Phase I study of RO4929097 with bevacizumab in patients with recurrent malignant glioma

Abstract

Antiangiogenic therapies for malignant gliomas often result in transient response, and recurrent disease is characterized by adoption of invasive and hypoxic phenotype. The notch signaling pathway is activated in gliomas, and augments cell migration and hypoxic response. Here we report a clinical study of the combination of bevacizumab and RO4929097, an inhibitor of the notch signaling cascade. A phase I clinical trial was conducted through the Adult Brain Tumor Consortium in subjects with recurrent malignant glioma. Primary objectives were to assess safety and to define the maximum tolerated dose of RO4929097 in combination with bevacizumab. Secondary objectives were to determine overall survival, progression free survival, radiographic response, pharmacokinetic evaluation, and tissue biomarker analysis. Thirteen subjects were enrolled. Of the three subjects treated with the highest dose of RO4929097, one grade 3 toxicity and one grade 2 toxicity were observed. Definitive maximum tolerated dose of RO4929097 in combination with bevacizumab was not identified due to manufacturer's decision to halt drug production. 2 of 12 evaluable subjects demonstrated radiographic response; one subject experienced CR and the second PR. The median overall survival was 10.9 months with a median progression-free survival of 3.7 months. Two subjects remained free of disease progression at 6 months from treatment initiation. PK evaluation did not identify clinically significant drug–drug interactions. All analyzed tissue specimens revealed activation of notch signaling. Combination of RO4929097 and bevacizumab was well-tolerated. Given the compelling scientific rationale, additional studies of antiangiogenic and notch signaling inhibitors should be considered.

http://ift.tt/2fWHr0c

Successful treatment of chronic recurrent multifocal osteomyelitis using low-dose radiotherapy

Abstract

Background

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory disease, which lacks an infectious genesis and predominantly involves the metaphysis of long bones. Common treatments range from nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids at first onset of disease, to immunosuppressive drugs and bisphosphonates in cases of insufficient remission. The therapeutic use of low-dose radiotherapy for CRMO constitutes a novelty.

Case report

A 67-year-old female patient presented with radiologically proven CRMO affecting the right tibia/talus and no response to immunosuppressive therapy. Two treatment series of radiation therapy were applied with an interval of 6 weeks. Each series contained six fractions (three fractions per week) with single doses of 0.5 Gy, thus the total applied dose was 6 Gy. Ten months later, pain and symptoms of osteomyelitis had completely vanished.

Conclusion

Radiotherapy seems to be an efficient and feasible complementary treatment option for conventional treatment refractory CRMO in adulthood. The application of low doses per fraction is justified by the inflammatory pathomechanism of disease.

http://ift.tt/2eIbzdQ

Endobronchial Carcinoid and Concurrent Carcinoid Syndrome in an Adolescent Female

Endobronchial carcinoid tumors are the most common intrabronchial tumors in children and adolescents. Common signs and symptoms include persistent cough and wheezing not responsive to bronchodilators, hemoptysis, and recurrent fever. Diagnosis is frequently made by imaging and direct visualization with flexible bronchoscopy; surgery remains the gold standard treatment, and lung-sparing resections should be performed whenever possible. Though carcinoid syndrome—characterized by flushing, palpitations, wheezing, shortness of breath, and diarrhea—has been found in association with adult bronchial carcinoid tumors, to our knowledge only one previous study has reported the presence of carcinoid syndrome in a pediatric patient with an endobronchial carcinoid. Here, we report a case of a 14-year-old girl with chronic cough found to have an endobronchial carcinoid tumor and signs and symptoms consistent with carcinoid syndrome.

http://ift.tt/2fceRqv

Phase II clinical trial using novel peptide cocktail vaccine as a postoperative adjuvant treatment for surgically resected pancreatic cancer patients

