an AKT inhibitor, and obtained a significant increase of K858-dependent apoptosis. These data demonstrate that K858 is a potent inhibitor of replication and induces apoptosis in breast tumor cells, independently from the tumor phenotype. This anti-proliferative response of tumor cells to K858 can be limited by the contemporaneous over-expression of survivin; consequently, the reduction of survivin levels, obtained with AKT inhibitors, can sensitize tumor cells to K858-induced apoptosis.

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Erratum to: Pharmacokinetic evaluation of nanoparticle albumin-bound paclitaxel delivered via hepatic arterial infusion in patients with predominantly hepatic metastases

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Early impact of the Patient Protection and Affordable Care Act on insurance among young adults with cancer: Analysis of the dependent insurance provision

BACKGROUND

The Patient Protection and Affordable Care Act (ACA) included provisions to extend dependent health care coverage up to the age of 26 years in 2010. The authors examined the early impact of the ACA (before the implementation of insurance exchanges in 2014) on insurance rates in young adults with cancer, a historically underinsured group.

METHODS

Using National Cancer Institute Surveillance, Epidemiology, and End Results data for 18 cancer registries, the authors examined insurance rates before (pre) (January 2007-September 2010) versus after (post) (October 2010-December 2012) dependent insurance provisions among young adults aged 18 to 29 years when diagnosed with cancer during 2007 through 2012. Using multivariate generalized mixed effect models, the authors conducted difference-in-differences analysis to examine changes in overall and Medicaid insurance after the ACA among young adults who were eligible (those aged 18-25 years) and ineligible (those aged 26-29 years) for policy changes.

RESULTS

Among 39,632 young adult cancer survivors, the authors found an increase in overall insurance rates in those aged 18 to 25 years after the dependent provisions (83.5% for pre-ACA vs 85.4% for post-ACA; P<.01), but not among individuals aged 26 to 29 years (83.4% for pre-ACA vs 82.9% for post-ACA; P = .38). After adjusting for patient sociodemographics and cancer characteristics, the authors found that those aged 18 to 25 years had a 3.1% increase in being insured compared with individuals aged 26 to 29 years (P<.01); however, there were no significant changes noted in Medicaid enrollment (P = .17).

CONCLUSIONS

The findings of the current study identify an increase in insurance rates for young adults aged 18 to 25 years compared with those aged 26 to 29 years (1.9% vs -0.5%) that was not due to increases in Medicaid enrollment, thereby demonstrating a positive impact of the ACA dependent care provisions on insurance rates in this population. Cancer 2016. © 2016 American Cancer Society.

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A phase II, open-label trial of bortezomib (VELCADE ® ) in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic non-small cell lung cancer

Abstract

Background

Bortezomib is a selective reversible proteasome inhibitor with proapoptotic effects. Preclinical and phase I clinical data suggest activity of bortezomib in NSCLC, either as monotherapy or in combination with chemotherapeutic agents including gemcitabine and cisplatin.

Methods

Chemotherapy-naïve patients with inoperable stage IIIB or IV NSCLC were administered bortezomib 1 mg/m2 i.v. on days 1 and 8, and starting on day 21 (cycle 2), bortezomib (days 1 and 8) in combination with gemcitabine 1000 mg/m2, (days 1 and 8), and cisplatin 70 mg/m2 (day 1) in cycles of 21 days. Up to 8 cycles of combination therapy could be administered; single-agent bortezomib was continued until disease progression or unacceptable toxicity.

Results

Fifty-three patients [median age 66 years; 79.2 % male; 96.2 % stage IV; performance status (ECOG) 0/1 73.6/26.4 %; adenocarcinoma 45.3 %, squamous cell carcinoma 41.5 %] were enrolled. All patients were evaluable for toxicity and 43 for efficacy. Grade 3–4 hematologic toxicity consisted of neutropenia (22.6 %) and thrombocytopenia (17 %). Grade 2–4 non-hematologic adverse events were fever (9.4 %), fatigue (20.8 %), infection (18.9 %), and dyspnea (15.1 %). There was no >grade 2 neurotoxicity. Febrile neutropenia occurred in two (1.9 %) patients, and there were three possibly treatment-related deaths (5.4 %). In the intention-to-treat population, the objective response rate was 17 % (95 % CI 6.9–27.1 %). No difference in response rate was observed for squamous versus other histology (18.2 vs. 16.1 %, p = 0.845). The median progression-free survival was 2.5 months, the median overall survival 10.6 months and the 1-year survival rate 38.1 %.

