Thoracic Vertebral Body Irradiation Contributes to Acute Hematologic Toxicity During Chemoradiation Therapy for Non-Small Cell Lung Cancer

Publication date: 1 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 94, Issue 1
Author(s): Matthew P. Deek, Brian Benenati, Sinae Kim, Ting Chen, Inaya Ahmed, Wei Zou, Joseph Aisner, Salma K. Jabbour
PurposeTo determine the relationships between radiation doses to the thoracic bone marrow and declines in blood cell counts in non-small cell lung cancer (NSCLC) patients treated with chemoradiation therapy (CRT).Methods and MaterialsWe included 52 patients with NSCLC treated with definitive concurrent carboplatin–paclitaxel and RT. Dose-volume histogram (DVH) parameters for the thoracic vertebrae (TV), sternum, scapulae, clavicles, and ribs were assessed for associations with changes in blood counts during the course of CRT. Linear and logistic regression analyses were performed to identify associations between hematologic nadirs and DVH parameters. A DVH parameter of Vx was the percentage of the total organ volume exceeding x radiation dose.ResultsGrade ≥3 hematologic toxicity including neutropenia developed in 21% (n=11), leukopenia in 42% (n=22), anemia in 6% (n=3), and throbocytopenia in 2% (n=1) of patients. Greater RT dose to the TV was associated with higher risk of grade ≥3 leukopenia across multiple DVH parameters, including TV V20 (TVV) (odds ratio [OR] 1.06; P=.025), TVV30 (OR 1.07; P=.013), and mean vertebral dose (MVD) (OR 1.13; P=.026). On multiple regression analysis, TVV30 (β = −0.004; P=.018) and TVV20 (β = −0.003; P=.048) were associated with white blood cell nadir. Additional bone marrow sites (scapulae, clavicles, and ribs) did not affect hematologic toxicity. A 20% chance of grade ≥3 leukopenia was associated with a MVD of 13.5 Gy and a TTV30 of 28%. Cutoff values to avoid grade ≥3 leukopenia were MVD ≤23.9 Gy, TVV20 ≤56.0%, and TVV30 ≤52.1%.ConclusionsHematologic toxicity is associated with greater RT doses to the TV during CRT for NSCLC. Sparing of the TV using advanced radiation techniques may improve tolerance of CRT and result in improved tolerance of concurrent chemotherapy.



from Cancer via ola Kala on Inoreader http://ift.tt/1Z5LGDC
via IFTTT

Outcomes of a Re-engineered Palliative Care and Radiation Therapy Care Model

Publication date: 1 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 94, Issue 1
Author(s): P.W. Read, L.J. Blackhall, G.J. Stukenborg, J. Harrison, J. Barclay, P.M. Dillon, D.D. Wilson, T.N. Showalter, L.L. Handsfield, Q. Chen, J.M. Larner




from Cancer via ola Kala on Inoreader http://ift.tt/1QcsmDB
via IFTTT

In Regard to Brachman et al

Publication date: 1 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 94, Issue 1
Author(s): Martin Brown, Eric Bernhard, James Mitchel, Helen Stone




from Cancer via ola Kala on Inoreader http://ift.tt/1QcspPx
via IFTTT

Report of NRG Oncology/RTOG 9601, A Phase 3 Trial in Prostate Cancer: Anti-androgen Therapy (AAT) With Bicalutamide During and After Radiation Therapy (RT) in Patients Following Radical Prostatectomy (RP) With pT2-3pN0 Disease and an Elevated PSA

Publication date: 1 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 94, Issue 1
Author(s): W.U. Shipley, W. Seiferheld, H. Lukka, P. Major, N.M. Heney, D. Grignon, O. Sartor, M. Patel, J.P. Bahary, A.L. Zietman, T.M. Pisansky, K.L. Zeitzer, C.A.F. Lawton, F.Y. Feng, R.D. Lovett, A. Balogh, L. Souhami, S.A. Rosenthal, K.J. Kerlin, H.M. Sandler




from Cancer via ola Kala on Inoreader http://ift.tt/1Z5LILO
via IFTTT

Issue Highlights

Publication date: 1 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 94, Issue 1





from Cancer via ola Kala on Inoreader http://ift.tt/1Qcsm6r
via IFTTT

NRG Oncology RTOG 0415: A Randomized Phase 3 Noninferiority Study Comparing 2 Fractionation Schedules in Patients With Low-Risk Prostate Cancer

Publication date: 1 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 94, Issue 1
Author(s): W.R. Lee, J.J. Dignam, M. Amin, D. Bruner, D. Low, G.P. Swanson, A.B. Shah, D.P. D'Souza, J.M. Michalski, I.S. Dayes, S.A. Seaward, W.A. Hall, P.L. Nguyen, T.M. Pisansky, S. Faria, Y. Chen, B.F. Koontz, R. Paulus, H.M. Sandler




from Cancer via ola Kala on Inoreader http://ift.tt/1Z5LGnj
via IFTTT

Accelerated Partial Breast Irradiation Using Sole Interstitial Multicatheter Brachytherapy Versus Whole Breast Irradiation for Early Breast Cancer: Five-Year Results of a Randomized Phase 3 Trial – Part I: Local Control and Survival Results

Publication date: 1 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 94, Issue 1
Author(s): V. Strnad, C. Polgar, O. Ott, G. Hildebrandt, D. Kauer-Dorner, H. Knauerhase, T. Major, J. Lyczek, J.L. Guinot, P. Niehoff, C. Gutierrez Miguelez, W. Uter




from Cancer via ola Kala on Inoreader http://ift.tt/1QcsjaJ
via IFTTT

Radiation Therapy With or Without Short-Term Androgen Deprivation Therapy in Intermediate-Risk Prostate Cancer: Results of a Phase 3 Trial

Publication date: 1 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 94, Issue 1
Author(s): A. Nabid, N. Carrier, E. Vigneault, L. Souhami, C. Lemaire, M.A. Brassard, B. Bahoric, R. Archambault, F. Vincent, T.V. Nguyen




from Cancer via ola Kala on Inoreader http://ift.tt/1Z5LGnb
via IFTTT

Decreasing Irradiated Rat Lung Volume Changes Dose-Limiting Toxicity From Early to Late Effects

Publication date: 1 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 94, Issue 1
Author(s): Sonja J. van der Veen, Hette Faber, Ghazaleh Ghobadi, Sytze Brandenburg, Johannes A. Langendijk, Robert P. Coppes, Peter van Luijk
PurposeTechnological developments in radiation therapy result in smaller irradiated volumes of normal tissue. Because the risk of radiation therapy-induced toxicity generally depends on irradiated volume, changing volume could change the dose-limiting toxicity of a treatment. Recently, in our rat model, we found that early radiation-induced lung dysfunction (RILD) was closely related to irradiated volume dependent vascular remodeling besides inflammation. The exact relationship between early and late RILD is still unknown. Therefore, in this preclinical study we investigated the dose-volume relationship of late RILD, assessed its dependence on early and late pathologies and studied if decreasing irradiated volume changed the dose-limiting toxicity.Methods and MaterialsA volume of 25%, 32%, 50%, 63%, 88%, or 100% of the rat lung was irradiated using protons. Until 26 weeks after irradiation, respiratory rates were measured. Macrovascular remodeling, pulmonary inflammation, and fibrosis were assessed at 26 weeks after irradiation. For all endpoints dose-volume response curves were made. These results were compared to our previously published early lung effects.ResultsEarly vascular remodeling and inflammation correlated significantly with early RILD. Late RILD correlated with inflammation and fibrosis, but not with vascular remodeling. In contrast to the early effects, late vascular remodeling, inflammation and fibrosis showed a primarily dose but not volume dependence. Comparison of respiratory rate increases early and late after irradiation for the different dose-distributions indicated that with decreasing irradiated volumes, the dose-limiting toxicity changed from early to late RILD.ConclusionsIn our rat model, different pathologies underlie early and late RILD with different dose-volume dependencies. Consequently, the dose-limiting toxicity changed from early to late dysfunction when the irradiated volume was reduced. In patients, early and late RILD are also due to different pathologies. As such, new radiation techniques reducing irradiated volume might change the dose-limiting toxicity of the radiation therapy treatment.