Abstract

We investigated peptide cocktail vaccine OCV-C01 containing epitope peptides derived from KIF20A, vascular endothelial growth factor receptor (VEGFR)1, and VEGFR2 combined with gemcitabine in the adjuvant treatment for resected pancreatic cancer patients. A single-arm multicenter phase II study was performed on 30 patients with pancreatic ductal carcinoma who underwent pancreatectomy. At each 28-day treatment cycle, patients received weekly subcutaneous injection of OCV-C01 for 48 weeks, and gemcitabine was administered intravenously at 1,000 mg/m² on days 1, 8, and 15 for 24 weeks. Patients were followed for 18 months. The primary endpoint was disease-free survival (DFS) and secondary endpoints included safety, overall survival (OS) and immunological assays on peptide-specific cytotoxic T lymphocyte (CTL) activity and KIF20A expression in resected pancreatic cancer. The median DFS was 15.8 months (95% confidence interval (CI), 11.1-20.6), and the DFS rate at 18 months was 34.6% (95% CI, 18.3-51.6). The median OS was not reached and the OS rate at 18 months was 69.0% (95% CI, 48.8-82.5). The administration of OCV-C01 was well tolerated. In the per protocol set, there were significant differences in DFS between patients with KIF20A-specific CTL responses and without (p=0.027), and between patients with KIF20A expression and without (p=0.014). In addition, all four patients who underwent R0 resection with KIF20A expression had no recurrence of pancreatic cancer with KIF20A-specific CTL responses. OCV-C01 combined with gemcitabine was tolerable with a median DFS of 15.8 months, which was favorable compared with previous data for resected pancreatic cancer. This article is protected by copyright. All rights reserved.

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Gamma-glutamyltransferase and risk of prostate cancer: Findings from the KIHD prospective cohort study

Abstract

Increased circulating serum gamma-glutamyltransferase (GGT) has been linked with an increased risk of chronic disease outcomes, including overall and several site-specific cancers. However, the relationship of GGT with prostate cancer risk is uncertain. We aimed to assess the prospective association of GGT with risk of prostate cancer. Serum GGT activity was assessed at baseline in the Finnish Kuopio Ischemic Heart Disease prospective cohort of 2,390 men aged 42-61 years without a history of cancer at baseline. We corrected for within-person variability in GGT values using data from repeat measurements taken several years apart. During a median follow-up of 24.6 years, 230 cases of prostate cancer occurred. The age-adjusted regression dilution ratio for log_e GGT was 0.69 [95% confidence interval (CI): 0.63-0.74]. Serum GGT was nonlinearly associated with risk of prostate cancer. In age-adjusted Cox regression analysis, the hazard ratio (HR) (95% CIs) for prostate cancer in a comparison of the top quartile versus bottom quartiles 1-3 of GGT values was 1.43 (1.07 to 1.93; P=0.017), which persisted on adjustment for several established cancer risk factors 1.46 (1.06 to 2.02; P=0.020). The association remained unchanged on further adjustment for total energy intake, socioeconomic status, physical activity, and C-reactive protein. The association did not importantly vary across several clinical subgroups. Gamma-glutamyltransferase is positively and independently associated with future risk of prostate cancer in a middle-aged Finnish male population over long-term follow-up. Further research is needed to understand the mechanistic pathways involved and if GGT may have potential relevance in prostate cancer prevention. This article is protected by copyright. All rights reserved.

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KRAS driven expression signature has prognostic power superior to mutation status in non-small cell lung cancer

Abstract

KRAS is the most frequently mutated oncogene in non–small cell lung cancer (NSCLC). However, the prognostic role of KRAS mutation status in NSCLC still remains controversial. We hypothesize that the expression changes of genes affected by KRAS mutation status will have the most prominent effect and could be used as a prognostic signature in lung cancer.

We divided NSCLC patients with mutation and RNA-seq data into KRAS mutated and wild type groups. Mann-Whitney test was used to identify genes showing altered expression between these cohorts. Mean expression of the top five genes was designated as a "transcriptomic fingerprint" of the mutation. We evaluated the effect of this signature on clinical outcome in 2,437 NSCLC patients using uni- and multivariate Cox regression analysis.

Mutation of KRAS was most common in adenocarcinoma. Mutation status and KRAS expression were not correlated to prognosis. The transcriptomic fingerprint of KRAS include FOXRED2, KRAS, TOP1, PEX3, and ABL2. The KRAS signature had a high prognostic power. Similar results were achieved when using the second and third set of strongest genes. Moreover, all cutoff values delivered significant prognostic power (p<0.01). The KRAS signature also remained significant (p<0.01) in a multivariate analysis including age, gender, smoking history and tumor stage.

