Liver PD-1 Immunobiology

Publication date: Available online 6 January 2018
Source:Seminars in Oncology
Author(s): Colleen S. Curran, Elad Sharon
Disruption of liver immune tolerance allows for the development autoimmune hepatitis (AIH) and hepatocellular carcinoma (HCC). AIH rarely progresses to HCC but the diseases similarly induce the production of IL-18 and matrix metalloproteinases. These molecules have distinct effects on the immune response, including the Programmed cell-death 1 (PD-1) axis. In this review, differences in PD-1 function and possible cell signals in AIH and HCC are highlighted.



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Can therapeutic drug monitoring increase the safety of Imatinib in GIST patients?

Abstract

Imatinib at 400 mg daily is the standard treatment for patients affected with CML and GIST. The intervariability in plasma concentration is very significant. In many reports, a good therapeutic effect is attributed to an adequate concentration of Imatinib. However, few studies have been conducted to investigate the association between plasma concentration and side effects. Besides, no upper concentration limit of Imatinib plasma concentration detection has been established. The correlation of Imatinib trough concentrations (C_min) with adverse effects (AEs) was described here. Plasma samples were obtained from patients after 3 months treatment with Imatinib (steady state, n = 122). Liquid chromatography/ tandem mass spectrometry was used to determine the concentration of Imatinib and its metabolite NDI. The incidence of myelosuppression was increased significantly with the increased Imatinib trough plasma concentration. The plasma level of Imatinib and NDI in patients who developed myelosuppression are 1698.3 ± 598.6 ng/mL and 242.1 ng/mL, respectively, which were significantly higher than those in patients who did not (1327.2 ± 623.4 ng/mL, P = 1.75 × 10^-4; 206.3 ng/mL, P = 0.006). Estimated exposure thresholds of Imatinib and NDI were 1451.6 ng/mL with ROC_AUC (95%CI) of 0.693 (0.597–0.789) and 207.1 ng/mL with ROC_AUC (95%CI) of 0.646 (0.546–0.745), respectively. Multivariate regression confirmed the correlation of Imatinib C_min with myelosuppression. Other side effects such as fluid retention and rash were not found to be correlated with Imatinib concentrations. These results suggest that trough concentration of Imatinib should be taken into consideration to increase the safety of Imatinib therapy in GIST patients.

Since Imatinib is usually administered for a prolonged period, rational management of its side effects is of great importance. Few studies have been conducted to investigate the association between plasma concentration and side effects. In this study, Imatinib-induced myelosuppression was found to be correlated significantly with Imatinib concentration, and the estimated exposure threshold for myelosuppression was 1451.6 ng/mL with ROCAUC (95% CI) of 0.693 (0.597–0.789).

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Can therapeutic drug monitoring increase the safety of Imatinib in GIST patients?

Abstract

Imatinib at 400 mg daily is the standard treatment for patients affected with CML and GIST. The intervariability in plasma concentration is very significant. In many reports, a good therapeutic effect is attributed to an adequate concentration of Imatinib. However, few studies have been conducted to investigate the association between plasma concentration and side effects. Besides, no upper concentration limit of Imatinib plasma concentration detection has been established. The correlation of Imatinib trough concentrations (C_min) with adverse effects (AEs) was described here. Plasma samples were obtained from patients after 3 months treatment with Imatinib (steady state, n = 122). Liquid chromatography/ tandem mass spectrometry was used to determine the concentration of Imatinib and its metabolite NDI. The incidence of myelosuppression was increased significantly with the increased Imatinib trough plasma concentration. The plasma level of Imatinib and NDI in patients who developed myelosuppression are 1698.3 ± 598.6 ng/mL and 242.1 ng/mL, respectively, which were significantly higher than those in patients who did not (1327.2 ± 623.4 ng/mL, P = 1.75 × 10^-4; 206.3 ng/mL, P = 0.006). Estimated exposure thresholds of Imatinib and NDI were 1451.6 ng/mL with ROC_AUC (95%CI) of 0.693 (0.597–0.789) and 207.1 ng/mL with ROC_AUC (95%CI) of 0.646 (0.546–0.745), respectively. Multivariate regression confirmed the correlation of Imatinib C_min with myelosuppression. Other side effects such as fluid retention and rash were not found to be correlated with Imatinib concentrations. These results suggest that trough concentration of Imatinib should be taken into consideration to increase the safety of Imatinib therapy in GIST patients.

Since Imatinib is usually administered for a prolonged period, rational management of its side effects is of great importance. Few studies have been conducted to investigate the association between plasma concentration and side effects. In this study, Imatinib-induced myelosuppression was found to be correlated significantly with Imatinib concentration, and the estimated exposure threshold for myelosuppression was 1451.6 ng/mL with ROCAUC (95% CI) of 0.693 (0.597–0.789).

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Three-Dimensional Cellular Arrangement in Epithelial Ovarian Cancer Cell Lines TOV-21G and SKOV-3 is Associated with Apoptosis-Related miRNA Expression Modulation

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, and the lack of chemoresistance biomarkers contributes to the poor prognosis. Cancer stem cells (CSC) have been investigated in EOC to understand its relationship with chemoresistance and recurrence. In this context, in vitro cultivation-models are important tools for CSC studies. MicroRNAs (miRNAs) play key roles in cancer, CSC regulation and apoptosis. Thus, this study aims to evaluate the tumorsphere model as CSC-enrichment method in EOC studies and investigate apoptosis-related miRNAs in tumorspheres-derived EOC cell lines. TOV-21G and SKOV-3 were cultured in monolayer and tumorspheres. Genetic profiles of cell lines were obtained using COSMIC database. CD24/CD44/CD146/CD177 and ALDH1 markers were evaluated in cell lines and tumorspheres-derived by flow cytometry. Eleven miRNAs were selected by in silico analysis for qPCR analysis. According to COSMIC, TOV-21G and SKOV-3 have eight and nine cancer-related mutations, respectively. TOV-21G showed a CD44^+/high/CD24^−/low/CD117^−/low/CD146^−/low/ALDH1^low profile in both culture models; thus, no significant difference between cultivation models was identified. SKOV-3 showed a CD44^+/high/CD24^+/high/ CD117^−/low/CD146^−/low/ALDH1^low profile in both culture models, although the tumorsphere model showed a significant increase in CD24^+/high subpopulation (ovarian CSC-like). Among eleven miRNAs, we observed differences in miRNA expression between culture models. MiR-26a was overexpressed in TOV-21G tumorspheres, albeit downregulated in SKOV-3 tumorspheres. MiR-125b-5p, miR-17-5p and miR-221 was downregulated in tumorsphere model in both cell lines. Given that tumorsphere-derived SKOV-3 had a higher ratio of CD24^+/high cells, we suggest that miR-26a, miR-125b-5p, miR-17-5p and miR-221 downregulation could be related to poor EOC prognosis.

http://ift.tt/2D1XQck

Three-Dimensional Cellular Arrangement in Epithelial Ovarian Cancer Cell Lines TOV-21G and SKOV-3 is Associated with Apoptosis-Related miRNA Expression Modulation

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, and the lack of chemoresistance biomarkers contributes to the poor prognosis. Cancer stem cells (CSC) have been investigated in EOC to understand its relationship with chemoresistance and recurrence. In this context, in vitro cultivation-models are important tools for CSC studies. MicroRNAs (miRNAs) play key roles in cancer, CSC regulation and apoptosis. Thus, this study aims to evaluate the tumorsphere model as CSC-enrichment method in EOC studies and investigate apoptosis-related miRNAs in tumorspheres-derived EOC cell lines. TOV-21G and SKOV-3 were cultured in monolayer and tumorspheres. Genetic profiles of cell lines were obtained using COSMIC database. CD24/CD44/CD146/CD177 and ALDH1 markers were evaluated in cell lines and tumorspheres-derived by flow cytometry. Eleven miRNAs were selected by in silico analysis for qPCR analysis. According to COSMIC, TOV-21G and SKOV-3 have eight and nine cancer-related mutations, respectively. TOV-21G showed a CD44^+/high/CD24^−/low/CD117^−/low/CD146^−/low/ALDH1^low profile in both culture models; thus, no significant difference between cultivation models was identified. SKOV-3 showed a CD44^+/high/CD24^+/high/ CD117^−/low/CD146^−/low/ALDH1^low profile in both culture models, although the tumorsphere model showed a significant increase in CD24^+/high subpopulation (ovarian CSC-like). Among eleven miRNAs, we observed differences in miRNA expression between culture models. MiR-26a was overexpressed in TOV-21G tumorspheres, albeit downregulated in SKOV-3 tumorspheres. MiR-125b-5p, miR-17-5p and miR-221 was downregulated in tumorsphere model in both cell lines. Given that tumorsphere-derived SKOV-3 had a higher ratio of CD24^+/high cells, we suggest that miR-26a, miR-125b-5p, miR-17-5p and miR-221 downregulation could be related to poor EOC prognosis.

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Juvenile idiopathic arthritis: magnetic resonance imaging of the clinically unaffected knee

Abstract

Background

Synovial thickening detected on magnetic resonance imaging (MRI) is present in a significant number of children with clinically inactive juvenile idiopathic arthritis (JIA).

Objective

To evaluate patient characteristics and disease activity parameters in a cohort of children with clinically inactive JIA, both with and without synovial thickening, in order to clarify the observed discrepancy between clinical and MRI assessments.

Materials and methods

We prospectively enrolled 52 clinically inactive JIA patients (median age 13.3 years, 63.5% girls) who underwent MRI of the knee as major target joint in JIA. Children were divided into two groups based on MRI outcome: group 1, with synovial thickening on MRI; and group 2, with no synovial thickening on MRI. We used the Juvenile Arthritis MRI Scoring system to evaluate synovial thickness. We compared patient characteristics and disease activity parameters between the groups.

Results

Synovial thickening on MRI was present in 18 clinically inactive patients (group 1, 34.6%). The age was significantly lower for the patients in group 1 (median 10.7 versus 14.4, P=0.008). No significant differences were observed in any of the other patient characteristics nor the disease activity parameters tested.

Conclusion

Synovial thickening on MRI was present in nearly 35% of the children with clinically inactive JIA. Children with synovial thickening on MRI were significantly younger than those without. This might indicate that younger patients are at risk of subclinical disease activity and under-treatment, although the exact clinical relevance of synovial thickening on MRI has not been determined.

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The role of tryptophan metabolism in postpartum depression

Abstract

The Postpartum depression (PPD) is the most common postpartum psychiatric disorder, afflicting approximately 10%–20% of new mothers. Clinical symptoms of the PPD include depressive disorder, agitation, insomnia, anxiety and confusion, resulting in an increase in suicidal tendencies, thereby having significant impacts on the puerpera, newborn and their family. A growing body of data indicate a role for alterations in tryptophan metabolism in the PPD. The metabolism of tryptophan produces an array of crucial factors that can differentially regulate key physiological processes linked to the PPD. Importantly, an increase in stress hormones and immune-inflammatory activity drives tryptophan to the production of neuroregulatory kynurenine pathway products and away from the serotonin and melatonin pathways. This links the PPD to other disorders of depressed mood, which are classically associated with decreased serotonin and melatonin, coupled to increases in kynurenine pathway products. Several kynurenine pathway products, such as kynurenic acid and quinolinic acid, can have neuroregulatory effects, with consequences pathological underpinnings of the PPD. The current article reviews the role of alterations in tryptophan metabolism in the PPD.