from Cancer via ola Kala on Inoreader http://ift.tt/1Z5LGn7
via IFTTT

NRG Oncology/RTOG 0937: Randomized Phase 2 Study Comparing Prophylactic Cranial Irradiation (PCI) Alone to PCI and Consolidative Extracranial Irradiation for Extensive Disease Small Cell Lung Cancer (ED-SCLC)

Publication date: 1 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 94, Issue 1
Author(s): E.M. Gore, C. Hu, A. Sun, D. Grimm, S. Ramalingam, N.E. Dunlap, K.A. Higgins, M. Werner-Wasik, A.M. Allen, P. Iyengar, G.M. Videtic, R.K. Hales, R.C. McGarry, J.J. Urbanic, A.T. Pu, C. Johnstone, J.N. Atkins, J.D. Bradley




from Cancer via ola Kala on Inoreader http://ift.tt/1QcsiUj
via IFTTT

Primary Study Endpoint Analysis for NRG Oncology/RTOG 0813 Trial of Stereotactic Body Radiation Therapy (SBRT) for Centrally Located Non-Small Cell Lung Cancer (NSCLC)

Publication date: 1 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 94, Issue 1
Author(s): A. Bezjak, R. Paulus, L.E. Gaspar, R.D. Timmerman, W.L. Straube, W.F. Ryan, Y. Garces, A.T. Pu, A.K. Singh, G.M. Videtic, R.C. McGarry, P. Iyengar, J.R. Pantarotto, J.J. Urbanic, A. Sun, M.E. Daly, I.S. Grills, D.P. Normolle, J.D. Bradley, H. Choy




from Cancer via ola Kala on Inoreader http://ift.tt/1Z5LG6O
via IFTTT

In Regard to Canyilmaz et al

Publication date: 1 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 94, Issue 1
Author(s): Daniel E. Roos, Jennifer G. Smith




from Cancer via ola Kala on Inoreader http://ift.tt/1Z5LG6I
via IFTTT

Treatment Responses and Survival in IDH1-Mutant Grade II and III Gliomas in NRG Oncology/RTOG 9802 and 9813

Publication date: 1 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 94, Issue 1
Author(s): E.H. Bell, P. Zhang, J.C. Buckner, S.M. Chang, A.L. Salavaggione, D. Brachman, R.J. Lee, A.D. Murtha, P.D. Brown, C.J. Schultz, S. Malone, M.P. Mehta, S.L. Pugh, A. Chakravarti




from Cancer via ola Kala on Inoreader http://ift.tt/1Z5LG6E
via IFTTT

Image-guided cervical brachytherapy: 2014 survey of the American Brachytherapy Society

Publication date: Available online 11 December 2015
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Surbhi Grover, Matthew M. Harkenrider, Linda P. Cho, Beth Erickson, Christina Small, William Small, Akila Viswanathan
IntroductionTreatment planning for gynecologic brachytherapy has evolved from point-based planning to volume-based, image-based planning with the goal of improving tumor control and lessening normal-tissue toxicity. The American Brachytherapy Society (ABS) conducted a survey in 2007, which showed although computed tomography (CT) was often used for treatment planning, most used point A for dose specification. This study is an update of the previous survey to assess treatment patterns and compare them to the 2007 results.MethodsA 45-question electronic survey on cervical-cancer brachytherapy practice patterns was sent to all ABS members and additional radiation oncologists and physicists based in the United States (U.S.) between January and September 2014. Responses from the 2007 survey and the current survey were compared using the chi-squared test.ResultsThere were 370 respondents. Of those, only respondents, not in training, who treat more than one cervical-cancer patient a year and practice in the U.S., were included in the analysis (219). For dose specification to the target, (cervix and tumor) 95% always use CT and 34% always use MRI. However, 46% use point A only for dose specification to the target. There was a lot of variation in parameters used for dose evaluation of target volume and normal tissues. Compared to the 2007 survey, use of MRI has increased from 2% to 34% (p<0.0001) for dose specification to the target. Use of volume-based dose delineation to the target has increased from 14% to 52% (p<0.0001).ConclusionAlthough use of IBBT has increased in the U.S. since the 2007 survey, there is room for further growth, particularly with the use of MRI. This increase may be in part due to educational initiatives. However, there is still significant heterogeneity in brachytherapy practice in the U.S. and future efforts should be geared toward standardizing treatment.

Teaser

The American Brachytherapy Society conducted a survey of image-guided cervical brachytherapy practices in the United States in 2007, which showed that most physicians used CT for planning and used a point-based system only for target-dose prescription. We present the updated results of a 2014 practice pattern survey showing that, compared to 2007, it appears that significantly more physicians are using CT and MRI for planning and more physicians are using a volume-based system for target-dose prescription.


from Cancer via ola Kala on Inoreader http://ift.tt/1Z5LG6y
via IFTTT

A Prognostic Analysis on Using the Combination of Tumor Volume and Epstein-Barr Virus DNA in Patients With Nasopharyngeal Carcinoma Treated With IMRT

Publication date: 1 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 94, Issue 1
Author(s): L. Lu, J. Li, W. Jia, C. Zhao, T. Lu




from Cancer via ola Kala on Inoreader http://ift.tt/1Z5LFQ6
via IFTTT

Learning and memory performance in breast cancer survivors 2 to 6 years post-treatment: the role of encoding versus forgetting

Abstract

Purpose

Our previous retrospective analysis of clinically referred breast cancer survivors' performance on learning and memory measures found a primary weakness in initial encoding of information into working memory with intact retention and recall of this same information at a delay. This suggests that survivors may misinterpret cognitive lapses as being due to forgetting when, in actuality, they were not able to properly encode this information at the time of initial exposure. Our objective in this study was to replicate and extend this pattern of performance to a research sample to increase the generalizability of this finding in a sample in which subjects were not clinically referred for cognitive issues.

Methods

We contrasted learning and memory performance between breast cancer survivors on endocrine therapy 2 to 6 years post-treatment with age- and education-matched healthy controls. We then stratified lower- and higher-performing breast cancer survivors to examine specific patterns of learning and memory performance. Contrasts were generated for four aggregate visual and verbal memory variables from the California Verbal Learning Test-2 (CVLT-2) and the Brown Location Test (BLT): Single-trial Learning: Trial 1 performance, Multiple-trial Learning: Trial 5 performance, Delayed Recall: Long-delay Recall performance, and Memory Errors: False-positive errors.

Results

As predicted, breast cancer survivors' performance as a whole was significantly lower on Single-trial Learning than the healthy control group but exhibited no significant difference in Delayed Recall. In the secondary analysis contrasting lower- and higher-performing survivors on cognitive measures, the same pattern of lower Single-trial Learning performance was exhibited in both groups, with the additional finding of significantly weaker Multiple-trial Learning performance in the lower-performing breast cancer group and intact Delayed Recall performance in both groups.

Conclusions

As with our earlier finding of weaker initial encoding with intact recall in a cohort of clinically referred breast cancer survivors, our results indicate this same profile in a research sample of breast cancer survivors. Further, when the breast cancer group was stratified by lower and higher performance, both groups exhibited significantly lower performance on initial encoding, with more pronounced encoding weakness in the lower-performing group. As in our previous research, survivors did not lose successfully encoded information over longer delays, either in the lower- or higher-performing group, again arguing against memory decay in survivors. The finding of weaker initial encoding of information together with intact delayed recall in survivors points to specific treatment interventions in rehabilitation of cognitive dysfunction.