Conclusion

The incorporation of bortezomib into the gemcitabine/cisplatin regimen, in the dose and schedule used in this study, could not improve the efficacy of the chemotherapy regimen and has not to be further investigated.

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The IL-1 cytokine family and its role in inflammation and fibrosis in the lung

Abstract

The IL-1 cytokine family comprises 11 members (7 ligands with agonist activity, 3 receptor antagonists and 1 anti-inflammatory cytokine) and is recognised as a key mediator of inflammation and fibrosis in multiple tissues including the lung. IL-1 targeted therapies have been successfully employed to treat a range of inflammatory conditions such as rheumatoid arthritis and gouty arthritis. This review will introduce the members of the IL-1 cytokine family, briefly discuss the cellular origins and cellular targets and provide an overview of the role of these molecules in inflammation and fibrosis in the lung.

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Higher EZH2 expression is associated with extramedullary infiltration in acute myeloid leukemia

Abstract

Accumulating evidence indicates that enhancer of zeste homolog 2 (EZH2) promotes the metastatic ability of solid tumors, but the role of EZH2 in extramedullary infiltration (EMI) in acute myeloid leukemia (AML) has not been thoroughly explored. In the present study, we investigated the possible association between EZH2 and EMI. We found that the messenger RNA (mRNA) and protein expression levels of EZH2 in AML patients were both significantly higher than in idiopathic thrombocytopenic purpura (ITP) patients. Furthermore, a positive correlation between EZH2 mRNA expression and percentage of peripheral blood blasts wa s found in AML patients (r = 0.404, p = 0.009). The migratory capacities of Kasumi-1 and HL-60, which both show a high level of EZH2 expression, were markedly higher than those of U937 and KG-1α. In contrast, silencing of EZH2 resulted in reduction in proliferation and migration ability and an increase in apoptosis. The latter observation was accompanied by reduced expression of associated proteins p-ERK, p-cmyc, and matrix metalloproteinase 2 (MMP-2) and an increase in epithelial cadherin (E-cadherin). These data suggest that higher expression of EZH2 may be associated with extramedullary infiltration in acute myeloid leukemia and affect pathogenesis via activation of the p-ERK/p-cmyc/MMP-2 and E-cadherin signaling pathways.

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Pearls & Oy-sters: Symptomatic innominate artery disease

A 64-year-old man presented to the emergency department with left-sided weakness and speech impairment upon awakening. He had a history of multiple myocardial infarctions and had undergone coronary angioplasty and coronary artery bypass graft surgery 1 year previously. He was a heavy smoker and had arterial hypertension. He was taking aspirin 100 mg QD, clopidogrel 75 mg QD, simvastatin 40 mg QD, and enalapril 5 mg BID.

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Hair dye use, regular exercise, and the risk and prognosis of prostate cancer: multicenter case–control and case-only studies

This study investigated the effects that hair dye use and regular exercise exert on the risk and prognosis of prostate cancer.

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Teaching NeuroImages: Severe vasospasm in traumatic brain injury

A 45-year-old man had a severe traumatic brain injury (TBI) with multicompartmental hemorrhages (figure 1). He was initially noted to be awake and following commands with his right side. Two weeks later, his examination deteriorated to coma with flaccid quadriplegia. Initial workup, including EEG, was unrevealing. MRI brain showed new multiterritorial infarcts (figure 1); a catheter-based angiogram confirmed severe vasospasm in several large vessels (figure 2).

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Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis and the pentose phosphate pathway

Abstract

Metabolic adaptations are intimately associated with changes in cell behavior. Cancers are characterized by a high metabolic plasticity resulting from mutations and the selection of metabolic phenotypes conferring growth and invasive advantages. While metabolic plasticity allows cancer cells to cope with various microenvironmental situations that can be encountered in a primary tumor, there is increasing evidence that metabolism is also a major driver of cancer metastasis. Rather than a general switch promoting metastasis as a whole, a succession of metabolic adaptations is more likely needed to promote different steps of the metastatic process. This review addresses the contribution of pH, glycolysis and the pentose phosphate pathway, and a companion paper summarizes current knowledge regarding the contribution of mitochondria, lipids and amino acid metabolism. Extracellular acidification, intracellular alkalinization, the glycolytic enzyme phosphoglucose isomerase acting as an autocrine cytokine, lactate and the pentose phosphate pathway are emerging as important factors controlling cancer metastasis.