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Juvenile idiopathic arthritis: magnetic resonance imaging of the clinically unaffected knee

Abstract

Background

Synovial thickening detected on magnetic resonance imaging (MRI) is present in a significant number of children with clinically inactive juvenile idiopathic arthritis (JIA).

Objective

To evaluate patient characteristics and disease activity parameters in a cohort of children with clinically inactive JIA, both with and without synovial thickening, in order to clarify the observed discrepancy between clinical and MRI assessments.

Materials and methods

We prospectively enrolled 52 clinically inactive JIA patients (median age 13.3 years, 63.5% girls) who underwent MRI of the knee as major target joint in JIA. Children were divided into two groups based on MRI outcome: group 1, with synovial thickening on MRI; and group 2, with no synovial thickening on MRI. We used the Juvenile Arthritis MRI Scoring system to evaluate synovial thickness. We compared patient characteristics and disease activity parameters between the groups.

Results

Synovial thickening on MRI was present in 18 clinically inactive patients (group 1, 34.6%). The age was significantly lower for the patients in group 1 (median 10.7 versus 14.4, P=0.008). No significant differences were observed in any of the other patient characteristics nor the disease activity parameters tested.

Conclusion

Synovial thickening on MRI was present in nearly 35% of the children with clinically inactive JIA. Children with synovial thickening on MRI were significantly younger than those without. This might indicate that younger patients are at risk of subclinical disease activity and under-treatment, although the exact clinical relevance of synovial thickening on MRI has not been determined.

http://ift.tt/2AB7q2T

The role of tryptophan metabolism in postpartum depression

Abstract

The Postpartum depression (PPD) is the most common postpartum psychiatric disorder, afflicting approximately 10%–20% of new mothers. Clinical symptoms of the PPD include depressive disorder, agitation, insomnia, anxiety and confusion, resulting in an increase in suicidal tendencies, thereby having significant impacts on the puerpera, newborn and their family. A growing body of data indicate a role for alterations in tryptophan metabolism in the PPD. The metabolism of tryptophan produces an array of crucial factors that can differentially regulate key physiological processes linked to the PPD. Importantly, an increase in stress hormones and immune-inflammatory activity drives tryptophan to the production of neuroregulatory kynurenine pathway products and away from the serotonin and melatonin pathways. This links the PPD to other disorders of depressed mood, which are classically associated with decreased serotonin and melatonin, coupled to increases in kynurenine pathway products. Several kynurenine pathway products, such as kynurenic acid and quinolinic acid, can have neuroregulatory effects, with consequences pathological underpinnings of the PPD. The current article reviews the role of alterations in tryptophan metabolism in the PPD.

http://ift.tt/2m41hXY

Letter to the Editor on Nevens et al.

We found the article by Nevens et al. [1] very original. In most of the series with up-front neck dissection (UFND), late toxicities were poorly reported [2], which is properly done in the current publication. Besides, this is the first study reporting the HPV status for the oropharyngeal subsites. However, the cohort was probably not large enough to look for any predictive role of HPV status for treatment selection.

http://ift.tt/2CO87v5

Proton beam therapy for skull base chordomas in 106 patients: A dose adaptive radiation protocol

To evaluate clinical results and safety of a dose adaptive protocol based on tumor volume coverage and critical structure constraints, for the treatment of skull base chordomas.

http://ift.tt/2m2gjNY

Patterns of Involved-Field Radiation Therapy (IFRT) Protocol Deviations in Pediatric versus Adolescent and Young Adults with Hodgkin Lymphoma: A Report from the Children’s Oncology Group (COG) AHOD0031

Publication date: Available online 6 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): A. Parzuchowski, Rizvan Bush, Qinglin Pei, D.L. Friedman, T.J. FitzGerald, S.L. Wolden, K.V. Dharmarajan, L.S. Constine, F. Laurie, S.K. Kessel, B. Appel, K. Fernandez, A. Punnett, C.L. Schwartz, J. Cox, S.A. Terezakis
BackgroundThis protocol for pediatric intermediate-risk Hodgkin Lymphoma (IRHL) evaluated the use of a dose-intensive chemotherapy regimen (ABVE-PC) with response-based therapy augmentation (addition of DECA) or therapy reduction (elimination of radiation). Central review of radiotherapy data for quality assurance (QA) was performed, and the association between radiation protocol deviation (RPD) and relapse was assessed in pediatric (<15) and AYA (≥15-21) groups.ProcedureIFRT treatment planning was reviewed prior to the start of treatment and at the completion of treatment. Records were reviewed through the Quality Assurance Review Center's (QARC) central review to identify RPD, classified according to dose (DD), volume (VD), under-treatment (UT), and over-treatment (OT). DD and VD were further classified as major or minor.ResultsOf the 1,712 patients enrolled, 1,155 received IFRT and 216 (18.7%) had RPD. DD and VD patterns were similar between pediatric and AYA groups. Minor VD was most common. UT RPD accounted for 69% in the pediatric group and 75% in the AYA group. Of 35 relapses and RPD, 29 had an under-treatment RPD. Among the patients who received IFRT, there was a significant difference in the cumulative incidence rates of relapse between pediatric and AYA groups (p=0.03) but no significant difference between patients with and without RPD (p=0.2).ConclusionsThe majority of RPD were minor and under-treatments in both the AYA and pediatrics population. There was no observed difference in RPD between the pediatric and AYA patients. Thus, in a well-defined and standardized protocol, RPD distributions for AYA patients are similar to the pediatrics population. However, the increased cumulative incidence of relapse in the AYA population who received IFRT compared to the pediatrics population needs to be further explored given the potential differences in clinical outcomes in the AYA population.

Teaser

As ******** is the largest phase III study to date on intermediate-risk Hodgkin Lymphoma in pediatric patients, we investigated the patterns of radiation protocol deviation and relapse between the pediatric and adolescent and young adult patient cohorts. We demonstrate that there were no statistically significant differences in deviation patterns between the two cohorts, though of those that received IFRT, there was a significant difference in cumulative incidence rates of relapse between the two groups.


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Phase II Study of Bortezomib in Combination with Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients with Newly-Diagnosed Glioblastoma Multiforme: Safety and Efficacy Assessment

Publication date: Available online 6 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Xiao-Tang Kong, Nhung T. Nguyen, Yoon J. Choi, Guicheng Zhang, HuyTram N. Nguyen, Emese Filka, Stacey Green, William H. Yong, Linda M. Liau, Richard M. Green, Tania Kaprealian, Whitney B. Pope, P. Leia Nghiemphu, Tim Cloughesy, Andrew Lassman, Albert Lai
Purpose/ObjectiveTo assess the safety and efficacy of upfront treatment using bortezomib in combination with standard radiation therapy (RT) and temozolomide, followed by adjuvant bortezomib and temozolomide for up to 24 cycles in patients with newly-diagnosed glioblastoma multiforme (GBM).Patients and MethodsTwenty-four newly-diagnosed GBM patients were enrolled. Patients received standard external beam regional RT with concurrent temozolomide commencing 3-6 weeks after surgery, followed by adjuvant temozolomide and bortezomib for up to 24 cycles or until tumor progression. During RT, bortezomib was given at 1.3 mg/m² on days 1, 4, 8, 11, 29, 32, 36, and 39. Post RT, bortezomib was given at 1.3 mg/m² on days 1, 4, 8, and 11 every 4 weeks.ResultsNo unexpected adverse events occurred from the addition of bortezomib. Efficacy analysis showed median progression free survival (PFS) of 6.2 months (95% CI, 3.7-8.8) with promising PFS rates at 18 months and beyond compared to historical norms (25.0% at 18 and 24 months, 16.7% at 30 months). In terms of overall survival (OS), the median OS was 19.1 months (95% CI, 6.7-31.4) with improved OS rates at 12 months and beyond (87.5% at 12, 50.0% at 24, 34.1% at 36 throughout 60 months) compared to historical norms. Median PFS was 24.7 months (95% CI 8.5-41.0) in 10 MGMT methylated and 5.1 months (95% CI 3.9-6.2) in 13 unmethylated patients. The estimated median OS was 61 months in the methylated (the upper bound of 95% CI could not be reached) and 16.4 months (95% CI 11.8-21.0) in the unmethylated patients.ConclusionAddition of bortezomib to current standard radio-chemotherapy in newly-diagnosed GBM patients was tolerable. The PFS and OS rates appeared promising with more benefit to MGMT methylated patients. Further clinical investigation is warranted in a larger cohort of patients.

Teaser

We conducted a phase II study of bortezomib in combination with temozolomide and regional radiotherapy (RT) in 24 newly-diagnosed GBM patients. Addition of bortezomib to current standard care was well-tolerated, and observed toxicities were acceptable. Overall survival rates were improved compared to historical norms, especially in MGMT methylated patients. Further clinical investigation is warranted in larger cohort of patients.


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Local Control following Stereotactic Body Radiation Therapy for Liver Tumors

Publication date: Available online 6 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Nitin Ohri, Wolfgang A. Tomé, Alejandra Méndez Romero, Moyed Mifften, Randall K. Ten Haken, Laura A. Dawson, Jimm Grimm, Ellen Yorke, Andrew Jackson
PurposeNumerous dosing and fractionation schedules have been used to treat hepatic tumors with stereotactic body radiation therapy (SBRT). In this report, we have quantitatively evaluated published experiences with hepatic SBRT to determine local control rates following treatment of primary and metastatic liver tumors and to examine if outcomes are affected by SBRT dosing regimen.MethodsWe identified published articles that reported local control rates following SBRT for primary or metastatic liver tumors. Biologically effective doses (BEDs) were calculated for each dosing regimen using the Linear Quadratic Equation. We excluded series in which a wide range of BEDs was used. Individual lesion data for local control were extracted from actuarial survival curves, and data were aggregated to form a single dataset. Actuarial local control curves were generated using the Kaplan-Meier method after grouping lesions by disease type and BED (<100 Gy10 v. >100 Gy10). Comparisons were made using logrank testing.ResultsThirteen papers met all inclusion criteria and formed the dataset for this analysis. One, two, and three-year actuarial local control rates following SBRT for primary liver tumors (n=431) were 93%, 89%, and 86%, respectively. Lower one (90%), two (79%), and three-year (76%) actuarial local control rates were observed for liver metastases (n=290, logrank p=0.011). Among patients treated with SBRT for primary liver tumors, there was no evidence that local control is influenced by BED within the range of schedules used. For liver metastases, on the other hand, outcomes were significantly better for lesions treated with BEDs exceeding 100 Gy10 (3-year local control 93%) than for those treated with BEDs less than or equal to 100 Gy10 (3-year local control 65%, p<0.001).ConclusionSBRT for primary liver tumors provides high rates of durable local control, with no clear evidence for a dose-response relationship among commonly-utilized schedules. Excellent local control rates are also seen following SBRT for liver metastases when biologically effective doses above 100 Gy10 are utilized.