Implications for Cancer Survivors

The finding of weaker initial encoding of information together with intact delayed recall in survivors points to specific treatment interventions in rehabilitation of cognitive dysfunction and is discussed.

from Cancer via ola Kala on Inoreader http://ift.tt/1mho6Wm
via IFTTT

Long-term outcome of a phase II trial using immunomodulatory in situ gene therapy in combination with intensity-modulated radiotherapy with or without hormonal therapy in the treatment of prostate cancer

Abstract

Objective

The objective of this study is to report the long-term outcome of a phase II trial of immune-modulatory in situ gene therapy (GT) in combination with intensity-modulated radiotherapy (IMRT) with or without hormonal therapy for the treatment of prostate cancer.

Methods

GT was comprised of intraprostatic injection of adenoviral vector containing herpes simplex thymidine kinase (ADV/HSV-tk) followed by valacyclovir. A mean dose of 76 Gy was delivered to the prostate with IMRT. Low-risk patients (arm A; T1–T2a, Gleason score <7, pretreatment PSA <10) were treated with two injections of ADV/HSV-tk, each followed by valacyclovir, and IMRT. Intermediate/high-risk patients (arm B; T2b–T3, Gleason score ≥7, pretreatment PSA ≥10) were treated with three injections of ADV/HSV-tk, each followed by valacyclovir, IMRT, and hormonal therapy.

Results

Sixty-six patients (33 patients in each arm) were enrolled. The median follow-up was 100 months. Five-year freedom from failure (FFF) rates were 94 and 91 % for arms A and B, respectively. Five-year overall survival (OS) rates were 97 and 94 % for arms A and B. Negative biopsy rates at 24 months were 83 and 79 % for arms A and B. One patient in arm B developed grade 3 elevation in liver enzyme. There was no grade 3 or higher hematologic toxicity. One patient had grade 3 genitourinary toxicity. There was no grade 3 or higher lower gastrointestinal toxicity.

Conclusion

The combination of immunomodulatory in situ gene therapy and IMRT with or without hormonal therapy is feasible, safe, and effective in the treatment of prostate cancer. The effectiveness of this combined approach was likely through enhanced cytotoxicity, antitumor immune response, and abscopal effects. This approach with long term follow up appears to provide better clinical outcome over historical controls. A randomized trial of this strategy is currently ongoing.

from Cancer via ola Kala on Inoreader http://ift.tt/1RgFZRX
via IFTTT

Dose Modifications in Asian Cancer Patients with Hepatic Dysfunction Receiving Weekly Docetaxel: A Prospective Pharmacokinetics and Safety Study

Summary

Hepatic dysfunction may modify the safety profile and pharmacokinetics of docetaxel in cancer patients, but no validated guideline exists to guide dose modification necessitated by this uncommon comorbidity. We conducted the first prospective study of a personalized dosage regimen for cancer patients with liver dysfunction treated with docetaxel. Weekly dosages were stratified by hepatic dysfunction classification as such: Category 1 [normal]; Category 2 [mild: ALP, AST and/or ALT≤5 ХULN, and TB within normal range]; Category 3 [moderate: any ALP, and AST or ALT≤5-10ХULN, and/or TB≤1-1.5 ХULN]. Category 1, 2 and 3 patients received starting dosages of 40mg/m², 30mg/m² and 20mg/m² docetaxel respectively. Pharmacokinetics was evaluated on Day 1 and 8 of the first treatment cycle, and entered into a multilevel model to delineate interindividual and interoccasion variability. Adverse event evaluation was performed weekly for two treatment cycles. We found that docetaxel clearance was significantly different between patient categories (P<0.001). Median clearance was 22.8, 16.4 and 11.3L/h/m² in Categories 1, 2 and 3 respectively, representing 28% and 50% reduced clearance in mild and moderate liver dysfunction patients, respectively. However, docetaxel exposure (AUC) and docetaxel-induced neutropenia (nadir and the maximum percentage decrease in neutrophil count) were not significantly different between categories. Median AUC was 1.74, 1.83 and 1.77mg·h/L in Categories 1, 2 and 3 respectively. The most common Grade 3/4 toxicity was neutropenia (30.0%). An unplanned comparison with the Child-Pugh and NCI-ODWG grouping systems suggests that the proposed classification system appears to more effectively discriminate patients by docetaxel clearance and dose requirements.

This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1I0GkFL
via IFTTT

ROR1, a target of NKX2-1/TTF-1 lineage-survival oncogene, inhibits ASK1-mediated pro-apoptotic signaling in lung adenocarcinoma

Summary

We previously identified receptor tyrosine kinase-like orphan receptor 1 (ROR1) as a transcriptional target of the NKX2-1/TTF-1 lineage-survival oncogene in lung adenocarcinoma. ROR1 consequently sustains a favorable balance between pro-survival PI3K-AKT and pro-apoptotic ASK1-p38MAPK signaling. In contrast to recent advances in understanding of how ROR1 sustains pro-survival signaling, the mechanism of ROR1 repression of pro-apoptotic signaling remains rather elusive. In the present study, we investigated the underlying mechanism of ROR1-mediated inhibition of the ASK1-p38MAPK signaling pathway. siROR1-mediated growth inhibition was partially but significantly alleviated by ASK1 co-knockdown in lung adenocarcinoma cell lines. Also, ASK1 phosphorylation at Thr845, which reflects its activated state, was clearly inhibited by ROR1 overexpression in both steady state and oxidative stress-elicited conditions in MSTO-211H cells. In addition, we found that ROR1 was physically associated with ASK1 at the C-terminal serine threonine-rich domain of ROR1. Furthermore, ROR1 kinase activity was shown to be required to repress the ASK1-p38 axis and oxidative stress-induced cell death. The present findings thus support our notion that ROR1 sustains lung adenocarcinoma survival, at least in part, through direct physical interaction with ASK1 and consequential repression of the pro-apoptotic ASK1-p38 axis in a ROR1 kinase activity-dependent manner.

This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1TIlvzl
via IFTTT

Clinical outcomes among HR+/HER2− metastatic breast cancer patients with multiple metastatic sites: a chart review study in the US

Abstract

Background

Hormone receptor-positive, human epidermal growth factor receptor-2-negative (HR+/HER2−) is the most common type of metastatic breast cancer (mBC). While mBC patients generally have poor prognosis with limited progression-free survival (PFS) and overall survival (OS), those with multiple metastatic sites may have even worse clinical outcomes due to multiple organ involvement. This study aimed to compare clinical outcomes including PFS, time on treatment (TOT), and OS between HR+/HER2− mBC patients with multiple metastases versus those with a single metastasis in a real-world clinical setting.

Methods

This was a retrospective chart review study of postmenopausal HR+/HER2− mBC women who had failed a non-steroidal aromatase inhibitor in the adjuvant or metastatic setting and initiated a new treatment for mBC between 07/01/2012 and 04/15/2013. Patients were classified to one of two study groups (multiple metastases or single metastasis) based on the number of non-lymph-node metastases at the initiation of the new treatment. PFS, TOT and OS were compared between the two groups using Kaplan–Meier analyses and multivariable Cox proportional hazard models adjusting for patient disease and treatment characteristics. Separate Cox models were conducted including models with an interaction term between line of therapy and study group to assess the impact of multiple metastases on clinical outcomes across different lines of therapy.

Results

A total of 699 patient charts were collected, including 291 patients with multiple metastases and 408 single metastasis patients. Worse performance status and a higher proportion of prior chemotherapy for mBC were observed among patients with multiple metastases. Overall, patients with multiple metastases had significantly shorter PFS [adjusted hazard ratio (HR) = 1.55, 95 % confidence interval (CI) 1.21–1.98], TOT (adjusted HR = 1.33, 95 % CI 1.05–1.67), and OS (adjusted HR = 1.77, 95 % CI 1.15–2.74) than single metastasis patients. Similar outcomes were observed in each line of therapy.