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TNF-alpha promotes lymphangiogenesis and lymphatic metastasis of gallbladder cancer through the ERK1/2/AP-1/VEGF-D pathway

Tumor necrosis factor-alpha (TNF-α), a key player in cancer-related inflammation, was recently demonstrated to be involved in the lymphatic metastasis of gallbladder cancer (GBC). Vascular endothelial growth f…

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Spotlight on the March 22 Issue

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cMET inhibitor crizotinib impairs angiogenesis and reduces tumor burden in the C3(1)-Tag model of basal-like breast cancer

Epidemiologic studies have associated obesity with increased risk of the aggressive basal-like breast cancer (BBC) subtype. Hepatocyte growth factor (HGF) signaling through its receptor, cMET, is elevated in o…

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Randomized phase II trial of cyclophosphamide and the oral poly (ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer

Summary

Background In tumors carrying BRCA mutations, DNA damage caused by standard cytotoxic chemotherapy can be potentiated by poly [ADP-ribose] polymerase (PARP) inhibitors, leading to increased cell death through synthetic lethality. Individuals carrying mutations in BRCA have an increased incidence of triple negative breast cancer (TNBC). In order to assess the role of PARP inhibition in the treatment of TNBC, we conducted a randomized phase II trial of the combination of veliparib, a small molecule PARP inhibitor, with the cytotoxic agent cyclophosphamide versus cyclophosphamide alone in patients with refractory TNBC. Methods Adult patients with TNBC were randomized to receive oral cyclophosphamide 50 mg once daily with or without oral veliparib at 60 mg daily in 21-day cycles. Patients on the cyclophosphamide arm could crossover to the combination arm at disease progression. Results Forty-five patients were enrolled; 18 received cyclophosphamide alone and 21 received the combination as their initial treatment regimen. Lymphopenia was the most common grade 3/4 toxicity noted in both arms. One patient in the cyclophosphamide alone arm, and 2 in the combination arm had objective responses. Response rates and median progression free survival did not significantly differ between both treatment arms. Conclusion The addition of veliparib to cyclophosphamide, at the dose and schedule evaluated, did not improve the response rate over cyclophosphamide treatment alone in patients with heavily pre-treated triple-negative breast cancer.

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Dengue virus infection in a French traveller to the hilly region of Nepal in 2015: a case report

Dengue viral infections are known to pose a significant risk during travel to tropical regions, but it is surprising to find dengue transmission in the hilly region of Nepal, which is over 1800mtr above sea le…

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The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

Summary

Inhibitors of kinesin spindle protein Eg5 are characterized by pronounced antitumor activity. Our group has recently synthesized and screened a library of 1,3,4-thiadiazoline analogues with the pharmacophoric structure of K858, an Eg5 inhibitor. We herein report the effects of K858 on four different breast cancer cell lines: MCF7 (luminal A), BT474 (luminal B), SKBR3 (HER2 like) and MDA-MB231 (basal like). We demonstrated that K858 displayed anti-proliferative activity on every analyzed breast cancer cell line by inducing apoptosis. However, at the same time, we showed that K858 up-regulated survivin, an anti-apoptotic molecule. We then performed a negative regulation of survivin expression, with the utilization of wortmannin, an AKT inhibitor, and obtained a significant increase of K858-dependent apoptosis. These data demonstrate that K858 is a potent inhibitor of replication and induces apoptosis in breast tumor cells, independently from the tumor phenotype. This anti-proliferative response of tumor cells to K858 can be limited by the contemporaneous over-expression of survivin; consequently, the reduction of survivin levels, obtained with AKT inhibitors, can sensitize tumor cells to K858-induced apoptosis.

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Early impact of the Patient Protection and Affordable Care Act on insurance among young adults with cancer: Analysis of the dependent insurance provision

BACKGROUND

The Patient Protection and Affordable Care Act (ACA) included provisions to extend dependent health care coverage up to the age of 26 years in 2010. The authors examined the early impact of the ACA (before the implementation of insurance exchanges in 2014) on insurance rates in young adults with cancer, a historically underinsured group.

METHODS

Using National Cancer Institute Surveillance, Epidemiology, and End Results data for 18 cancer registries, the authors examined insurance rates before (pre) (January 2007-September 2010) versus after (post) (October 2010-December 2012) dependent insurance provisions among young adults aged 18 to 29 years when diagnosed with cancer during 2007 through 2012. Using multivariate generalized mixed effect models, the authors conducted difference-in-differences analysis to examine changes in overall and Medicaid insurance after the ACA among young adults who were eligible (those aged 18-25 years) and ineligible (those aged 26-29 years) for policy changes.