Teaser

We have quantitatively evaluated published experiences with hepatic SBRT to determine local control rates for primary and metastatic liver tumors and have examined if outcomes are affected by SBRT dosing regimen. We found that for primary liver tumors SBRT provides high rates of durable local control, with no clear evidence of a dose-response relationship for commonly-utilized schedules. While for liver metastases following SBRT excellent local control rates are seen when utilizing biologically effective doses above 100 Gy10.


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Radiation Dose-Volume Effects for Liver SBRT

Publication date: Available online 6 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Moyed Miften, Yevgeniy Vinogradskiy, Vitali Moiseenko, Jimm Grimm, Ellen Yorke, Andrew Jackson, Wolfgang A. Tomé, Randall Ten Haken, Nitin Ohri, Alejandra Méndez Romero, Karyn A. Goodman, Lawrence B. Marks, Brian Kavanagh, Laura A. Dawson
Stereotactic Body Radiation Therapy (SBRT) has emerged as an effective, non-invasive treatment option for primary liver cancer and metastatic disease occurring in the liver. While SBRT can be highly effective for establishing local control in hepatic malignancies, there is a tradeoff between tumor control and normal tissue complications. The objective of this work was to review the normal tissue dose-volume effects for SBRT-induced liver and gastrointestinal (GI) toxicities, and derive normal tissue complication probability models.



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Early Tissue Effects of Stereotactic Body Radiotherapy in Spinal Metastases

Publication date: Available online 6 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jasper G. Steverink, Stefan M. Willems, Marielle E.P. Philippens, Nicolien Kasperts, Wietse S.C. Eppinga, Anne L. Versteeg, Joanne M. van der Velden, Salman Faruqi, Arjun Sahgal, Jorrit-Jan Verlaan
IntroductionStereotactic body radiotherapy (SBRT) is a highly effective and potentially ablative treatment for complex spinal metastases. Recent literature suggests radio-biologic effects of SBRT expanding beyond the traditional concept of DNA-damage. Anti-tumor immunity, vascular damage leading to tumor necrosis and increased rates of tumor apoptosis are implied, yet in-human evidence remains scarce. This study reports unique pathologic confirmation of SBRT-induced biologic effects within spinal metastases treated with pre-operative SBRT.Materials and MethodsTen patients with spinal metastases secondary to various solid tumors were treated with pre-operative single-fraction SBRT (18 Gy) to the MRI-defined macroscopic metastasis followed by spinal stabilization within 24 hours. Perioperative samples of spinal metastases were obtained, and 6 patients also had a pre-SBRT biopsy for matched comparison. Samples were stained for tumor necrosis on routine HE slices and subsequently underwent immunohistochemical staining for T-cells (CD3+, CD4+, CD8+), NK-cells (CD56+), endothelium (CD31+) and apoptotic activity (Caspase-3).ResultsPerioperative biopsies were obtained approximately 6 hours (range 4.5-7.5h) or 21 hours (range 18.5-22.5h) post-SBRT. Necrosis was observed in 83% of 21h post-SBRT samples (5/6), as compared to 0% in pre-SBRT biopsies (0/6) and 6h post-SBRT biopsies (0/4). Tumor cell apoptosis increased greatly in 21h post-SBRT samples compared to pre- and 6h post-SBRT. CD31+ vessel counts decreased post-SBRT as did mitotic activity. Notably, both of the renal cell metastases displayed major decreases in vessel density. Desmoplastic reaction was visible in 67% (4/6) with pre-SBRT samples compared to 100% (10/10) post-SBRT samples. T- and NK-cell counts were relatively unaffected.ConclusionHigh-dose single-fraction SBRT induced tumor necrosis, desmoplasia and tumor apoptosis and decreased tumor vessel density within 24 hours, even in renal cell metastases. The role of immune cells seems limited in this early phase. These first-in-man results imply direct vascular- and DNA-damage mechanisms important in the clinical efficacy specific to spine SBRT.



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Radiation as an Effective Salvage Therapy for Secondary CNS Lymphoma

Publication date: Available online 6 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sarah A. Milgrom, Chelsea C. Pinnix, T Linda Chi, Thinh H. Vu, Jillian R. Gunther, Tommy Sheu, Nathan Fowler, Jason R. Westin, Loretta J. Nastoupil, Yasuhiro Oki, Luis E. Fayad, Sattva Neelapu, Maria Alma Rodriguez, Frederick B. Hagemeister, Michelle A. Fanale, Hun J. Lee, Chitra Hosing, Sairah Ahmed, Yago Nieto, Elizabeth J. Shpall, Bouthaina S. Dabaja
We assessed the efficacy of radiation therapy (RT) in the management of secondary central nervous system (CNS) lymphoma. The cohort comprised 44 patients with systemic diffuse large-B cell lymphoma (DLBCL) secondarily involving the brain and/or leptomeninges at initial diagnosis or relapse, who received RT. Twenty-nine patients (66%) were in systemic remission when diagnosed with CNS disease. The overall response rate to RT by magnetic resonance imaging was 88% (42% complete, 46% partial). The median overall survival (OS) after RT initiation was 7 months (95% CI: 4-10 months). The OS curve plateaued at 31% from 2 to 8 years. OS was superior in patients who achieved a complete or partial response to RT, underwent stem cell transplantation (SCT) after RT, and had brain parenchymal (vs. leptomeningeal) disease. Eight cases of CNS disease progression occurred after RT: one involved the brain parenchyma and 7 involved the spine and/or CSF/meninges. We conclude that RT is associated with high response rates and may contribute to long-term OS. Additionally, RT may provide CNS disease control that facilitates successful salvage with SCT in patients with chemorefractory disease.

Teaser

We reviewed the outcomes of patients with secondary central nervous system involvement by diffuse large-B cell lymphoma, who were treated with radiation therapy (RT) at a single institution. RT was associated with high rates of radiographic disease response and local control. Overall survival was superior in patients who achieved a complete or partial response to RT, who underwent autologous stem cell transplantation after RT, and who had brain parenchymal (vs. leptomeningeal) disease.


http://ift.tt/2AyVT4t

Local Control following Stereotactic Body Radiation Therapy for Liver Tumors

Publication date: Available online 6 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Nitin Ohri, Wolfgang A. Tomé, Alejandra Méndez Romero, Moyed Mifften, Randall K. Ten Haken, Laura A. Dawson, Jimm Grimm, Ellen Yorke, Andrew Jackson
PurposeNumerous dosing and fractionation schedules have been used to treat hepatic tumors with stereotactic body radiation therapy (SBRT). In this report, we have quantitatively evaluated published experiences with hepatic SBRT to determine local control rates following treatment of primary and metastatic liver tumors and to examine if outcomes are affected by SBRT dosing regimen.MethodsWe identified published articles that reported local control rates following SBRT for primary or metastatic liver tumors. Biologically effective doses (BEDs) were calculated for each dosing regimen using the Linear Quadratic Equation. We excluded series in which a wide range of BEDs was used. Individual lesion data for local control were extracted from actuarial survival curves, and data were aggregated to form a single dataset. Actuarial local control curves were generated using the Kaplan-Meier method after grouping lesions by disease type and BED (<100 Gy10 v. >100 Gy10). Comparisons were made using logrank testing.ResultsThirteen papers met all inclusion criteria and formed the dataset for this analysis. One, two, and three-year actuarial local control rates following SBRT for primary liver tumors (n=431) were 93%, 89%, and 86%, respectively. Lower one (90%), two (79%), and three-year (76%) actuarial local control rates were observed for liver metastases (n=290, logrank p=0.011). Among patients treated with SBRT for primary liver tumors, there was no evidence that local control is influenced by BED within the range of schedules used. For liver metastases, on the other hand, outcomes were significantly better for lesions treated with BEDs exceeding 100 Gy10 (3-year local control 93%) than for those treated with BEDs less than or equal to 100 Gy10 (3-year local control 65%, p<0.001).ConclusionSBRT for primary liver tumors provides high rates of durable local control, with no clear evidence for a dose-response relationship among commonly-utilized schedules. Excellent local control rates are also seen following SBRT for liver metastases when biologically effective doses above 100 Gy10 are utilized.

Teaser

We have quantitatively evaluated published experiences with hepatic SBRT to determine local control rates for primary and metastatic liver tumors and have examined if outcomes are affected by SBRT dosing regimen. We found that for primary liver tumors SBRT provides high rates of durable local control, with no clear evidence of a dose-response relationship for commonly-utilized schedules. While for liver metastases following SBRT excellent local control rates are seen when utilizing biologically effective doses above 100 Gy10.


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Patterns of Involved-Field Radiation Therapy (IFRT) Protocol Deviations in Pediatric versus Adolescent and Young Adults with Hodgkin Lymphoma: A Report from the Children’s Oncology Group (COG) AHOD0031

Publication date: Available online 6 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): A. Parzuchowski, Rizvan Bush, Qinglin Pei, D.L. Friedman, T.J. FitzGerald, S.L. Wolden, K.V. Dharmarajan, L.S. Constine, F. Laurie, S.K. Kessel, B. Appel, K. Fernandez, A. Punnett, C.L. Schwartz, J. Cox, S.A. Terezakis
BackgroundThis protocol for pediatric intermediate-risk Hodgkin Lymphoma (IRHL) evaluated the use of a dose-intensive chemotherapy regimen (ABVE-PC) with response-based therapy augmentation (addition of DECA) or therapy reduction (elimination of radiation). Central review of radiotherapy data for quality assurance (QA) was performed, and the association between radiation protocol deviation (RPD) and relapse was assessed in pediatric (<15) and AYA (≥15-21) groups.ProcedureIFRT treatment planning was reviewed prior to the start of treatment and at the completion of treatment. Records were reviewed through the Quality Assurance Review Center's (QARC) central review to identify RPD, classified according to dose (DD), volume (VD), under-treatment (UT), and over-treatment (OT). DD and VD were further classified as major or minor.ResultsOf the 1,712 patients enrolled, 1,155 received IFRT and 216 (18.7%) had RPD. DD and VD patterns were similar between pediatric and AYA groups. Minor VD was most common. UT RPD accounted for 69% in the pediatric group and 75% in the AYA group. Of 35 relapses and RPD, 29 had an under-treatment RPD. Among the patients who received IFRT, there was a significant difference in the cumulative incidence rates of relapse between pediatric and AYA groups (p=0.03) but no significant difference between patients with and without RPD (p=0.2).ConclusionsThe majority of RPD were minor and under-treatments in both the AYA and pediatrics population. There was no observed difference in RPD between the pediatric and AYA patients. Thus, in a well-defined and standardized protocol, RPD distributions for AYA patients are similar to the pediatrics population. However, the increased cumulative incidence of relapse in the AYA population who received IFRT compared to the pediatrics population needs to be further explored given the potential differences in clinical outcomes in the AYA population.