Conclusions

Among HR+/HER2− mBC patients, patients with multiple metastases had significantly shorter PFS, TOT, and OS than single metastasis patients, highlighting the substantial clinical burden and unmet need for more efficacious treatments for the former group of patients.

from Cancer via ola Kala on Inoreader http://ift.tt/1UilOli
via IFTTT

High post-treatment absolute monocyte count predicted hepatocellular carcinoma risk in HCV patients who failed peginterferon/ribavirin therapy

Abstract

Salient studies have investigated the association between host inflammatory response and cancer. This study was conducted to test the hypothesis that peripheral absolute monocyte counts (AMC) could impart an increased risk of hepatocellular carcinoma (HCC) development in hepatitis C virus (HCV)-infected patients after a failed peginterferon/ribavirin (PR) combination therapy. A total of 723 chronic HCV-infected patients were treated with PR, of which 183 (25.3 %) patients did not achieve a sustained virological response (non-SVR). Post-treatment AMC values were measured at 6 months after end of PR treatment. Fifteen (2.8 %) of 540 patients with an SVR developed HCC during a median follow-up period of 41.4 months, and 14 (7.7 %) of 183 non-SVR patients developed HCC during a median follow-up of 36.8 months (log rank test for SVR vs. non-SVR, P = 0.002). Cox regression analysis revealed that post-treatment AFP level (HR 1.070; 95 % CI = 1.024–1.119, P = 0.003) and post-treatment aspartate aminotransferase (AST)-to-platelet ratio index (APRI) ≥0.5 (HR 4.401; 95 % CI = 1.463–13.233, P = 0.008) were independent variables associated with HCC development for SVR patients. For non-SVR patients, diabetes (HR 5.750; 95 % CI = 1.387–23.841, P = 0.016), post treatment AMC ≥370 mm⁻³ (HR 5.805; 95 % CI = 1.268–26.573, P = 0.023), and post-treatment APRI ≥1.5 (HR 10.905; 95 % CI = 2.493–47.697, P = 0.002) were independent risks associated with HCC. In conclusion, post-treatment AMC has a role in prognostication of HCC development in HCV-infected patients who failed to achieve an SVR after PR combination therapy.

from Cancer via ola Kala on Inoreader http://ift.tt/1UicLAJ
via IFTTT

Overexpression of Sirtuin-1 is associated with poor clinical outcome in esophageal squamous cell carcinoma

Abstract

Sirtuin-1 (SIRT1), one member of the mammalian sirtuin family, has been suggested to play an essential role in the development and progression of many tumors. However, the relationship between expression of SIRT1 and prognosis of esophageal cancer is still unknown. This study aimed to investigate SIRT1 expression and its possible prognostic value in esophageal squamous cell carcinoma (ESCC). A total of 86 patients with ESCC were enrolled in our study group. Clinical data and matched tissues were collected. Western blotting and real-time quantitative reverse transcription PCR (RT-PCR) were carried out to explore the expression of SIRT1 in four human ESCC cell lines, one human normal epithelial cell line, and clinical ESCC tissues. Expression levels of SIRT1 protein in tissues of specimens were detected by immunohistochemistry (IHC). Survival analysis was carried out using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to evaluate the correlation of SIRT1 expression with clinical features and prognosis of ESCC patients. Basal expression levels of SIRT1 protein in ESCC tumor tissues and cell lines were higher than those in the control groups. IHC analysis showed that expression levels of SIRT1 protein significantly correlated with TNM stage and lymph node status of ESCC patients. Moreover, upregulated SIRT1 expression was associated with poor clinical prognosis. High SIRT1 expression in ESCC could serve as an independent predictive biomarker for diagnosis and prognosis in ESCC patients.

from Cancer via ola Kala on Inoreader http://ift.tt/1UicL3H
via IFTTT

Krüppel-like factor 17, a novel tumor suppressor: its low expression is involved in cancer metastasis

Abstract

Krüppel-like factor (KLF) family is highly conserved zinc finger transcription factors that regulate cell proliferation, differentiation, apoptosis, and migration. KLF17 is a member of the KLF family. Recent studies have demonstrated that KLF17 low expression and inactivation are caused by microRNA, gene mutation, and loss of heterozygosity in human tumors, which participates in tumor progression. KLF17 low expression increases cancer metastatic viability; its mechanism is that low KLF17 mediates epithelial-mesenchymal transition (EMT) through regulating EMT-related genes expression; the reduced-KLF17 also increases cancer metastasis though upregulating inhibitor of DNA binding 1 (ID1). Additionally, mutant p53 proteins are capable of developing a complex with KLF17, which mediate the depletion of KLF17 inhibiting EMT gene transcription and increases cancer metastasis. KLF17 downregulation also mediates the activation of TGF-β pathway.

from Cancer via ola Kala on Inoreader http://ift.tt/1OYUIj6
via IFTTT

Distinct prognostic values of four-Notch-receptor mRNA expression in ovarian cancer

Abstract

Notch signaling pathway includes ligands and Notch receptors, which are frequently deregulated in several human malignancies including ovarian cancer. Aberrant activation of Notch signaling has been linked to ovarian carcinogenesis and progression. In the current study, we used the "Kaplan-Meier plotter" (KM plotter) database, in which updated gene expression data and survival information from a total of 1306 ovarian cancer patients were used to access the prognostic value of four Notch receptors in ovarian cancer patients. Hazard ratio (HR), 95 % confidence intervals, and log-rank P were calculated. Notch1 messenger RNA (mRNA) high expression was not found to be correlated to overall survival (OS) for all ovarian cancer, as well as in serous and endometrioid cancer patients followed for 20 years. However, Notch1 mRNA high expression is significantly associated with worsen OS in TP53 wild-type ovarian cancer patients, while it is significantly associated with better OS in TP53 mutation-type ovarian cancer patients. Notch2 mRNA high expression was found to be significantly correlated to worsen OS for all ovarian cancer patients, as well as in grade II ovarian cancer patients. Notch3 mRNA high expression was found to be significantly correlated to better OS for all ovarian cancer patients, but not in serous cancer patients and endometrioid cancer patients. Notch4 mRNA high expression was not found to be significantly correlated to OS for all ovarian cancer patients, serous cancer patients, and endometrioid cancer patients. These results indicate that there are distinct prognostic values of four Notch receptors in ovarian cancer. This information will be useful for better understanding of the heterogeneity and complexity in the molecular biology of ovarian cancer and for developing tools to more accurately predict their prognosis. Based on our results, Notch1 could be a potential drug target of TP53 wild-type ovarian cancer and Notch2 could be a potential drug target of ovarian cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/1OYUGrg
via IFTTT

Synergistic effect of fisetin combined with sorafenib in human cervical cancer HeLa cells through activation of death receptor-5 mediated caspase-8/caspase-3 and the mitochondria-dependent apoptotic pathway

Abstract

Combining antitumor agents with bioactive compounds is a potential strategy for improving the effect of chemotherapy on cancer cells. The goal of this study was to elucidate the antitumor effect of the flavonoid, fisetin, combined with the multikinase inhibitor, sorafenib, against human cervical cancer cells in vitro and in vivo. The combination of fisetin and sorafenib synergistically induced apoptosis in HeLa cells, which is accompanied by a marked increase in loss of mitochondrial membrane potential. Apoptosis induction was achieved by caspase-3 and caspase-8 activation which increased the ratio of Bax/Bcl-2 and caused the subsequent cleavage of PARP level while disrupting the mitochondrial membrane potential in HeLa cells. Decreased Bax/Bcl-2 ratio level and mitochondrial membrane potential were also observed in siDR5-treated HeLa cells. In addition, in vivo studies revealed that the combined fisetin and sorafenib treatment was clearly superior to sorafenib treatment alone using a HeLa xenograft model. Our study showed that the combination of fisetin and sorafenib exerted better synergistic effects in vitro and in vivo than either agent used alone against human cervical cancer, and this synergism was based on apoptotic potential through a mitochondrial- and DR5-dependent caspase-8/caspase-3 signaling pathway. This combined fisetin and sorafenib treatment represents a novel therapeutic strategy for further clinical developments in advanced cervical cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/1UicGgE
via IFTTT