RESULTS

Among 39,632 young adult cancer survivors, the authors found an increase in overall insurance rates in those aged 18 to 25 years after the dependent provisions (83.5% for pre-ACA vs 85.4% for post-ACA; P<.01), but not among individuals aged 26 to 29 years (83.4% for pre-ACA vs 82.9% for post-ACA; P = .38). After adjusting for patient sociodemographics and cancer characteristics, the authors found that those aged 18 to 25 years had a 3.1% increase in being insured compared with individuals aged 26 to 29 years (P<.01); however, there were no significant changes noted in Medicaid enrollment (P = .17).

CONCLUSIONS

The findings of the current study identify an increase in insurance rates for young adults aged 18 to 25 years compared with those aged 26 to 29 years (1.9% vs -0.5%) that was not due to increases in Medicaid enrollment, thereby demonstrating a positive impact of the ACA dependent care provisions on insurance rates in this population. Cancer 2016. © 2016 American Cancer Society.

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A phase II, open-label trial of bortezomib (VELCADE ® ) in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic non-small cell lung cancer

Abstract

Background

Bortezomib is a selective reversible proteasome inhibitor with proapoptotic effects. Preclinical and phase I clinical data suggest activity of bortezomib in NSCLC, either as monotherapy or in combination with chemotherapeutic agents including gemcitabine and cisplatin.

Methods

Chemotherapy-naïve patients with inoperable stage IIIB or IV NSCLC were administered bortezomib 1 mg/m2 i.v. on days 1 and 8, and starting on day 21 (cycle 2), bortezomib (days 1 and 8) in combination with gemcitabine 1000 mg/m2, (days 1 and 8), and cisplatin 70 mg/m2 (day 1) in cycles of 21 days. Up to 8 cycles of combination therapy could be administered; single-agent bortezomib was continued until disease progression or unacceptable toxicity.

Results

Fifty-three patients [median age 66 years; 79.2 % male; 96.2 % stage IV; performance status (ECOG) 0/1 73.6/26.4 %; adenocarcinoma 45.3 %, squamous cell carcinoma 41.5 %] were enrolled. All patients were evaluable for toxicity and 43 for efficacy. Grade 3–4 hematologic toxicity consisted of neutropenia (22.6 %) and thrombocytopenia (17 %). Grade 2–4 non-hematologic adverse events were fever (9.4 %), fatigue (20.8 %), infection (18.9 %), and dyspnea (15.1 %). There was no >grade 2 neurotoxicity. Febrile neutropenia occurred in two (1.9 %) patients, and there were three possibly treatment-related deaths (5.4 %). In the intention-to-treat population, the objective response rate was 17 % (95 % CI 6.9–27.1 %). No difference in response rate was observed for squamous versus other histology (18.2 vs. 16.1 %, p = 0.845). The median progression-free survival was 2.5 months, the median overall survival 10.6 months and the 1-year survival rate 38.1 %.

Conclusion

The incorporation of bortezomib into the gemcitabine/cisplatin regimen, in the dose and schedule used in this study, could not improve the efficacy of the chemotherapy regimen and has not to be further investigated.

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Erratum to: Pharmacokinetic evaluation of nanoparticle albumin-bound paclitaxel delivered via hepatic arterial infusion in patients with predominantly hepatic metastases

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Downregulation and tumor-suppressive role of XPO5 in hepatocellular carcinoma

Abstract

XPO5 (Exp5, Exportin-5) is a transporter protein mainly mediating pre-microRNAs' nuclear export. Recent studies have demonstrated that XPO5 may play crucial roles in a few of cancers. However, little is known about XPO5 in hepatocellular carcinoma (HCC). In the present study, we elucidated the expression of XPO5 by quantitative real-time PCR (qRT-PCR) and immunohistochemical staining in HCC samples and conducted several functional analyses to address its effects on HCC development. The results demonstrated that both mRNA and protein levels of XPO5 were downregulated in HCC tissues compared to adjacent non-cancerous livers. Ectopic expression of XPO5 significantly suppressed cell proliferation, colony formation, growth in soft agar, and tumorigenicity in nude mice, whereas knockdown of XPO5 by RNA inference showed opposite phenotypes. Moreover, XPO5 knockdown promoted HCC cell migration and decreased the expression of E-cadherin and p53. Additionally, after treatment with DAC and TSA, the mRNA level of XPO5 was upregulated in HCC cells tested, implicating that epigenetic modulation may be involved in the transcription of XPO5. Collectively, our findings suggest that XPO5 functions as a potential tumor suppressor in the development and progression of HCC as well as a promising molecular target for HCC therapy.