Teaser

As ******** is the largest phase III study to date on intermediate-risk Hodgkin Lymphoma in pediatric patients, we investigated the patterns of radiation protocol deviation and relapse between the pediatric and adolescent and young adult patient cohorts. We demonstrate that there were no statistically significant differences in deviation patterns between the two cohorts, though of those that received IFRT, there was a significant difference in cumulative incidence rates of relapse between the two groups.


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Phase II Study of Bortezomib in Combination with Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients with Newly-Diagnosed Glioblastoma Multiforme: Safety and Efficacy Assessment

Publication date: Available online 6 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Xiao-Tang Kong, Nhung T. Nguyen, Yoon J. Choi, Guicheng Zhang, HuyTram N. Nguyen, Emese Filka, Stacey Green, William H. Yong, Linda M. Liau, Richard M. Green, Tania Kaprealian, Whitney B. Pope, P. Leia Nghiemphu, Tim Cloughesy, Andrew Lassman, Albert Lai
Purpose/ObjectiveTo assess the safety and efficacy of upfront treatment using bortezomib in combination with standard radiation therapy (RT) and temozolomide, followed by adjuvant bortezomib and temozolomide for up to 24 cycles in patients with newly-diagnosed glioblastoma multiforme (GBM).Patients and MethodsTwenty-four newly-diagnosed GBM patients were enrolled. Patients received standard external beam regional RT with concurrent temozolomide commencing 3-6 weeks after surgery, followed by adjuvant temozolomide and bortezomib for up to 24 cycles or until tumor progression. During RT, bortezomib was given at 1.3 mg/m² on days 1, 4, 8, 11, 29, 32, 36, and 39. Post RT, bortezomib was given at 1.3 mg/m² on days 1, 4, 8, and 11 every 4 weeks.ResultsNo unexpected adverse events occurred from the addition of bortezomib. Efficacy analysis showed median progression free survival (PFS) of 6.2 months (95% CI, 3.7-8.8) with promising PFS rates at 18 months and beyond compared to historical norms (25.0% at 18 and 24 months, 16.7% at 30 months). In terms of overall survival (OS), the median OS was 19.1 months (95% CI, 6.7-31.4) with improved OS rates at 12 months and beyond (87.5% at 12, 50.0% at 24, 34.1% at 36 throughout 60 months) compared to historical norms. Median PFS was 24.7 months (95% CI 8.5-41.0) in 10 MGMT methylated and 5.1 months (95% CI 3.9-6.2) in 13 unmethylated patients. The estimated median OS was 61 months in the methylated (the upper bound of 95% CI could not be reached) and 16.4 months (95% CI 11.8-21.0) in the unmethylated patients.ConclusionAddition of bortezomib to current standard radio-chemotherapy in newly-diagnosed GBM patients was tolerable. The PFS and OS rates appeared promising with more benefit to MGMT methylated patients. Further clinical investigation is warranted in a larger cohort of patients.

Teaser

We conducted a phase II study of bortezomib in combination with temozolomide and regional radiotherapy (RT) in 24 newly-diagnosed GBM patients. Addition of bortezomib to current standard care was well-tolerated, and observed toxicities were acceptable. Overall survival rates were improved compared to historical norms, especially in MGMT methylated patients. Further clinical investigation is warranted in larger cohort of patients.


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Radiation Dose-Volume Effects for Liver SBRT

Publication date: Available online 6 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Moyed Miften, Yevgeniy Vinogradskiy, Vitali Moiseenko, Jimm Grimm, Ellen Yorke, Andrew Jackson, Wolfgang A. Tomé, Randall Ten Haken, Nitin Ohri, Alejandra Méndez Romero, Karyn A. Goodman, Lawrence B. Marks, Brian Kavanagh, Laura A. Dawson
Stereotactic Body Radiation Therapy (SBRT) has emerged as an effective, non-invasive treatment option for primary liver cancer and metastatic disease occurring in the liver. While SBRT can be highly effective for establishing local control in hepatic malignancies, there is a tradeoff between tumor control and normal tissue complications. The objective of this work was to review the normal tissue dose-volume effects for SBRT-induced liver and gastrointestinal (GI) toxicities, and derive normal tissue complication probability models.



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Early Tissue Effects of Stereotactic Body Radiotherapy in Spinal Metastases

Publication date: Available online 6 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jasper G. Steverink, Stefan M. Willems, Marielle E.P. Philippens, Nicolien Kasperts, Wietse S.C. Eppinga, Anne L. Versteeg, Joanne M. van der Velden, Salman Faruqi, Arjun Sahgal, Jorrit-Jan Verlaan
IntroductionStereotactic body radiotherapy (SBRT) is a highly effective and potentially ablative treatment for complex spinal metastases. Recent literature suggests radio-biologic effects of SBRT expanding beyond the traditional concept of DNA-damage. Anti-tumor immunity, vascular damage leading to tumor necrosis and increased rates of tumor apoptosis are implied, yet in-human evidence remains scarce. This study reports unique pathologic confirmation of SBRT-induced biologic effects within spinal metastases treated with pre-operative SBRT.Materials and MethodsTen patients with spinal metastases secondary to various solid tumors were treated with pre-operative single-fraction SBRT (18 Gy) to the MRI-defined macroscopic metastasis followed by spinal stabilization within 24 hours. Perioperative samples of spinal metastases were obtained, and 6 patients also had a pre-SBRT biopsy for matched comparison. Samples were stained for tumor necrosis on routine HE slices and subsequently underwent immunohistochemical staining for T-cells (CD3+, CD4+, CD8+), NK-cells (CD56+), endothelium (CD31+) and apoptotic activity (Caspase-3).ResultsPerioperative biopsies were obtained approximately 6 hours (range 4.5-7.5h) or 21 hours (range 18.5-22.5h) post-SBRT. Necrosis was observed in 83% of 21h post-SBRT samples (5/6), as compared to 0% in pre-SBRT biopsies (0/6) and 6h post-SBRT biopsies (0/4). Tumor cell apoptosis increased greatly in 21h post-SBRT samples compared to pre- and 6h post-SBRT. CD31+ vessel counts decreased post-SBRT as did mitotic activity. Notably, both of the renal cell metastases displayed major decreases in vessel density. Desmoplastic reaction was visible in 67% (4/6) with pre-SBRT samples compared to 100% (10/10) post-SBRT samples. T- and NK-cell counts were relatively unaffected.ConclusionHigh-dose single-fraction SBRT induced tumor necrosis, desmoplasia and tumor apoptosis and decreased tumor vessel density within 24 hours, even in renal cell metastases. The role of immune cells seems limited in this early phase. These first-in-man results imply direct vascular- and DNA-damage mechanisms important in the clinical efficacy specific to spine SBRT.



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Radiation as an Effective Salvage Therapy for Secondary CNS Lymphoma

Publication date: Available online 6 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sarah A. Milgrom, Chelsea C. Pinnix, T Linda Chi, Thinh H. Vu, Jillian R. Gunther, Tommy Sheu, Nathan Fowler, Jason R. Westin, Loretta J. Nastoupil, Yasuhiro Oki, Luis E. Fayad, Sattva Neelapu, Maria Alma Rodriguez, Frederick B. Hagemeister, Michelle A. Fanale, Hun J. Lee, Chitra Hosing, Sairah Ahmed, Yago Nieto, Elizabeth J. Shpall, Bouthaina S. Dabaja
We assessed the efficacy of radiation therapy (RT) in the management of secondary central nervous system (CNS) lymphoma. The cohort comprised 44 patients with systemic diffuse large-B cell lymphoma (DLBCL) secondarily involving the brain and/or leptomeninges at initial diagnosis or relapse, who received RT. Twenty-nine patients (66%) were in systemic remission when diagnosed with CNS disease. The overall response rate to RT by magnetic resonance imaging was 88% (42% complete, 46% partial). The median overall survival (OS) after RT initiation was 7 months (95% CI: 4-10 months). The OS curve plateaued at 31% from 2 to 8 years. OS was superior in patients who achieved a complete or partial response to RT, underwent stem cell transplantation (SCT) after RT, and had brain parenchymal (vs. leptomeningeal) disease. Eight cases of CNS disease progression occurred after RT: one involved the brain parenchyma and 7 involved the spine and/or CSF/meninges. We conclude that RT is associated with high response rates and may contribute to long-term OS. Additionally, RT may provide CNS disease control that facilitates successful salvage with SCT in patients with chemorefractory disease.

Teaser

We reviewed the outcomes of patients with secondary central nervous system involvement by diffuse large-B cell lymphoma, who were treated with radiation therapy (RT) at a single institution. RT was associated with high rates of radiographic disease response and local control. Overall survival was superior in patients who achieved a complete or partial response to RT, who underwent autologous stem cell transplantation after RT, and who had brain parenchymal (vs. leptomeningeal) disease.


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Chemotherapy-induced metastasis: mechanisms and translational opportunities

Abstract

Tumors often overcome the cytotoxic effects of chemotherapy through either acquired or environment-mediated drug resistance. In addition, signals from the microenvironment obfuscate the beneficial effects of chemotherapy and may facilitate progression and metastatic dissemination. Seminal mediators in chemotherapy-induced metastasis appear to be a wide range of hematopoietic, mesenchymal and immune progenitor cells, originating from the bone marrow. The actual purpose of these cells is to orchestrate the repair response to the cytotoxic damage of chemotherapy. However, these repair responses are exploited by tumor cells at every step of the metastatic cascade, ranging from tumor cell invasion, intravasation and hematogenous dissemination to extravasation and effective colonization at the metastatic site. A better understanding of the mechanistic underpinnings of chemotherapy-induced metastasis will allow us to better predict which patients are more likely to exhibit pro-metastatic responses to chemotherapy and will help develop new therapeutic strategies to neutralize chemotherapy-driven prometastatic changes.

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Chemotherapy-induced metastasis: mechanisms and translational opportunities

Abstract

Tumors often overcome the cytotoxic effects of chemotherapy through either acquired or environment-mediated drug resistance. In addition, signals from the microenvironment obfuscate the beneficial effects of chemotherapy and may facilitate progression and metastatic dissemination. Seminal mediators in chemotherapy-induced metastasis appear to be a wide range of hematopoietic, mesenchymal and immune progenitor cells, originating from the bone marrow. The actual purpose of these cells is to orchestrate the repair response to the cytotoxic damage of chemotherapy. However, these repair responses are exploited by tumor cells at every step of the metastatic cascade, ranging from tumor cell invasion, intravasation and hematogenous dissemination to extravasation and effective colonization at the metastatic site. A better understanding of the mechanistic underpinnings of chemotherapy-induced metastasis will allow us to better predict which patients are more likely to exhibit pro-metastatic responses to chemotherapy and will help develop new therapeutic strategies to neutralize chemotherapy-driven prometastatic changes.