Effect of CD44 gene polymorphisms on risk of transitional cell carcinoma of the urinary bladder in Taiwan

Abstract

The carcinogenesis of transitional cell carcinoma (TCC) of the urinary bladder involves etiological factors, such as ethnicity, the environment, genetics, and diet. Cluster of differentiation (CD44), a well-known tumor marker, plays a crucial role in regulating tumor cell differentiation and metastasis. This study investigated the effect of CD44 single nucleotide polymorphisms (SNPs) on TCC risk and clinicopathological characteristics. Five SNPs of CD44 were analyzed through real-time polymerase chain reaction in 275 patients with TCC and 275 participants without cancer. In this study, we observed that CD44 rs187115 polymorphism carriers with the genotype of at least one G were associated with TCC risk. Furthermore, TCC patients who carried at least one G allele at CD44 rs187115 had a higher stage risk than did patients carrying the wild-type allele (p < 0.05). In addition, The AATAC or GACGC haplotype among the five CD44 sites was also associated with a reduced risk of TCC. In conclusion, our results suggest that CD44 SNPs influence the risk of TCC. Patients with CD44 rs187115 variant genotypes (AG + GG) exhibited a higher risk of TCC; these patients may possess chemoresistance to developing late-stage TCC compared with those with the wild-type genotype. The CD44 rs187115 SNP may predict poor prognosis in patients with TCC.

from Cancer via ola Kala on Inoreader http://ift.tt/1OYUEQb
via IFTTT

Synthesis and antitumor activity evaluation of a novel porphyrin derivative for photodynamic therapy in vitro and in vivo

Abstract

A novel porphyrin derivative, 5, 10, 15, 20-tetrakis (5-morpholinopentyl)-21H, 23H-Porphin (MPP, 4) and its photophysical characteristics, therapeutic efficacy of photodynamic therapy (PDT) in vitro and in vivo, tumor selectivity, and clearance from normal tissues were investigated here. MPP has strong absorption at relatively long wavelength (λ_max = 648 nm, molar absorption coefficient ε ∼ 17,200 M⁻¹cm⁻¹) and can emit strong fluorescence at 653 and 718 nm. When administered to the animal tumor models by tail vein injection, MPP was capable of accumulating in the tumor site, as examined in vivo with the fluorescence signal of MPP. By the combination of MPP and a 650-nm laser irradiation, the viability of T24 cells could decrease by 4.37 %, and inhibition rate of T24 tumor could increase up to 91.21 % compared with control group, demonstrating the potential of MPP as an effective photosensitizer in PDT for tumor treatment.

from Cancer via ola Kala on Inoreader http://ift.tt/1UicDkI
via IFTTT

Circulating epigenetic biomarkers in melanoma

Abstract

Recent researches have shed new light on the importance of epigenetic alterations, including promoter hypermethylation and microRNA dysregulation, in the initiation and progression of melanoma. The clinical utilization of circulating epigenetic markers in melanoma has also been investigated. In this review, we explored the literature and summarized the latest progress in the discovery of circulating epigenetic markers, namely methylated DNA and microRNAs, for non-invasive diagnosis of melanoma, as well as their measurability and predictability. We also discussed the utility of these epigenetic markers as novel prognostic and predictive markers and their association with melanoma clinical phenotypes, including recurrence and patients' survival. Large-cohort validations are warranted to maximize the clinical utilization of these markers.

from Cancer via ola Kala on Inoreader http://ift.tt/1UicFJB
via IFTTT

The MSHA strain of Pseudomonas aeruginosa (PA-MSHA) inhibits gastric carcinoma progression by inducing M1 macrophage polarization

Abstract

Macrophages play crucial roles in promoting tumor development and progression. In the present study, we found that the mannose-sensitive hemagglutination pilus strain of Pseudomonas aeruginosa (PA-MSHA) was efficient in inducing M1 macrophage polarization. PA-MSHA treatment increases expression of M1-related cytokines and promotes activation of murine peritoneal macrophages (MPM). Interestingly, PA-MSHA inhibits cell proliferation and migration and induces the apoptosis of gastric carcinoma cells. These effects of PA-MSHA on M1 polarization were associated with activation of NF-κB expression. Thus, inducing polarization of M1 by PA-MSHA may be one potential strategy for inhibiting gastric carcinoma progression in mice.

from Cancer via ola Kala on Inoreader http://ift.tt/1OYUCrC
via IFTTT

Identification of carboxyl terminal peptide of Fibrinogen as a potential serum biomarker for gastric cancer

Abstract

Gastric cancer (GC) is a very common disease worldwide where new serum biomarkers are urgently needed to improve their early diagnosis. In this study, we aim to search for the potential serum protein/peptide biomarkers of GC by using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). We first obtained the serum protein/peptide profiles from a training dataset including 30 patients with GC, 16 cases with chronic benign gastric disease (CGD), and 30 normal controls (CON) where 15 protein peaks were identified to exhibit the obvious deviation (P < 0.001, Wilcoxon rank sum test) among GC, CGD, and CON analyzed by Biomarker Wizard 3.1 software with three protein peaks with mass-to-charge (m/z) ratio 5910, 5342, and 6439 further confirmed in the validation dataset. Among the three protein peaks, peak 5910 displayed the most significantly different which could distinguish GC patients from CGD and CON with a sensitivity of 86.3 %, a specificity of 91.3 %, and the area under the receiver operating characteristic curve (AUC) of 0.89 by using the optimal cutoff value of 17.3. We further identified peak 5910 as the carboxyl terminal fraction of Fibrinogen α by LC-MS and validated its identity by antiserum-mediated SELDI-based immunodepletion assays. In sum, SELDI-TOF-MS method could effectively generate serum peptidome in cancer patients and provide a new approach to identify potentially diagnostic and prognostic biomarkers for cancer. The carboxyl terminal fraction of Fibrinogen α may be a potential serological biomarker for GC diagnosis.

from Cancer via ola Kala on Inoreader http://ift.tt/1UicCNK
via IFTTT

Assessment of changes in expression and presentation of NKG2D under influence of MICA serum factor in different stages of breast cancer

Abstract

Breast cancer is the most common cancer in women worldwide. In this study, we correlated the serum level of major histocompatibility complex class I-related chain A (sMICA) with expression and presentation of NKG2D receptors on NK cells among patients with breast cancer. Peripheral blood (PB) samples were collected from 49 healthy and 49 breast cancer patients before surgery and chemotherapy. The expression and presentation of NKG2D were assessed using qRT-PCR and flow cytometry, respectively. Furthermore, sMICA levels were determined using ELISA. In flow cytometry, whole blood samples were stained with anti-CD56/NKG2D/CD3 and the obtained results were analyzed using WinMDI software. In addition, SPSS software was used for statistical analysis of data. Significantly higher levels sMICA were detected in the sera of the majority of cancer patients in contrast to healthy volunteers (P < 0.001). The expression and presentation of NKG2D receptor were significantly lower than those in healthy persons, and with an inverse correlation to sMICA and positively correlated with tumor stage. Our study showed that sMICA may have an important role in diminishing the expression and presentation of NKG2D receptor in breast cancer patients and proposes the notion that sMICA can be a target candidate for treatment of breast cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/1OYUDvG
via IFTTT

Aberrant expression of Notch1, HES1, and DTX1 genes in glioblastoma formalin-fixed paraffin-embedded tissues