We generated a "surrogate signature" of KRAS mutation status in NSCLC patients by computationally linking genotype and gene expression. We show that secondary effects of a mutation can have a higher prognostic relevance than the primary genetic alteration itself. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2fOxuTl
via IFTTT

Phase II clinical trial using novel peptide cocktail vaccine as a postoperative adjuvant treatment for surgically resected pancreatic cancer patients

Abstract

We investigated peptide cocktail vaccine OCV-C01 containing epitope peptides derived from KIF20A, vascular endothelial growth factor receptor (VEGFR)1, and VEGFR2 combined with gemcitabine in the adjuvant treatment for resected pancreatic cancer patients. A single-arm multicenter phase II study was performed on 30 patients with pancreatic ductal carcinoma who underwent pancreatectomy. At each 28-day treatment cycle, patients received weekly subcutaneous injection of OCV-C01 for 48 weeks, and gemcitabine was administered intravenously at 1,000 mg/m² on days 1, 8, and 15 for 24 weeks. Patients were followed for 18 months. The primary endpoint was disease-free survival (DFS) and secondary endpoints included safety, overall survival (OS) and immunological assays on peptide-specific cytotoxic T lymphocyte (CTL) activity and KIF20A expression in resected pancreatic cancer. The median DFS was 15.8 months (95% confidence interval (CI), 11.1-20.6), and the DFS rate at 18 months was 34.6% (95% CI, 18.3-51.6). The median OS was not reached and the OS rate at 18 months was 69.0% (95% CI, 48.8-82.5). The administration of OCV-C01 was well tolerated. In the per protocol set, there were significant differences in DFS between patients with KIF20A-specific CTL responses and without (p=0.027), and between patients with KIF20A expression and without (p=0.014). In addition, all four patients who underwent R0 resection with KIF20A expression had no recurrence of pancreatic cancer with KIF20A-specific CTL responses. OCV-C01 combined with gemcitabine was tolerable with a median DFS of 15.8 months, which was favorable compared with previous data for resected pancreatic cancer. This article is protected by copyright. All rights reserved.

http://ift.tt/2fOtzpD

Gamma-glutamyltransferase and risk of prostate cancer: Findings from the KIHD prospective cohort study

Abstract

Increased circulating serum gamma-glutamyltransferase (GGT) has been linked with an increased risk of chronic disease outcomes, including overall and several site-specific cancers. However, the relationship of GGT with prostate cancer risk is uncertain. We aimed to assess the prospective association of GGT with risk of prostate cancer. Serum GGT activity was assessed at baseline in the Finnish Kuopio Ischemic Heart Disease prospective cohort of 2,390 men aged 42-61 years without a history of cancer at baseline. We corrected for within-person variability in GGT values using data from repeat measurements taken several years apart. During a median follow-up of 24.6 years, 230 cases of prostate cancer occurred. The age-adjusted regression dilution ratio for log_e GGT was 0.69 [95% confidence interval (CI): 0.63-0.74]. Serum GGT was nonlinearly associated with risk of prostate cancer. In age-adjusted Cox regression analysis, the hazard ratio (HR) (95% CIs) for prostate cancer in a comparison of the top quartile versus bottom quartiles 1-3 of GGT values was 1.43 (1.07 to 1.93; P=0.017), which persisted on adjustment for several established cancer risk factors 1.46 (1.06 to 2.02; P=0.020). The association remained unchanged on further adjustment for total energy intake, socioeconomic status, physical activity, and C-reactive protein. The association did not importantly vary across several clinical subgroups. Gamma-glutamyltransferase is positively and independently associated with future risk of prostate cancer in a middle-aged Finnish male population over long-term follow-up. Further research is needed to understand the mechanistic pathways involved and if GGT may have potential relevance in prostate cancer prevention. This article is protected by copyright. All rights reserved.

http://ift.tt/2fuRF4W

KRAS driven expression signature has prognostic power superior to mutation status in non-small cell lung cancer

Abstract

KRAS is the most frequently mutated oncogene in non–small cell lung cancer (NSCLC). However, the prognostic role of KRAS mutation status in NSCLC still remains controversial. We hypothesize that the expression changes of genes affected by KRAS mutation status will have the most prominent effect and could be used as a prognostic signature in lung cancer.

We divided NSCLC patients with mutation and RNA-seq data into KRAS mutated and wild type groups. Mann-Whitney test was used to identify genes showing altered expression between these cohorts. Mean expression of the top five genes was designated as a "transcriptomic fingerprint" of the mutation. We evaluated the effect of this signature on clinical outcome in 2,437 NSCLC patients using uni- and multivariate Cox regression analysis.

Mutation of KRAS was most common in adenocarcinoma. Mutation status and KRAS expression were not correlated to prognosis. The transcriptomic fingerprint of KRAS include FOXRED2, KRAS, TOP1, PEX3, and ABL2. The KRAS signature had a high prognostic power. Similar results were achieved when using the second and third set of strongest genes. Moreover, all cutoff values delivered significant prognostic power (p<0.01). The KRAS signature also remained significant (p<0.01) in a multivariate analysis including age, gender, smoking history and tumor stage.