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The sentinel lymph node spread determines quantitatively melanoma seeding to non-sentinel lymph nodes and survival

Publication date: March 2018
Source:European Journal of Cancer, Volume 91
Author(s): Anja Ulmer, Klaus Dietz, Melanie Werner-Klein, Hans-Martin Häfner, Claudia Schulz, Philipp Renner, Florian Weber, Helmut Breuninger, Martin Röcken, Claus Garbe, Gerhard Fierlbeck, Christoph A. Klein
IntroductionComplete lymph node dissection (CLND) after a positive sentinel node (SN) biopsy provides important prognostic information in melanoma patients but has been questioned for therapeutic use recently. We explored whether quantification of the tumour spread to SNs may replace histopathology of non-sentinel nodes (NSNs) for staging purposes.Patients and methodsWe quantified melanoma spread in SNs and NSNs in 128 patients undergoing CLND for a positive SN. In addition to routine histopathology, one-half of each of all 1496 SNs and NSNs was disaggregated into a single cell suspension and stained immunocytochemically to determine the number of melanoma cells per 10⁶ lymph node cells, i.e. the disseminated cancer cell density (DCCD).ResultsWe uncovered melanoma spread to NSNs in the majority of patients; however, the tumour load and the proportion of positive nodes were significantly lower in NSNs than in SNs. The relation between SN and NSN spread could be described by a mathematical function with DCCDNSN = DCCDSN^c/10^1−c (c = 0.69; 95% confidence interval [CI]: 0.62–0.76). At a median follow-up of 67 months, multivariable Cox regression analyses revealed that DCCDSN (p = 0.02; HR 1.34, 95% CI: 1.05–1.71) and the total number of pathologically positive nodes (p = 0.02; HR 1.53, 95% CI: 1.07–2.22) were significant risk factors after controlling for age, gender, thickness of melanoma and ulceration status. A prognostic model based on DCCDSN and melanoma thickness predicted outcome as accurately as a model including pathological information of both SNs and NSNs.ConclusionThe assessment of DCCDSN renders CLND for staging purposes unnecessary.



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Is Ki67 still a powerful ally in predicting the clinical benefit of anthracyclines for the adjuvant treatment of early breast cancer?

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A case of Shewanella algae endocarditis: an emerging pathogen with a diverse clinical spectrum

Shewanella algae is a rare pathogen related to water exposure in temperate climates. It is commonly associated with skin and soft tissue infections, peritonitis and bacteraemia. We report the first-ever case of S. algae infective endocarditis in a patient with previous splenectomy and explore the difficulties in treatment as well as highlight the importance of this organism as an emerging pathogen.

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Management of homozygous familial hypercholesterolaemia in two brothers

Homozygous familial hypercholesterolaemia (HoFH) is a rare, genetic disorder of abnormally high levels of low-density lipoprotein cholesterol (LDL-C) requiring aggressive interventions to retard the evolution of atherosclerotic cardiovascular disease. We treated two brothers (ages 46 years and 47 years) with HoFH with statins, lipoproteinapheresis (LA) and the microsomal triglyceride transfer protein inhibitor lomitapide. Both brothers carried the p.Thr434Arg homozygous LDLR mutation and had childhood total cholesterol levels >700 mg/dL. Inter-LA LDL-C levels remained high; therefore, they were given escalating doses of oral lomitapide (5–10 mg/day). One brother was able to maintain LDL-C levels <70 mg/dL and stop LA. Lomitapide was well tolerated, with only an episode of headache requiring dose reduction from 40 mg/day to 20 mg/day in one patient. In two HoFH cases, lomitapide was an effective and well-tolerated adjunct therapy. Lomitapide doses required to maintain LDL-C goal levels appear to be lower in clinical practice than in clinical trials.

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Colovesical fistula: a rare complication after renal transplantation

Colovesical fistula per se is a rare condition and most commonly occurs secondary to diverticular disease in normal patients. Colovesical fistula in the setting of post-renal transplantation is even rarer and very few cases have been reported in literature. Patients with autosomal-dominant polycystic kidney disease (ADPKD) are predisposed to diverticulosis and hence are at a higher risk for fistula formation. Herein, we report a case of colovesical fistula in a renal allograft recipient with ADPKD in the absence of diverticulosis. The patient was successfully operated and is stable with no complications at 1-year follow-up.

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Successful management of a 24-year-old pregnant woman with necrotising fasciitis of the forearm

A 24-year-old woman who was 24 weeks pregnant presented to the emergency department with septic shock and an elbow wound that had become infected. She sustained an injury to the tip of the right elbow on a light switch 4 days prior. In the space of 1 day, she developed a necrotising soft tissue infection, which was rapidly spread to the forearm with florid sepsis. Her initial serum C reactive protein was 392 mg/L, and white cell count was 32x10⁹/L. The patient was treated promptly with aggressive surgical debridement and broad-spectrum antibiotics. An early multidisciplinary approach including orthopaedic surgeons, anaesthetics, intensive care, obstetrics, microbiologists and paediatrics was taken. Ultimately, both mother and child had an excellent outcome, the former of whom only had minimal soft tissue resection and primary wound closure. Emphasis is made on first treating the mother as the patient and priority.

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Mycophenolate mofetil treatment in a patient with recurrent lymphocytic hypophysitis

Lymphocytic hypophysitis (LHP) is a relatively rare disease characterised by lymphocytic infiltration of the pituitary gland, resulting in pituitary dysfunction. LHP is generally responsive to corticosteroid therapy, but cases with recurrence require clinicians to select second-line therapy. We report here the case of a 58-year-old patient with LHP who developed panhypopituitarism and bitemporal hemianopia. He responded to prednisolone 40 mg/day but relapsed during tapering. The prednisolone dose was increased again and mycophenolate mofetil (MMF) was added. Thereafter, over the course of 1 year, prednisolone was tapered to 8 mg/day without relapse. Because of the rarity of LHP, there are no standard treatment protocols that support the choice of a specific immunosuppressive drug. MMF was effective for recurrent LHP in our case. Further accumulation of cases is needed to establish the standard treatment for this disease.

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Ureteral intramural metastatic deposit of prostate cancer with ureteric obstruction

True metastatic ureteric lesions are exceptionally rare when sourced from any primary tumour. Primary prostatic cancer metastasis to the ureter is understandably even more atypical with very few cases reported in current literature. True intramural ureteric metastatic disease deposited from prostate cancer is an even rarer occurrence. We present a case of a man in his mid-60s with left-sided hydronephrosis in the setting of biochemical recurrence of Gleason 9 prostate cancer. Initially misdiagnosed as obstruction secondary to mass effect from a large trigonal lesion, subsequent investigation revealed solid intramural metastatic deposit of prostate primary tumour in the distal ureter. We detail current hypotheses regarding the subsequent pathophysiology of the disease and its common clinical presentations. Our case highlights that prostatic metastasis should be considered as a differential in coexisting prostate cancer and ureteric obstruction despite its low incidence.

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Guillain-Barre syndrome with exaggerated pleocytosis and anti-GM1 ganglioside antibodies

An 81-year-old man presented with fever, confusion and rapidly-progressive flaccid tetraparesis. Clinical presentation and neurophysiology were consistent with a severe axonal polyneuropathy. Anti-GM1 and Campylobacter serology were both positive, consistent with postinfectious axonal-variant Guillain-Barré syndrome (GBS). GBS is characterised by albuminocytological dissociation, where an elevated protein and acellular cerebrospinal fluid are typical. However, in this case, CSF analysis revealed an exaggerated pleocytosis (72 white blood cells (WBC)/mm³). No source of central nervous system infection or inflammation was identified despite thorough investigation. The patient was treated with intravenous immunoglobulin and intensive rehabilitation.

Albuminocytological dissociation classically distinguishes GBS from infective causes of flaccid weakness (eg, enteroviruses, flaviviruses and HIV). Diagnostic criteria frequently cite a pleocytosis of <50 WBC/mm³ as required in the diagnosis of GBS. However, this case demonstrates that pleocytosis exceeding this level can occur in the presence of convincing evidence of GBS and without demonstrable neurotropic infection.

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Neonatal small left colon syndrome (NSLCS): Rare but important complication in an infant of diabetic mother

Description

A female infant born at 35+6 weeks by caesarean section to a mother with poorly controlled type 1 diabetes was admitted to the neonatal unit due to hypoglycaemia. Birth weight was 3.2 kg (91–98th centile). On day 1, the baby required a glucose load of 10 mg/kg/min to maintain normoglycaemia. By day 2, her blood sugar levels stabilised, feeds were started and intravenous fluids were weaned. With the introduction of feeds, she had milky vomits and abdominal distension. Feeds were stopped and an abdominal X-ray showed a dilated transverse colon with an abrupt transition zone at splenic flexure (figure 1, arrow indicates transition zone). Symptoms resolved after passage of a large, thick plug of mucus and meconium that resembled an intestinal cast (figure 2). 

Figure 1

Patient's plain abdominal X-ray. There is a dilated transverse colon and calibre change at the splenic flexure indicates...

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Trichosporon asahii septic thrombophlebitis following lower extremity amputation in an immunocompetent host

A 59-year-old man with a history of peripheral vascular disease status post femoral popliteal bypass presented with critical limb ischaemia of the left leg. An arterial Doppler ultrasound showed an occluded graft requiring an above knee amputation. Five days after surgery, the patient developed fever, leucocytosis, significant stump swelling and pain, and serosanguinous discharge from his wound. Wound swab cultures from the stump grew Trichosporon asahii. A venous Doppler ultrasound revealed extensive thrombosis of the left lower extremity. Biopsy of the left thigh muscle showed necrotic thrombus with fungal hyphae in the clotted blood vessel. The left femoral vein was subsequently resected, and the excised venous tissue also grew T. asahii. The patient was successfully treated with voriconazole based on antifungal susceptibilities. This case describes an invasive fungal infection in the absence of typical immunosuppressive conditions commonly associated with Trichosporon spp. It also illustrates the role of a combination of antimicrobial and surgical management in achieving cure.

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Flaxseed Lignans Enhance the Cytotoxicity of Chemotherapeutic Agents against Breast Cancer Cell Lines MDA-MB-231 and SKBR3.

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Flaxseed Lignans Enhance the Cytotoxicity of Chemotherapeutic Agents against Breast Cancer Cell Lines MDA-MB-231 and SKBR3.

Nutr Cancer. 2018 Jan 05;:1-10

Authors: Di Y, De Silva F, Krol ES, Alcorn J

Abstract
Systemic cytotoxic chemotherapy remains the mainstay of metastatic breast cancer; however, prognosis and overall survival is unfavorable due to inadequate treatment response and/or unacceptable toxicity. Natural compounds and their active metabolites receive increasing attention as possible adjuvant therapy with cancer chemotherapeutics to improve treatment response, survival rates, and quality of life of breast cancer patients. This study investigated the combination of flaxseed lignans (Secoisolariciresinol and Enterolactone) with classic chemotherapeutic agents (Docetaxel, Doxorubicin, and Carboplatin) with different mechanisms of action to determine whether flaxseed lignans could enhance the cytotoxic effect of such drugs in the metastatic breast cancer cell lines, SKBR3 and MDA-MB-231. The experimental data suggests that flaxseed lignans significantly enhanced the ability of chemotherapeutic agents to cause cytotoxicity in SKBR3 and MDA-MB-231 breast cancer cells. A three compound combination study found that enterolactone and metformin together in combination with relatively low concentrations of chemotherapeutic drugs were able to significantly decrease cancer cell viability, compared to low concentrations of the individual chemotherapeutic drug alone. Our in vitro evaluation suggests a future direction in improving chemotherapeutic efficacy in breast cancer by adjuvant therapy with the flaxseed lignans.