Abstract

Glioblastoma is the most common malignant brain tumor accounting for more than 54 % of all gliomas. Despite aggressive treatments, median survival remains less than 1 year. This might be due to the unavailability of effective molecular diagnostic markers and targeted therapy. Thus, it is essential to discover molecular mechanisms underlying disease by identifying dysregulated pathways involved in tumorigenesis. Notch signaling is one such pathway which plays an important role in determining cell fates. Since it is found to play a critical role in many cancers, we investigated the role of Notch genes in glioblastoma with an aim to identify biomarkers that can improve diagnosis. Using real-time PCR, we assessed the expression of Notch genes including receptors (Notch1, Notch2, Notch3, and Notch4), ligands (JAG1, JAG2, and DLL3), downstream targets (HES1 and HEY2), regulator Deltex1 (DTX1), inhibitor NUMB along with transcriptional co-activator MAML1, and a component of gamma-secretase complex APH1A in 15 formalin-fixed paraffin-embedded (FFPE) patient samples. Relative quantification was done by the 2^−ΔΔCt method; the data are presented as fold change in gene expression normalized to an internal control gene and relative to the calibrator. The data revealed aberrant expression of Notch genes in glioblastoma compared to normal brain. More than 85 % of samples showed high Notch1 (P = 0.0397) gene expression and low HES1 (P = 0.011) and DTX1 (P = 0.0001) gene expression. Our results clearly show aberrant expression of Notch genes in glioblastoma which can be used as putative biomarkers together with histopathological observation to improve diagnosis, therapeutic strategies, and patient prognosis.

from Cancer via ola Kala on Inoreader http://ift.tt/1UicCxi
via IFTTT

SLC27A4 regulate ATG4B activity and control reactions to chemotherapeutics-induced autophagy in human lung cancer cells

Abstract

Autophagy is a highly conserved self-digestion process to promote cell survival in response to nutrient starvation and other metabolic stresses in eukaryotic cells. Dysregulation of this system is linked with numerous human diseases, including cancers. ATG4B, a cysteine protease required for autophagy, cleaves the C-terminal amino acid of ATG8 family proteins to reveal a C-terminal glycine which is necessary for ATG8 proteins conjugation to phosphatidylethanolamine (PE) and insertion to autophagosome precursor membranes. However, the mechanism governing the protein stability of ATG4B in human cancer cells is not fully understood. In this study, tandem affinity purification/mass spectrometry (TAP/MS) were applied to the investigation of the interaction between ATG4B and potential candidate proteins. Then, co-immunoprecipitation (Co-IP) and GST-pull down assays indicated that the candidate protein-SLC27A4 directly interacts with ATG4B in lung cancer cell lines. Intriguingly, we also found that ATG4B protein expression was increased in parallel with SLC27A4 in lung cancer cell lines as well as lung tumor tissues. However, relevant functional research of SLC27A4 in autophagy or oncotherapy has not been investigated before. In this study, we hypothesized that SLC27A4 might act as a mediator of ATG4B, in some respects, through the protein binding directly. Further, we found that the high expression level of SLC7A4 increased the ATG4B stability and was conducive to rapid reaction to everolimus (RAD001)-induced autophagy in human lung cancer cells. As expected, the results showed that SLC27A4 could help to maintain the protein stability and intracellular concentration of ATG4B, thereby triggering rapid autophagy through releasing ATG4B to cytoplasm under conditions of reduced nutrient availability or during stress of chemotherapy in lung cancer cells. Reduced SLC27A4 by si-RNA also showed the enhanced therapeutic efficiency of everolimus, doxorubicin, and cisplatin in human lung cancer cell lines. Collectively, this study may help researchers better understand the mechanism of autophagy vitality in human cancers and SLC27A4/ATG4B complex might act as a new potential therapeutic target of lung tumor chemotherapy.

from Cancer via ola Kala on Inoreader http://ift.tt/1UicEVQ
via IFTTT

Chemoprotection of murine hematopoietic cells by combined gene transfer of cytidine deaminase (CDD) and multidrug resistance 1 gene (MDR1)

Abstract

Background

Hematologic toxicity represents a major side effect of cytotoxic chemotherapy frequently preventing adequately dosed chemotherapy application and impeding therapeutic success. Transgenic (over)expression of chemotherapy resistance (CTX-R) genes in hematopoietic stem- and progenitor cells represents a potential strategy to overcome this problem. To apply this concept in the context of acute myeloid leukemia and myelodysplasia, we have investigated the overexpression of the multidrug resistance 1 (MDR1) and the cytidine deaminase (CDD) gene conferring resistance to anthracyclines and cytarabine (Ara-C), the two most important drugs in the treatment of these diseases.

Methods

State-of-the-art, third generation, self-inactivating (SIN) lentiviral vectors were utilized to overexpress a human CDD-cDNA and a codon-optimized human MDR1-cDNA corrected for cryptic splice sites from a spleen focus forming virus derived internal promoter. Studies were performed in myeloid 32D cells as well as primary lineage marker negative (lin⁻) murine bone marrow cells and flow cytometric analysis of suspension cultures and clonogenic analysis of vector transduced cells following cytotoxic drug challenge were utilized as read outs.

Results

Efficient chemoprotection of CDD and MDR1 transduced hematopoietic 32D as well as primary lin⁻ cells was proven in the context of Ara-C and anthracycline application. Both, CTX-R transduced 32D as well as primary hematopoietic cells displayed marked resistance at concentrations 5–20 times the LD₅₀ of non-transduced control cells. Moreover, simultaneous CDD/MDR1 gene transfer resulted in similar protection levels even when combined Ara-C anthracycline treatment was applied. Furthermore, significant enrichment of transduced cells was observed upon cytotoxic drug administration.

Conclusions

Our data demonstrate efficient chemoprotection as well as enrichment of transduced cells in hematopoietic cell lines as well as primary murine hematopoietic progenitor cells following Ara-C and/or anthracycline application, arguing for the efficacy as well as feasibility of our approach and warranting further evaluation of this concept.

from Cancer via ola Kala on Inoreader http://ift.tt/1J30Vnw
via IFTTT

Trends in early-stage hepatocellular carcinoma, California 1988–2010

Abstract

Purpose

California Cancer Registry data were used to explore the impact of hepatocellular carcinoma (HCC) surveillance on patient outcomes. The purpose of this analysis was to determine the trend in diagnosis of early-stage HCC in California from 1988 to 2010.

Methods

Patients 20+ years old, diagnosed with early HCC during 1988–2010 in California, were included. Stratified proportions of early HCC were evaluated to estimate any trends and significant disparities. The primary endpoint was the average annual percent change (AAPC) of the proportion of early-stage HCC; 2- and 5-year survival trends were calculated for age, sex, race, SES, and stage.

Results

A total of 13,855 patients were diagnosed with early HCC. The proportion of patients diagnosed early increased from 19.2 to 49.2 % between 1988 and 2010, at an AAPC of 4.3 %. The proportion of cases diagnosed with early HCC increased in all demographic groups. Both the 2- and 5-year cause-specific survival analyses showed that survival among HCC patients has been increasing since 1988.

Conclusion

The proportion of HCC cases diagnosed early, and the 2- and 5-year survival trends of all HCC patients have increased in California since 1988. It is not entirely clear whether better diagnostic imaging or better surveillance has led to these findings and whether earlier diagnosis has led to improved patient survival. This increase in survival among patients with HCC may be correlated with the innovation of new treatments and most importantly that patients are being diagnosed earlier to receive such treatments.

from Cancer via ola Kala on Inoreader http://ift.tt/1mgNdsk
via IFTTT

Hydroxyurea with or without imatinib in the treatment of recurrent or progressive meningiomas: a randomized phase II trial by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)

Abstract

Purpose

Hydroxyurea (HU) is among the most widely used salvage therapies in progressive meningiomas. Platelet-derived growth factor receptors are expressed in virtually all meningiomas. Imatinib sensitizes transformed cells to the cytotoxic effects of chemotherapeutic agents that interfere with DNA metabolism. The combination of HU with imatinib yielded intriguing results in recurrent malignant glioma. The current trial addressed the activity of this association against meningioma.

Methods

Patients with recurrent or progressive WHO grade I–III meningioma, without therapeutic indication for surgery, radiotherapy, or stereotactic radiosurgery, aged 18–75 years, ECOG performance status 0–2, and not on enzyme-inducing anti-epileptic drugs were randomized to receive HU 500 mg BID ± imatinib 400 mg QD until progression, unacceptable toxicity, or patient's refusal. The primary endpoint was progression-free survival rate at 9 months (PFS-9).