We generated a "surrogate signature" of KRAS mutation status in NSCLC patients by computationally linking genotype and gene expression. We show that secondary effects of a mutation can have a higher prognostic relevance than the primary genetic alteration itself. This article is protected by copyright. All rights reserved.

http://ift.tt/2fOxuTl

Targeting CXCR4 and FAK reverses doxorubicin resistance and suppresses invasion in non-small cell lung carcinoma

Abstract

Background

Current high lung cancer mortality rates are mainly due to the occurrence of metastases and therapeutic resistance. Therefore, simultaneous targeting of these processes may be a valid approach for the treatment of this type of cancer. Here, we assessed relationships between CXC chemokine receptor type 4 (CXCR4) and focal adhesion kinase (FAK) gene expression levels and expression levels of the drug resistance-related genes ABCB1 and ABCC1, and tested the potential of CXCR4 and FAK inhibitors to reverse doxorubicin (DOX) resistance and to decrease the invasive capacity of non-small cell lung carcinoma (NSCLC) cells.

Methods

qRT-PCR was used for gene expression analyses in primary lung tissue samples obtained from 30 NSCLC patients and the human NSCLC-derived cell lines NCI-H460, NCI-H460/R and COR-L23. MTT, flow cytometry, cell death and β-galactosidase activity assays were used to assess the in vitro impact of CXCR4 and FAK inhibitors on DOX sensitivity. In addition, invasion and gelatin degradation assays were used to assess the in vitro impact of the respective inhibitors on metastasis-related processes in combination with DOX treatment.

Results

We found that ABCB1 over-expression was significantly associated with CXCR4 and FAK over-expression, whereas ABCC1 over-expression was associated with increased FAK expression. We also found that CXCR4 and FAK inhibitors strongly synergized with DOX in reducing cell viability, arresting the cell cycle in the S or G₂/M phases and inducing senescence. Additionally, we found that DOX enhanced the anti-invasive potential of CXCR4 and FAK inhibitors by reducing gelatin degradation and invasion.

Conclusions

From our data we conclude that targeting of CXCR4 and FAK may overcome ABCB1 and ABCC1-dependent DOX resistance in NSCLC cells and that simultaneous treatment of these cells with DOX may potentiate the anti-invasive effects of CXCR4 and FAK inhibitors.

http://ift.tt/2fWpIWK

Targeting CXCR4 and FAK reverses doxorubicin resistance and suppresses invasion in non-small cell lung carcinoma

Abstract

Background

Current high lung cancer mortality rates are mainly due to the occurrence of metastases and therapeutic resistance. Therefore, simultaneous targeting of these processes may be a valid approach for the treatment of this type of cancer. Here, we assessed relationships between CXC chemokine receptor type 4 (CXCR4) and focal adhesion kinase (FAK) gene expression levels and expression levels of the drug resistance-related genes ABCB1 and ABCC1, and tested the potential of CXCR4 and FAK inhibitors to reverse doxorubicin (DOX) resistance and to decrease the invasive capacity of non-small cell lung carcinoma (NSCLC) cells.

Methods

qRT-PCR was used for gene expression analyses in primary lung tissue samples obtained from 30 NSCLC patients and the human NSCLC-derived cell lines NCI-H460, NCI-H460/R and COR-L23. MTT, flow cytometry, cell death and β-galactosidase activity assays were used to assess the in vitro impact of CXCR4 and FAK inhibitors on DOX sensitivity. In addition, invasion and gelatin degradation assays were used to assess the in vitro impact of the respective inhibitors on metastasis-related processes in combination with DOX treatment.

Results

We found that ABCB1 over-expression was significantly associated with CXCR4 and FAK over-expression, whereas ABCC1 over-expression was associated with increased FAK expression. We also found that CXCR4 and FAK inhibitors strongly synergized with DOX in reducing cell viability, arresting the cell cycle in the S or G₂/M phases and inducing senescence. Additionally, we found that DOX enhanced the anti-invasive potential of CXCR4 and FAK inhibitors by reducing gelatin degradation and invasion.

Conclusions

From our data we conclude that targeting of CXCR4 and FAK may overcome ABCB1 and ABCC1-dependent DOX resistance in NSCLC cells and that simultaneous treatment of these cells with DOX may potentiate the anti-invasive effects of CXCR4 and FAK inhibitors.

from Cancer via ola Kala on Inoreader http://ift.tt/2fWpIWK
via IFTTT