PMID: 29303360 [PubMed - as supplied by publisher]

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Flaxseed Lignans Enhance the Cytotoxicity of Chemotherapeutic Agents against Breast Cancer Cell Lines MDA-MB-231 and SKBR3.

Related Articles

Flaxseed Lignans Enhance the Cytotoxicity of Chemotherapeutic Agents against Breast Cancer Cell Lines MDA-MB-231 and SKBR3.

Nutr Cancer. 2018 Jan 05;:1-10

Authors: Di Y, De Silva F, Krol ES, Alcorn J

Abstract
Systemic cytotoxic chemotherapy remains the mainstay of metastatic breast cancer; however, prognosis and overall survival is unfavorable due to inadequate treatment response and/or unacceptable toxicity. Natural compounds and their active metabolites receive increasing attention as possible adjuvant therapy with cancer chemotherapeutics to improve treatment response, survival rates, and quality of life of breast cancer patients. This study investigated the combination of flaxseed lignans (Secoisolariciresinol and Enterolactone) with classic chemotherapeutic agents (Docetaxel, Doxorubicin, and Carboplatin) with different mechanisms of action to determine whether flaxseed lignans could enhance the cytotoxic effect of such drugs in the metastatic breast cancer cell lines, SKBR3 and MDA-MB-231. The experimental data suggests that flaxseed lignans significantly enhanced the ability of chemotherapeutic agents to cause cytotoxicity in SKBR3 and MDA-MB-231 breast cancer cells. A three compound combination study found that enterolactone and metformin together in combination with relatively low concentrations of chemotherapeutic drugs were able to significantly decrease cancer cell viability, compared to low concentrations of the individual chemotherapeutic drug alone. Our in vitro evaluation suggests a future direction in improving chemotherapeutic efficacy in breast cancer by adjuvant therapy with the flaxseed lignans.

PMID: 29303360 [PubMed - as supplied by publisher]

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Corrigendum.

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Corrigendum.

Cancer Biol Ther. 2018 Jan 05;:1

Authors:

PMID: 29303676 [PubMed - as supplied by publisher]

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Expression of aromatase in tumor related stroma is associated with human bladder cancer progression.

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Expression of aromatase in tumor related stroma is associated with human bladder cancer progression.

Cancer Biol Ther. 2018 Jan 05;:0

Authors: Wu S, Ye J, Wang Z, Lin SX, Lu M, Liang Y, Zhu X, Olumi AF, Zhong WD, Wu CL

Abstract
Putative gender differences in bladder cancer (BCa) have been proposed to result from sex hormone influence. Aromatase is the key enzyme catalyzing the conversion of androgens to estrogens which may result in an intratumoral microenviroment with increased estrogen production. In this study, we investigated the expression pattern of aromatase and its association with BCa progression. Tissue samples from 88 BCa patients who underwent cystectomy were obtained. Using immunohistochemistry (IHC), expression of aromatase in tumor epithelium (TE) and tumor related stroma (TS) were evaluated separately, and the association of aromatase expression status with pathologic variables and overall survival (OS) outcome was examined. High aromatase expression was found in 33/88 (37.5%) of TE and in 65/88 (73.9%) of TS. Increased aromatase expression in TE had a trend to correlate with male gender. Increased aromatase in TS was significantly associated with adverse pathologic variables including higher pathologic pT, positive lymph node metastasis (pN), lymphovascular invasion (LVI), and distant metastasis. In univariate analysis, high aromatase expression in TS was significantly associated with poorer overall survival (p = 0.014), but this association was not significant (p = 0.163) in multivariate cox analysis adjusted for independent factors including age at surgery and pN. These results demonstrate that aromatase expression in TS but not TE may play a critical role in BCa progression. Our findings provide direct evidence of aromatase involvement in BCa and suggest endocrine therapy may have a potential role in the treatment of BCa.

PMID: 29303414 [PubMed - as supplied by publisher]

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UBE2C promotes rectal carcinoma via miR-381.

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UBE2C promotes rectal carcinoma via miR-381.

Cancer Biol Ther. 2018 Jan 05;:0

Authors: Zhang Y, Tian S, Li X, Ji Y, Wang Z, Liu C

Abstract
We aimed to characterize the expression pattern of UBE2C in rectal carcinoma and elucidate its fundamental involvement in rectal carcinoma biology. The relative expression of UBE2C in rectal carcinoma was determined by immunoblotting and QPCR. The cell viability was measured using CCK-8 assay. The anchorage-independent growth was evaluated with soft agar assay. Cell apoptosis was detected by Annexin V-PI staining. Invasion capacity was determined by transwell chamber. Tumor growth was monitored in xenograft mice model. We demonstrated that UBE2C was aberrantly up-regulated in rectal carcinoma. SiRNA-mediated knockdown of UBE2C significantly inhibited cell viability, proliferation, colony formation, invasion and induced apoptosis in vitro. Moreover, tumor growth in xenograft mice was markedly suppressed upon UBE2C silencing. Furthermore, we have identified that miR-381 was involved in regulation of UBE2C in rectal carcinoma. Here we demonstrated that UBE2C was over-expressed in rectal carcinoma, which was subjected to miR-381 modulation and in turn promoted cell proliferation, invasion and inhibited cell apoptosis.

PMID: 29303411 [PubMed - as supplied by publisher]

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EUS dating with laser ablation against the caudate lobe or left liver tumors: a win-win proposition?

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EUS dating with laser ablation against the caudate lobe or left liver tumors: a win-win proposition?

Cancer Biol Ther. 2018 Jan 05;:0

Authors: Jiang T, Tian G, Bao H, Chen F, Deng Z, Li J, Chai W

Abstract
Endoscopic ultrasound (EUS) have been not only a diagnostic tool, but also available in interventional therapy, which often previously needed surgical approaches to achieve. The study aimed to evaluate the effectiveness and safety of EUS-guided Nd:YAG laser ablation in unresectable tumors of the caudate lobe and left liver. We discussed ten cases of the caudate lobe and left liver tumors underwent laser ablation with EUS guidance. And we also have reviewed previous publication of EUS-guided thermal ablation for liver tumors in several decade years. EUS-guided Nd:YAG laser ablation (LA) of these tumors were successfully completed in ten patients, who had favourable prognosis with no complications in two-month follow-up. Based on our early observations, this suggested that EUS-guided LA might be technically feasible in selected patients with tumors of the caudate lobe and left liver. However, the safety of this technique need to be further confirmed in the future and if possible larger, prospective trials.

PMID: 29303406 [PubMed - as supplied by publisher]

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Focal Adhesion Kinase a Potential Therapeutic Target for Pancreatic Cancer and Malignant Pleural Mesothelioma.

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Focal Adhesion Kinase a Potential Therapeutic Target for Pancreatic Cancer and Malignant Pleural Mesothelioma.

Cancer Biol Ther. 2018 Jan 05;:0

Authors: Kanteti R, Mirzapoiazova T, Riehm JJ, Dhanasingh I, Mambetsariev B, Wang J, Kulkarni P, Kaushik G, Seshacharyulu P, Ponnusamy MP, Kindler HL, Nasser MW, Batra SK, Salgia R

Abstract
The non-receptor cytoplasmic tyrosine kinase, Focal Adhesion Kinase (FAK) is known to play a key role in a variety of normal and cancer cellular functions such as survival, proliferation, migration and invasion. It is highly active and overexpressed in various cancers including Pancreatic Ductal Adenocarcinoma (PDAC) and Malignant Pleural Mesothelioma (MPM). Here, initially, we demonstrate that FAK is overexpressed in both PDAC and MPM cell lines. Then we analyze effects of two small molecule inhibitors PF-573228, and PF-431396, which are dual specificity inhibitors of FAK and proline rich tyrosine kinase 2 (PYK2), as well as VS-6063, another small molecule inhibitor that specifically inhibits FAK but not PYK2 for cell growth, motility and invasion of PDAC and MPM cell lines. Treatment with PF-573228, PF-431396 and VS-6063 cells resulted in a dose-dependent inhibition of growth and anchorage-independent colony formation in both cancer cell lines. Furthermore, these compounds suppressed the phosphorylation of FAK at its active site, Y397, and functionally induced significant apoptosis and cell cycle arrest in both cell lines. Using the ECIS (Electric cell-substrate impedance sensing) system, we found that treatment of both PF compounds suppressed adherence and migration of PDAC cells on fibronectin. Interestingly, 3D-tumor organoids derived from autochthonous KC (Kras;PdxCre) mice treated with PF-573228 revealed a significant decrease in tumor organoid size and increase in organoid cell death. Taken together, our results show that FAK is an important target for mesothelioma and pancreatic cancer therapy that merit further translational studies.

PMID: 29303405 [PubMed - as supplied by publisher]

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EUS dating with laser ablation against the caudate lobe or left liver tumors: a win-win proposition?

Related Articles

EUS dating with laser ablation against the caudate lobe or left liver tumors: a win-win proposition?

Cancer Biol Ther. 2018 Jan 05;:0

Authors: Jiang T, Tian G, Bao H, Chen F, Deng Z, Li J, Chai W

Abstract
Endoscopic ultrasound (EUS) have been not only a diagnostic tool, but also available in interventional therapy, which often previously needed surgical approaches to achieve. The study aimed to evaluate the effectiveness and safety of EUS-guided Nd:YAG laser ablation in unresectable tumors of the caudate lobe and left liver. We discussed ten cases of the caudate lobe and left liver tumors underwent laser ablation with EUS guidance. And we also have reviewed previous publication of EUS-guided thermal ablation for liver tumors in several decade years. EUS-guided Nd:YAG laser ablation (LA) of these tumors were successfully completed in ten patients, who had favourable prognosis with no complications in two-month follow-up. Based on our early observations, this suggested that EUS-guided LA might be technically feasible in selected patients with tumors of the caudate lobe and left liver. However, the safety of this technique need to be further confirmed in the future and if possible larger, prospective trials.

PMID: 29303406 [PubMed - as supplied by publisher]

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Corrigendum.

Related Articles

Corrigendum.

Cancer Biol Ther. 2018 Jan 05;:1

Authors:

PMID: 29303676 [PubMed - as supplied by publisher]

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Expression of aromatase in tumor related stroma is associated with human bladder cancer progression.

Related Articles

Expression of aromatase in tumor related stroma is associated with human bladder cancer progression.