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Physalin A induces G2/M phase cell cycle arrest in human non-small cell lung cancer cells: involvement of the p38 MAPK/ROS pathway

Abstract

Physalin A (PA) is an active withanolide isolated from Physalis alkekengi var. franchetii, a traditional Chinese herbal medicine named Jindenglong, which has long been used for the treatment of sore throat, hepatitis, and tumors in China. In the present study, we firstly investigated the effects of PA on proliferation and cell cycle distribution of the human non-small cell lung cancer (NSCLC) A549 cell line, and the potential mechanisms involved. Here, PA inhibited cell growth in dose- and time-dependent manners. Treatment of A549 cells with 28.4 μM PA for 24 h resulted in approximately 50 % cell death. PA increased the amount of intracellular ROS and the proportion of cells in G2/M. G2/M arrest was attenuated by the addition of ROS scavenger NAC. ERK and P38 were triggered by PA through phosphorylation in a time-dependent manner. The phosphorylation of ERK and P38 were not attenuated by the addition of NAC, but the use of the p38 inhibitor could reduce, at least in part, PA-induced ROS and the proportion of cells in G2/M. PA induces G2/M cell cycle arrest in A549 cells involving in the p38 MAPK/ROS pathway. This study suggests that PA might be a promising therapeutic agent against NSCLC.

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Kollagenosen bei Jugendlichen

Zusammenfassung

In diesem Beitrag werden Lupus erythematodes, juvenile Dermatomyositis, systemische Sklerodermie und Mischkollagenosen mit ihren Besonderheiten im Jugendalter erläutert. Der Dermatologe spielt eine wichtige Rolle bei der Diagnostik und Betreuung von Patienten mit Kollagenosen, da die Hautmanifestationen oftmals auf die Erkrankung primär hinweisen und mit einer beträchtlichen Einschränkung der Lebensqualität verbunden sein können. Die frühzeitige Diagnosestellung und Therapieeinleitung sind sehr wichtig für die Prognose der Patienten.

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Higher EZH2 expression is associated with extramedullary infiltration in acute myeloid leukemia

Abstract

Accumulating evidence indicates that enhancer of zeste homolog 2 (EZH2) promotes the metastatic ability of solid tumors, but the role of EZH2 in extramedullary infiltration (EMI) in acute myeloid leukemia (AML) has not been thoroughly explored. In the present study, we investigated the possible association between EZH2 and EMI. We found that the messenger RNA (mRNA) and protein expression levels of EZH2 in AML patients were both significantly higher than in idiopathic thrombocytopenic purpura (ITP) patients. Furthermore, a positive correlation between EZH2 mRNA expression and percentage of peripheral blood blasts wa s found in AML patients (r = 0.404, p = 0.009). The migratory capacities of Kasumi-1 and HL-60, which both show a high level of EZH2 expression, were markedly higher than those of U937 and KG-1α. In contrast, silencing of EZH2 resulted in reduction in proliferation and migration ability and an increase in apoptosis. The latter observation was accompanied by reduced expression of associated proteins p-ERK, p-cmyc, and matrix metalloproteinase 2 (MMP-2) and an increase in epithelial cadherin (E-cadherin). These data suggest that higher expression of EZH2 may be associated with extramedullary infiltration in acute myeloid leukemia and affect pathogenesis via activation of the p-ERK/p-cmyc/MMP-2 and E-cadherin signaling pathways.

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Panorama Dermatologische Praxis

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Nonalcoholic fatty liver disease is associated with cognitive function in adults

Objective:

We hypothesized that nonalcoholic fatty liver disease (NAFLD) is independently associated with cognitive impairment in a representative sample of the general US population regardless of the presence of cardiovascular disease (CVD) or its risk factors.

Methods:

This was a cross-sectional study of 4,472 adults aged 20–59 years who participated in the Third National Health and Nutritional Examination Survey. The participants underwent assessment of liver enzyme activity and hepatic steatosis by ultrasound, and underwent cognitive evaluation using the following computer-administered tests: the Simple Reaction Time Test (SRTT), the Symbol-Digit Substitution Test (SDST), and the Serial Digit Learning Test (SDLT). We defined NAFLD as moderate/severe steatosis as determined by ultrasound in the absence of hepatitis B or C or excessive alcohol consumption. We used multiple linear regression models to examine the association between NAFLD and cognitive function while controlling for potential confounders.