Results

Between September 2009 and February 2012, 15 patients were randomized to receive HU + imatinib (N = 7; Arm A) or HU alone (N = 8; Arm B). Afterward the trial was prematurely closed due to slow enrollment rate. PFS-9 (A/B) was 0/75 %, and median PFS was 4/19.5 months. Median and 2-year overall survival (A/B) rates were: 6/27.5 months; 28.5/75 %, respectively. Main G3-4 toxicities were: G3 neutropenia in 1/0, G4 headache in 1/1, and G3 vomiting in 1/0.

Conclusion

The conduction of a study in recurrent or progressive meningioma remains a challenge. Given the limited number of patients enrolled, no firm conclusions can be drawn about the combination of imatinib and HU. The optimal systemic therapy for meningioma failing surgery and radiation has yet to be identified.

from Cancer via ola Kala on Inoreader http://ift.tt/1NnFyPQ
via IFTTT

Early metabolic change in 18 F-FDG-PET by measuring the single largest lesion predicts chemotherapeutic effects and patients’ survival: PEACH study

Abstract

Purpose

The objective of this study was to investigate the predictive value of F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) for early assessment of tumor response to chemotherapy and for patient survival in gynecologic malignancies.

Methods

We performed CT and FDG-PET scans before initiation of chemotherapy to determine baseline conditions. PET scan was repeated after the first cycle of chemotherapy. The tumor response was later evaluated by CT scans after three cycles of chemotherapy, using RECIST. The PET response was analyzed in terms of the difference in SUV_max for FDG of the patient's largest lesion between the baseline scan and after the first cycle of chemotherapy. The metabolic response for the tumor was defined as a 30 % reduction in its SUV_max.

Results

Eleven patients received platinum-based regimens, and 20 patients received non-platinum-based regimens. The mean progression-free survival (PFS) for the patients with a metabolic response was 13 months (range 5–29). In contrast, the mean PFS of the patients with no metabolic response was only 4.3 months (range 1–18). There was a statistically significant difference between the metabolic response and PFS (p = 0.002, Mann–Whitney U test). There was a strong correlation between the metabolic response and RECIST, regardless of the chemotherapy regimens used (platinum-based group, p = 0.006; non-platinum group, p = 0.046, Fisher's exact test). The metabolic change in SUV_max was clearly predictive of tumor response in 93.5 % of patients.

Conclusion

Early FDG-PET assessment by measuring the single largest lesion is a very promising tool for rapidly predicting tumor responses and patient survival, regardless of the chemotherapy regimen.

from Cancer via ola Kala on Inoreader http://ift.tt/1STXa9B
via IFTTT

Hydroxyurea with or without imatinib in the treatment of recurrent or progressive meningiomas: a randomized phase II trial by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)

Abstract

Purpose

Hydroxyurea (HU) is among the most widely used salvage therapies in progressive meningiomas. Platelet-derived growth factor receptors are expressed in virtually all meningiomas. Imatinib sensitizes transformed cells to the cytotoxic effects of chemotherapeutic agents that interfere with DNA metabolism. The combination of HU with imatinib yielded intriguing results in recurrent malignant glioma. The current trial addressed the activity of this association against meningioma.

Methods

Patients with recurrent or progressive WHO grade I–III meningioma, without therapeutic indication for surgery, radiotherapy, or stereotactic radiosurgery, aged 18–75 years, ECOG performance status 0–2, and not on enzyme-inducing anti-epileptic drugs were randomized to receive HU 500 mg BID ± imatinib 400 mg QD until progression, unacceptable toxicity, or patient's refusal. The primary endpoint was progression-free survival rate at 9 months (PFS-9).

Results

Between September 2009 and February 2012, 15 patients were randomized to receive HU + imatinib (N = 7; Arm A) or HU alone (N = 8; Arm B). Afterward the trial was prematurely closed due to slow enrollment rate. PFS-9 (A/B) was 0/75 %, and median PFS was 4/19.5 months. Median and 2-year overall survival (A/B) rates were: 6/27.5 months; 28.5/75 %, respectively. Main G3-4 toxicities were: G3 neutropenia in 1/0, G4 headache in 1/1, and G3 vomiting in 1/0.

Conclusion

The conduction of a study in recurrent or progressive meningioma remains a challenge. Given the limited number of patients enrolled, no firm conclusions can be drawn about the combination of imatinib and HU. The optimal systemic therapy for meningioma failing surgery and radiation has yet to be identified.

from Cancer via ola Kala on Inoreader http://ift.tt/1NnFyPQ
via IFTTT

Early metabolic change in 18 F-FDG-PET by measuring the single largest lesion predicts chemotherapeutic effects and patients’ survival: PEACH study

Abstract

Purpose

The objective of this study was to investigate the predictive value of F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) for early assessment of tumor response to chemotherapy and for patient survival in gynecologic malignancies.

Methods

We performed CT and FDG-PET scans before initiation of chemotherapy to determine baseline conditions. PET scan was repeated after the first cycle of chemotherapy. The tumor response was later evaluated by CT scans after three cycles of chemotherapy, using RECIST. The PET response was analyzed in terms of the difference in SUV_max for FDG of the patient's largest lesion between the baseline scan and after the first cycle of chemotherapy. The metabolic response for the tumor was defined as a 30 % reduction in its SUV_max.

Results

Eleven patients received platinum-based regimens, and 20 patients received non-platinum-based regimens. The mean progression-free survival (PFS) for the patients with a metabolic response was 13 months (range 5–29). In contrast, the mean PFS of the patients with no metabolic response was only 4.3 months (range 1–18). There was a statistically significant difference between the metabolic response and PFS (p = 0.002, Mann–Whitney U test). There was a strong correlation between the metabolic response and RECIST, regardless of the chemotherapy regimens used (platinum-based group, p = 0.006; non-platinum group, p = 0.046, Fisher's exact test). The metabolic change in SUV_max was clearly predictive of tumor response in 93.5 % of patients.

Conclusion

Early FDG-PET assessment by measuring the single largest lesion is a very promising tool for rapidly predicting tumor responses and patient survival, regardless of the chemotherapy regimen.

from Cancer via ola Kala on Inoreader http://ift.tt/1STXa9B
via IFTTT

Chemoprotection of murine hematopoietic cells by combined gene transfer of cytidine deaminase (CDD) and multidrug resistance 1 gene (MDR1)

Hematologic toxicity represents a major side effect of cytotoxic chemotherapy frequently preventing adequately dosed chemotherapy application and impeding therapeutic success. Transgenic (over)expression of ch...

from Cancer via ola Kala on Inoreader http://ift.tt/1THyQbg
via IFTTT

Novel drug targets for personalized precision medicine in relapsed/refractory diffuse large B-cell lymphoma: a comprehensive review

Abstract

Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous lymphoid malignancy and the most common subtype of non-Hodgkin's lymphoma in adults, with one of the highest mortality rates in most developed areas of the world. More than half of DLBLC patients can be cured with standard R-CHOP regimens, however approximately 30 to 40 % of patients will develop relapsed/refractory disease that remains a major cause of morbidity and mortality due to the limited therapeutic options.

Recent advances in gene expression profiling have led to the identification of at least three distinct molecular subtypes of DLBCL: a germinal center B cell-like subtype, an activated B cell-like subtype, and a primary mediastinal B-cell lymphoma subtype. Moreover, recent findings have not only increased our understanding of the molecular basis of chemotherapy resistance but have also helped identify molecular subsets of DLBCL and rational targets for drug interventions that may allow for subtype/subset-specific molecularly targeted precision medicine and personalized combinations to both prevent and treat relapsed/refractory DLBCL. Novel agents such as lenalidomide, ibrutinib, bortezomib, CC-122, epratuzumab or pidilizumab used as single-agent or in combination with (rituximab-based) chemotherapy have already demonstrated promising activity in patients with relapsed/refractory DLBCL. Several novel potential drug targets have been recently identified such as the BET bromodomain protein (BRD)-4, phosphoribosyl-pyrophosphate synthetase (PRPS)-2, macrodomain-containing mono-ADP-ribosyltransferase (ARTD)-9 (also known as PARP9), deltex-3-like E3 ubiquitin ligase (DTX3L) (also known as BBAP), NF-kappaB inducing kinase (NIK) and transforming growth factor beta receptor (TGFβR).