Cancer Biol Ther. 2018 Jan 05;:0

Authors: Wu S, Ye J, Wang Z, Lin SX, Lu M, Liang Y, Zhu X, Olumi AF, Zhong WD, Wu CL

Abstract
Putative gender differences in bladder cancer (BCa) have been proposed to result from sex hormone influence. Aromatase is the key enzyme catalyzing the conversion of androgens to estrogens which may result in an intratumoral microenviroment with increased estrogen production. In this study, we investigated the expression pattern of aromatase and its association with BCa progression. Tissue samples from 88 BCa patients who underwent cystectomy were obtained. Using immunohistochemistry (IHC), expression of aromatase in tumor epithelium (TE) and tumor related stroma (TS) were evaluated separately, and the association of aromatase expression status with pathologic variables and overall survival (OS) outcome was examined. High aromatase expression was found in 33/88 (37.5%) of TE and in 65/88 (73.9%) of TS. Increased aromatase expression in TE had a trend to correlate with male gender. Increased aromatase in TS was significantly associated with adverse pathologic variables including higher pathologic pT, positive lymph node metastasis (pN), lymphovascular invasion (LVI), and distant metastasis. In univariate analysis, high aromatase expression in TS was significantly associated with poorer overall survival (p = 0.014), but this association was not significant (p = 0.163) in multivariate cox analysis adjusted for independent factors including age at surgery and pN. These results demonstrate that aromatase expression in TS but not TE may play a critical role in BCa progression. Our findings provide direct evidence of aromatase involvement in BCa and suggest endocrine therapy may have a potential role in the treatment of BCa.

PMID: 29303414 [PubMed - as supplied by publisher]

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UBE2C promotes rectal carcinoma via miR-381.

Related Articles

UBE2C promotes rectal carcinoma via miR-381.

Cancer Biol Ther. 2018 Jan 05;:0

Authors: Zhang Y, Tian S, Li X, Ji Y, Wang Z, Liu C

Abstract
We aimed to characterize the expression pattern of UBE2C in rectal carcinoma and elucidate its fundamental involvement in rectal carcinoma biology. The relative expression of UBE2C in rectal carcinoma was determined by immunoblotting and QPCR. The cell viability was measured using CCK-8 assay. The anchorage-independent growth was evaluated with soft agar assay. Cell apoptosis was detected by Annexin V-PI staining. Invasion capacity was determined by transwell chamber. Tumor growth was monitored in xenograft mice model. We demonstrated that UBE2C was aberrantly up-regulated in rectal carcinoma. SiRNA-mediated knockdown of UBE2C significantly inhibited cell viability, proliferation, colony formation, invasion and induced apoptosis in vitro. Moreover, tumor growth in xenograft mice was markedly suppressed upon UBE2C silencing. Furthermore, we have identified that miR-381 was involved in regulation of UBE2C in rectal carcinoma. Here we demonstrated that UBE2C was over-expressed in rectal carcinoma, which was subjected to miR-381 modulation and in turn promoted cell proliferation, invasion and inhibited cell apoptosis.

PMID: 29303411 [PubMed - as supplied by publisher]

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Focal Adhesion Kinase a Potential Therapeutic Target for Pancreatic Cancer and Malignant Pleural Mesothelioma.

Related Articles

Focal Adhesion Kinase a Potential Therapeutic Target for Pancreatic Cancer and Malignant Pleural Mesothelioma.

Cancer Biol Ther. 2018 Jan 05;:0

Authors: Kanteti R, Mirzapoiazova T, Riehm JJ, Dhanasingh I, Mambetsariev B, Wang J, Kulkarni P, Kaushik G, Seshacharyulu P, Ponnusamy MP, Kindler HL, Nasser MW, Batra SK, Salgia R

Abstract
The non-receptor cytoplasmic tyrosine kinase, Focal Adhesion Kinase (FAK) is known to play a key role in a variety of normal and cancer cellular functions such as survival, proliferation, migration and invasion. It is highly active and overexpressed in various cancers including Pancreatic Ductal Adenocarcinoma (PDAC) and Malignant Pleural Mesothelioma (MPM). Here, initially, we demonstrate that FAK is overexpressed in both PDAC and MPM cell lines. Then we analyze effects of two small molecule inhibitors PF-573228, and PF-431396, which are dual specificity inhibitors of FAK and proline rich tyrosine kinase 2 (PYK2), as well as VS-6063, another small molecule inhibitor that specifically inhibits FAK but not PYK2 for cell growth, motility and invasion of PDAC and MPM cell lines. Treatment with PF-573228, PF-431396 and VS-6063 cells resulted in a dose-dependent inhibition of growth and anchorage-independent colony formation in both cancer cell lines. Furthermore, these compounds suppressed the phosphorylation of FAK at its active site, Y397, and functionally induced significant apoptosis and cell cycle arrest in both cell lines. Using the ECIS (Electric cell-substrate impedance sensing) system, we found that treatment of both PF compounds suppressed adherence and migration of PDAC cells on fibronectin. Interestingly, 3D-tumor organoids derived from autochthonous KC (Kras;PdxCre) mice treated with PF-573228 revealed a significant decrease in tumor organoid size and increase in organoid cell death. Taken together, our results show that FAK is an important target for mesothelioma and pancreatic cancer therapy that merit further translational studies.

PMID: 29303405 [PubMed - as supplied by publisher]

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EUS dating with laser ablation against the caudate lobe or left liver tumors: a win-win proposition?

EUS dating with laser ablation against the caudate lobe or left liver tumors: a win-win proposition?

Cancer Biol Ther. 2018 Jan 05;:0

Authors: Jiang T, Tian G, Bao H, Chen F, Deng Z, Li J, Chai W

Abstract
Endoscopic ultrasound (EUS) have been not only a diagnostic tool, but also available in interventional therapy, which often previously needed surgical approaches to achieve. The study aimed to evaluate the effectiveness and safety of EUS-guided Nd:YAG laser ablation in unresectable tumors of the caudate lobe and left liver. We discussed ten cases of the caudate lobe and left liver tumors underwent laser ablation with EUS guidance. And we also have reviewed previous publication of EUS-guided thermal ablation for liver tumors in several decade years. EUS-guided Nd:YAG laser ablation (LA) of these tumors were successfully completed in ten patients, who had favourable prognosis with no complications in two-month follow-up. Based on our early observations, this suggested that EUS-guided LA might be technically feasible in selected patients with tumors of the caudate lobe and left liver. However, the safety of this technique need to be further confirmed in the future and if possible larger, prospective trials.

PMID: 29303406 [PubMed - as supplied by publisher]

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Expression of aromatase in tumor related stroma is associated with human bladder cancer progression.

Expression of aromatase in tumor related stroma is associated with human bladder cancer progression.

Cancer Biol Ther. 2018 Jan 05;:0

Authors: Wu S, Ye J, Wang Z, Lin SX, Lu M, Liang Y, Zhu X, Olumi AF, Zhong WD, Wu CL

Abstract
Putative gender differences in bladder cancer (BCa) have been proposed to result from sex hormone influence. Aromatase is the key enzyme catalyzing the conversion of androgens to estrogens which may result in an intratumoral microenviroment with increased estrogen production. In this study, we investigated the expression pattern of aromatase and its association with BCa progression. Tissue samples from 88 BCa patients who underwent cystectomy were obtained. Using immunohistochemistry (IHC), expression of aromatase in tumor epithelium (TE) and tumor related stroma (TS) were evaluated separately, and the association of aromatase expression status with pathologic variables and overall survival (OS) outcome was examined. High aromatase expression was found in 33/88 (37.5%) of TE and in 65/88 (73.9%) of TS. Increased aromatase expression in TE had a trend to correlate with male gender. Increased aromatase in TS was significantly associated with adverse pathologic variables including higher pathologic pT, positive lymph node metastasis (pN), lymphovascular invasion (LVI), and distant metastasis. In univariate analysis, high aromatase expression in TS was significantly associated with poorer overall survival (p = 0.014), but this association was not significant (p = 0.163) in multivariate cox analysis adjusted for independent factors including age at surgery and pN. These results demonstrate that aromatase expression in TS but not TE may play a critical role in BCa progression. Our findings provide direct evidence of aromatase involvement in BCa and suggest endocrine therapy may have a potential role in the treatment of BCa.

PMID: 29303414 [PubMed - as supplied by publisher]

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UBE2C promotes rectal carcinoma via miR-381.

UBE2C promotes rectal carcinoma via miR-381.

Cancer Biol Ther. 2018 Jan 05;:0

Authors: Zhang Y, Tian S, Li X, Ji Y, Wang Z, Liu C

Abstract
We aimed to characterize the expression pattern of UBE2C in rectal carcinoma and elucidate its fundamental involvement in rectal carcinoma biology. The relative expression of UBE2C in rectal carcinoma was determined by immunoblotting and QPCR. The cell viability was measured using CCK-8 assay. The anchorage-independent growth was evaluated with soft agar assay. Cell apoptosis was detected by Annexin V-PI staining. Invasion capacity was determined by transwell chamber. Tumor growth was monitored in xenograft mice model. We demonstrated that UBE2C was aberrantly up-regulated in rectal carcinoma. SiRNA-mediated knockdown of UBE2C significantly inhibited cell viability, proliferation, colony formation, invasion and induced apoptosis in vitro. Moreover, tumor growth in xenograft mice was markedly suppressed upon UBE2C silencing. Furthermore, we have identified that miR-381 was involved in regulation of UBE2C in rectal carcinoma. Here we demonstrated that UBE2C was over-expressed in rectal carcinoma, which was subjected to miR-381 modulation and in turn promoted cell proliferation, invasion and inhibited cell apoptosis.

PMID: 29303411 [PubMed - as supplied by publisher]

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Focal Adhesion Kinase a Potential Therapeutic Target for Pancreatic Cancer and Malignant Pleural Mesothelioma.

Focal Adhesion Kinase a Potential Therapeutic Target for Pancreatic Cancer and Malignant Pleural Mesothelioma.

Cancer Biol Ther. 2018 Jan 05;:0

Authors: Kanteti R, Mirzapoiazova T, Riehm JJ, Dhanasingh I, Mambetsariev B, Wang J, Kulkarni P, Kaushik G, Seshacharyulu P, Ponnusamy MP, Kindler HL, Nasser MW, Batra SK, Salgia R

Abstract
The non-receptor cytoplasmic tyrosine kinase, Focal Adhesion Kinase (FAK) is known to play a key role in a variety of normal and cancer cellular functions such as survival, proliferation, migration and invasion. It is highly active and overexpressed in various cancers including Pancreatic Ductal Adenocarcinoma (PDAC) and Malignant Pleural Mesothelioma (MPM). Here, initially, we demonstrate that FAK is overexpressed in both PDAC and MPM cell lines. Then we analyze effects of two small molecule inhibitors PF-573228, and PF-431396, which are dual specificity inhibitors of FAK and proline rich tyrosine kinase 2 (PYK2), as well as VS-6063, another small molecule inhibitor that specifically inhibits FAK but not PYK2 for cell growth, motility and invasion of PDAC and MPM cell lines. Treatment with PF-573228, PF-431396 and VS-6063 cells resulted in a dose-dependent inhibition of growth and anchorage-independent colony formation in both cancer cell lines. Furthermore, these compounds suppressed the phosphorylation of FAK at its active site, Y397, and functionally induced significant apoptosis and cell cycle arrest in both cell lines. Using the ECIS (Electric cell-substrate impedance sensing) system, we found that treatment of both PF compounds suppressed adherence and migration of PDAC cells on fibronectin. Interestingly, 3D-tumor organoids derived from autochthonous KC (Kras;PdxCre) mice treated with PF-573228 revealed a significant decrease in tumor organoid size and increase in organoid cell death. Taken together, our results show that FAK is an important target for mesothelioma and pancreatic cancer therapy that merit further translational studies.