Results:

Participants with NAFLD showed lower overall performance on the SDLT (β = 0.726, 95% confidence interval [CI] 0.105–1.347), while associations with SRTT and SDST did not reach significance. Increased activity of the liver enzymes alanine aminotransferase (β = 0.018, 95% CI 0.006–0.030) and aspartate aminotransferase (β = 0.021, 95% CI 0.005–0.037) correlated with lower performance on the SDLT, while increased alanine aminotransferase was also correlated with lower performance in the SDST (β = 0.002, 95% CI 0.0001–0.004).

Conclusions:

NAFLD was independently associated with lower cognitive performance independent of CVD and its risk factors. Given the scarcity of risk factors associated with age-related cognitive decline, these findings may have significant implications.

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Clinical Reasoning: Stepwise paralysis in a patient with adenocarcinoma of lung

A 54-year-old man presented with pain in the left chest for 3 days. His medical history was remarkable for hyperlipidemia managed with diet and statin. He denied tobacco smoking and consumption of alcohol. Physical examination was unrevealing. The patient was diagnosed with an adenocarcinoma of the lung harboring an epidermal growth factor receptor (EGFR) mutation that metastasized to T2-T4 levels. He was treated with radiotherapy and dexamethasone followed by Gefitinib.

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Mystery case: Intracranial hemorrhage in adult vein of Galen malformation

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Fulminant corticobasal degeneration: Agrypnia excitata in corticobasal syndrome

Corticobasal degeneration (CBD) may be expressed as an atypical parkinsonism with a mean disease survival of about 7 years,1 the shortest reported survival being 24 months.2 We report a patient with corticobasal syndrome (CBS) and pathology-confirmed CBD whose 10-month course was manifested as a frontal alien hand evolving into agrypnia excitata.

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Teaching NeuroImages: Severe vasospasm in traumatic brain injury

A 45-year-old man had a severe traumatic brain injury (TBI) with multicompartmental hemorrhages (figure 1). He was initially noted to be awake and following commands with his right side. Two weeks later, his examination deteriorated to coma with flaccid quadriplegia. Initial workup, including EEG, was unrevealing. MRI brain showed new multiterritorial infarcts (figure 1); a catheter-based angiogram confirmed severe vasospasm in several large vessels (figure 2).

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Pearls & Oy-sters: Symptomatic innominate artery disease

A 64-year-old man presented to the emergency department with left-sided weakness and speech impairment upon awakening. He had a history of multiple myocardial infarctions and had undergone coronary angioplasty and coronary artery bypass graft surgery 1 year previously. He was a heavy smoker and had arterial hypertension. He was taking aspirin 100 mg QD, clopidogrel 75 mg QD, simvastatin 40 mg QD, and enalapril 5 mg BID.

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Spotlight on the March 22 Issue

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10-Second heart rate variability and cognitive function in old age

Objective:

To investigate the cross-sectional and longitudinal associations of 10-second heart rate variability (HRV) with various domains of cognitive function in older participants at risk of cardiovascular disease.

Methods:

We studied 3,583 participants, mean age of 75.0 years, who were enrolled in the Prospective Study of Pravastatin in the Elderly at Risk. From baseline 10-second ECGs, standard deviation of normal-to-normal intervals was calculated as the index of HRV. Four cognitive domains were assessed at baseline and repeated during a mean follow-up period of 3.2 years.

Results:

Lower HRV at baseline was associated with worse performance in reaction time (mean difference between low third vs high third of HRV = 1.96 seconds, 95% confidence interval [CI] 0.20 to 3.71) and processing speed (–0.57 digits coded, 95% CI –1.09 to –0.05). During follow-up, participants with lower HRV had a steeper decline in processing speed (mean annual change between low third vs high third of HRV = –0.16 digits coded, 95% CI –0.28 to –0.04). There was no difference in annual changes of reaction time or immediate and delayed memory among HRV thirds during follow-up. All these associations remained unchanged after adjustment for medications, cardiovascular risk factors, and comorbidities.

Conclusions:

Participants with lower 10-second HRV have worse performance in reaction time and processing speed and experience steeper decline in their processing speed, independent of medications, cardiovascular risk factors, and comorbidities.

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