PMID: 29303405 [PubMed - as supplied by publisher]

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Corrigendum

.


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Stromal CD10 expression in breast cancer correlates with tumor invasion and cancer stem cell phenotype

Abstract

Background

Previous investigations have indicated that CD10 is associated with biological aggressivity in human cancers, but the use of this marker for diagnosis and prognosis is more complex. The aim of this study was to evaluate the expression of CD10 in breast cancer and its association with the clinicopathological features. In addition, we investigated whether a relationship exists between CD10 expression and cancer stem cells.

Methods

CD10 expression was examined by the immunohistochemistry in a series of 133 invasive breast carcinoma cases. Results were correlated to several clinicopathological parameters. Cancer stem cell phenotype was assessed by the immunohistochemical analysis of CD44 and ALDH1.

Results

Significant CD10 expression was found in the fusiform stromal cells in 19.5% of the cases and in the neoplastic cells in 7% of the cases. The stromal CD10 positivity was more frequently found in tumors with lymph node metastasis (p = 0.01) and a high histological grade (p = 0.01). However, CD10 expression by the neoplastic cells correlates with a high histological grade (p = 0.03) and the absence of estrogen (p = 0.002) as well as progesterone (p = 0.001) receptor expression.

We also found that CD10 expression by the stromal cells, but not by the neoplastic cells, correlates significantly with the expression of cancer stem cell markers (CD44+/ALDH1+) (p = 0.002).

Conclusion

These findings support the role of the stromal CD10 expression in breast cancer progression and dissemination, and suggest a relationship with cancer stem cells.

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Corrigendum

.


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Mechanism of recipient cell-dependent differences in exosome uptake

Abstract

Background

Exosomes, small-membrane vesicles, are secreted by cells and include several types of proteins and nucleic acids. Exosomes transfer cellular information derived from donor cells and are involved in various physiological and pathological events, such as organ-specific metastasis. Elucidating the exosome uptake mechanisms is important for understanding the progression processes of organ-specific metastasis. However, whether the exosomes secreted by the donor cells are selectively or non-selectively incorporated into the recipient cells is unknown.

Methods

In this study, three human carcinoma cell lines, A549 (lung), HCT116 and COLO205 (colon), were used. The exosome isolation efficiency was compared between three methods: ultracentrifugation, ExoQuick-TC and Total Exosome Isolation kits. Recipient cells were treated with Pitstop 2, an inhibitor of clathrin-dependent endocytosis, or genistein, an inhibitor of caveolae-dependent endocytosis, and then incubated with DiO-labeled exosomes.

Results

Among the three methods examined, ultracentrifugation was the most efficient and reproducible. Exosomes derived from a donor cell line are incorporated into the three cell lines, but the exosome uptake capability was different depending on the recipient cell type and did not depend on the donor cell type. Exosome uptake in COLO205 was inhibited by Pitstop 2 and genistein. Exosome uptake in HCT116 was inhibited by Pitstop 2, but not genistein, while that in A549 cells was not inhibited by these inhibitors. Taken together, these results suggest that the exosomes secreted by donor cells are non-selectively incorporated into recipient cells and that the exosome uptake mechanism is different depending on the recipient cells.

Conclusions

Different recipient cells' exosome uptake capabilities may be involved in organ-specific metastasis.

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Gene-expression signature regulated by the KEAP1-NRF2-CUL3 axis is associated with a poor prognosis in head and neck squamous cell cancer

Abstract

Background

NRF2 is the key regulator of oxidative stress in normal cells and aberrant expression of the NRF2 pathway due to genetic alterations in the KEAP1 (Kelch-like ECH-associated protein 1)-NRF2 (nuclear factor erythroid 2 like 2)-CUL3 (cullin 3) axis leads to tumorigenesis and drug resistance in many cancers including head and neck squamous cell cancer (HNSCC). The main goal of this study was to identify specific genes regulated by the KEAP1-NRF2-CUL3 axis in HNSCC patients, to assess the prognostic value of this gene signature in different cohorts, and to reveal potential biomarkers.

Methods

RNA-Seq V2 level 3 data from 279 tumor samples along with 37 adjacent normal samples from patients enrolled in the The Cancer Genome Atlas (TCGA)-HNSCC study were used to identify upregulated genes using two methods (altered KEAP1-NRF2-CUL3 versus normal, and altered KEAP1-NRF2-CUL3 versus wild-type). We then used a new approach to identify the combined gene signature by integrating both datasets and subsequently tested this signature in 4 independent HNSCC datasets to assess its prognostic value. In addition, functional annotation using the DAVID v6.8 database and protein-protein interaction (PPI) analysis using the STRING v10 database were performed on the signature.

Results

A signature composed of a subset of 17 genes regulated by the KEAP1-NRF2-CUL3 axis was identified by overlapping both the upregulated genes of altered versus normal (251 genes) and altered versus wild-type (25 genes) datasets. We showed that increased expression was significantly associated with poor survival in 4 independent HNSCC datasets, including the TCGA-HNSCC dataset. Furthermore, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and PPI analysis revealed that most of the genes in this signature are associated with drug metabolism and glutathione metabolic pathways.

Conclusions

Altogether, our study emphasizes the discovery of a gene signature regulated by the KEAP1-NRF2-CUL3 axis which is strongly associated with tumorigenesis and drug resistance in HNSCC. This 17-gene signature provides potential biomarkers and therapeutic targets for HNSCC cases in which the NRF2 pathway is activated.

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A train the trainer program for healthcare professionals tasked with providing psychosocial support to breast cancer survivors

Abstract

Background

The objective of this study is to develop, implement, and evaluate a training program for healthcare providers to improve ability to provide psychosocial support to breast cancer survivors in Korea.

Methods

Based on a needs assessment survey and in-depth interviews with breast cancer survivors, a multidisciplinary team developed two-day intensive training program as well as education materials and counseling notes. Participants' overall satisfaction was evaluated after the training.

Results

The training program included a total of 16 lectures held over the course of seven sessions. Forty-one nurses and 3 social workers participated in the training program. Mean age was 37.5(± 6.4) years, and on average, they had 11.1 (± 5.6) years of experience. Participants' overall satisfaction was good as following: program contents (4.04), trainee guidebook (3.82), location and environment (4.10), and program organization (4.19). Among the participants, 31 (70.4%) received certification after submitting real consultation cases after the training.

Conclusion

Two day intensive training can provide a comprehensive and coordinated education to healthcare professionals for implementing survivorship care with an emphasis on psychosocial support. Furthermore, the program should resume as a periodic continuing education course for healthcare providers. Similar education for graduate students in oncology nursing would be beneficial.

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Incidence of bone metastases in patients with solid tumors: analysis of oncology electronic medical records in the United States

Abstract

Background

Bone metastases commonly occur in conjunction with solid tumors, and are associated with serious bone complications. Population-based estimates of bone metastasis incidence are limited, often based on autopsy data, and may not reflect current treatment patterns.

Methods

Electronic medical records (OSCER, Oncology Services Comprehensive Electronic Records, 569,000 patients, 52 US cancer centers) were used to identify patients ≥18 years with a solid tumor diagnosis recorded between 1/1/2004 and 12/31/2013, excluding patients with hematologic tumors or multiple primaries. Each patient's index date was set to the date of his or her first solid tumor diagnosis in the selection period. Kaplan-Meier analyses were used to quantify the cumulative incidence of bone metastasis with follow-up for each patient from the index date to the earliest of the following events: last clinic visit in the OSCER database, occurrence of a new primary tumor or bone metastasis, end of study (12/31/2014). Incidence estimates and associated 95% confidence intervals (CI) are provided for up to 10 years of follow-up for all tumor types combined and stratified by tumor type and stage at diagnosis.

Results

Among 382,733 study patients (mean age 64 years; mean follow-up 940 days), breast (36%), lung (16), and colorectal (12%) tumors were most common. Mean time to bone metastasis was 400 days (1.1 years). Cumulative incidence of bone metastasis was 2.9% (2.9–3.0) at 30 days, 4.8% (4.7–4.8) at one year, 5.6% (5.5–5.6) at two years, 6.9% (6.8–7.0) at five years, and 8.4% (8.3–8.5) at ten years. Incidence varied substantially by tumor type with prostate cancer patients at highest risk (18% – 29%) followed by lung, renal or breast cancer. Cumulative incidence of bone metastasis increased by stage at diagnosis, with markedly higher incidence among patients diagnosed at Stage IV of whom11% had bone metastases diagnosed within 30 days.

Conclusions

These estimates of bone metastasis incidence represent the experience of a population with longer follow-up than previously published, and represent experience in the recent treatment landscape. Underestimation is possible given reliance on coded diagnoses but the clinical detail available in electronic medical records contributes to the accuracy of these estimates.

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Relationship between the extent of resection and the survival of patients with low-grade gliomas: a systematic review and meta-analysis

Abstract

Background

Surgical resection is necessary to conduct a pathological biopsy and to achieve a reduction of intracranial pressure in low-grade gliomas patients. This study aimed to determine whether a greater extent of resection would increase the overall 5-year and 10-year survival of patients with low-grade gliomas.

Methods

The studies addressing relationship between the extent of resection and the prognosis of low-grade gliomas updated until March 2017 were systematically searched in two databases (Pubmed and EMBASE). The relationships among categorical variables were analyzed using an odds ratio (OR) and a95% confidence interval (CI). Significance was established using CIs at a level of 95% or P < 0.05. Funnel plot was used to detect the publication bias.

Results

Twenty articles (a total of 2128 patients) were identified. The meta-analysis showed that the 5-year (Odds ratio (OR), 3.90;95% Confidence Interval (CI), 2.79~5.45; P < 0.01; Z = 7.95) and 10-year OS (OR, 7.91; 95%CI, 5.12~12.22; P < 0.01; Z = 9.33) associated with gross total resection (GTR) were higher than those associated with subtotal resection (STR). Similarly, as compared with biopsy(BX), the 5-year and 10-year OS were higher after either GTR (5-year: OR, 5.43; 95%CI, 3.57~8.26; P < 0.01; Z = Z = 7.9; 10-year: OR, 10.17; 95%CI, 4.02~25.71; P < 0.00001; Z = 4.9) or STR (5-year: OR, 2.59; 95%CI, 1.81~ − 3.71; P < 0.00001; Z = 5.19; 10-year: OR, 2.21; 95%CI, 1.164.25; P = 0.02; Z = 2.39).

Conclusions

Our research found that a greater extent of resection could significantly increase the OS of patients with low-grade gliomas.

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