This review highlights the new insights into the molecular basis of relapsed/refractory DLBCL and summarizes the most promising drug targets and experimental treatments for relapsed/refractory DLBCL, including the use of novel agents such as lenalidomide, ibrutinib, bortezomib, pidilizumab, epratuzumab, brentuximab-vedotin or CAR T cells, dual inhibitors, as well as mechanism-based combinatorial experimental therapies. We also provide a comprehensive and updated list of current drugs, drug targets and preclinical and clinical experimental studies in DLBCL. A special focus is given on STAT1, ARTD9, DTX3L and ARTD8 (also known as PARP14) as novel potential drug targets in distinct molecular subsets of DLBCL.

from Cancer via ola Kala on Inoreader http://ift.tt/1STENSl
via IFTTT

Acknowledgement of Reviewers 2015

from Cancer via ola Kala on Inoreader http://ift.tt/1NUf5IX
via IFTTT

Table of Content Volume 55, Number 2, February 2016

from Cancer via ola Kala on Inoreader http://ift.tt/1NhtD8e
via IFTTT

Results of a Multicenter, Randomized, Double-Masked, Placebo-Controlled Clinical Study of the Efficacy and Safety of Visomitin Eye Drops in Patients with Dry Eye Syndrome

Abstract

Introduction

This article presents the results of an international, multicenter, randomized, double-masked, placebo-controlled clinical study of Visomitin (Mitotech LLC, Moscow, Russian Federation) eye drops in patients with dry eye syndrome (DES). Visomitin is the first registered (in Russia) drug with a mitochondria-targeted antioxidant (SkQ1) as the active ingredient.

Methods

In this multicenter (10 sites) study of 240 subjects with DES, study drug (Visomitin or placebo) was self-administered three times daily (TID) for 6 weeks, followed by a 6-week follow-up period. Seven in-office study visits occurred every 2 weeks during both the treatment and follow-up periods. Efficacy measures included Schirmer's test, tear break-up time, fluorescein staining, meniscus height, and visual acuity. Safety measures included adverse events, slit lamp biomicroscopy, tonometry, blood pressure, and heart rate. Tolerability was also evaluated.

Results

This clinical study showed the effectiveness of Visomitin eye drops in the treatment of signs and symptoms of DES compared with placebo. The study showed that a 6-week course of TID topical instillation of Visomitin significantly improved the functional state of the cornea; Visomitin increased tear film stability and reduced corneal damage. Significant reduction of dry eye symptoms (such as dryness, burning, grittiness, and blurred vision) was also observed.

Conclusion

Based on the results of this study, Visomitin is effective and safe for use in eye patients with DES for protection from corneal damage.

Funding

Mitotech LLC.

from Cancer via ola Kala on Inoreader http://ift.tt/1lVhJI1
via IFTTT

The Effect on Sodium/Iodide Symporter and Pendrin in Thyroid Colloid Retention Developed by Excess Iodide Intake

Abstract

It is well known that excess iodide can lead to thyroid colloid retention, a classic characteristic of iodide-induced goiter. However, the mechanism has not been fully unrevealed. Iodide plays an important role in thyroid function at multiple steps of thyroid colloid synthesis and transport among which sodium/iodide symporter (NIS) and pendrin are essential. In our study, we fed female BALB/c mice with different concentrations of high-iodine water including group A (control group, 0 μg/L), group B (1500 μg/L), group C (3000 μg/L), group D (6000 μg/L), and group E (12,000 μg/L). After 7 months of feeding, we found that excess iodide could lead to different degrees of thyroid colloid retention. Besides, NIS and pendrin expression were downregulated in the highest dose group. The thyroid iodide intake function detected by urine iodine assay and thyroidal ¹²⁵I experiments showed that the urine level of iodine increased, while the iodine intake rate decreased when the concentration of iodide used in feeding water increased (all p < 0.05 vs. control group). In addition, transmission electron microscopy (TEM) indicated a reduction in the number of intracellular mitochondria of thyroid cells. Based on these findings, we concluded that the occurrence of thyroid colloid retention exacerbated by excess iodide was associated with the suppression of NIS and pendrin expression, providing an additional insight of the potential mechanism of action of excess iodide on thyroid gland.

from Cancer via ola Kala on Inoreader http://ift.tt/1Y4k58T
via IFTTT

Physical activity, hormone replacement therapy and breast cancer risk: A meta-analysis of prospective studies

Publication date: January 2016
Source:European Journal of Cancer, Volume 52
Author(s): Cécile Pizot, Mathieu Boniol, Patrick Mullie, Alice Koechlin, Magali Boniol, Peter Boyle, Philippe Autier
BackgroundLower risk of breast cancer has been reported among physically active women, but the risk in women using hormone replacement therapy (HRT) appears to be higher. We quantified the association between physical activity and breast cancer, and we examined the influence that HRT use and other risk factors had on this association.MethodsAfter a systematic literature search, prospective studies were meta-analysed using random-effect models applied on highest versus lowest level of physical activity. Dose–response analyses were conducted with studies reporting physical activity either in hours per week or in hours of metabolic equivalent per week (MET-h/week).ResultsThe literature search identified 38 independent prospective studies published between 1987 and 2014 that included 116,304 breast cancer cases. Compared to the lowest level of physical activity, the highest level was associated with a summary relative risk (SRR) of 0.88 (95% confidence interval [CI] 0.85, 0.90) for all breast cancer, 0.89 (95% CI 0.83, 0.95) for ER+/PR+ breast cancer and 0.80 (95% CI 0.69, 0.92) for ER−/PR− breast cancer. Risk reductions were not influenced by the type of physical activity (occupational or non-occupational), adiposity, and menopausal status. Risk reductions increased with increasing amounts of physical activity without threshold effect. In six studies, the SRR was 0.78 (95% CI 0.70, 0.87) in women who never used HRT and 0.97 (95% CI 0.88, 1.07) in women who ever used HRT, without heterogeneity in results. Findings indicate that a physically inactive women engaging in at least 150 min per week of vigorous physical activity would reduce their lifetime risk of breast cancer by 9%, a reduction that might be two times greater in women who never used HRT.ConclusionIncreasing physical activity is associated with meaningful reductions in the risk of breast cancer, but in women who ever used HRT, the preventative effect of physical activity seems to be cancelled out.



from Cancer via ola Kala on Inoreader http://ift.tt/1jUAzO7
via IFTTT

The ‘death pace’ in the CO.17 trial

Publication date: January 2016
Source:European Journal of Cancer, Volume 53
Author(s): Vincenzo Formica, Domenico Formica, Giovanni Formica
In an era where the cost of care in oncology is rising, suggestions of new frameworks that may help in orienting biomarker discovery are highly desirable. We propose a different perspective for looking at survival data, which we call 'death pace' analysis, which focuses on the variation of the gap between survival curves over time and that may make it easier to identify subpopulations with distinct predictive molecular features. The recently published data on EJC on the impact of the primary colonic site in the CO.17 trial seem to be particularly suitable for the death pace analysis.



from Cancer via ola Kala on Inoreader http://ift.tt/1jUAz0B
via IFTTT

Statins and survival outcomes in patients with metastatic renal cell carcinoma

Publication date: January 2016
Source:European Journal of Cancer, Volume 52
Author(s): Rana R. McKay, Xun Lin, Laurence Albiges, Andre P. Fay, Marina D. Kaymakcalan, Suzanne S. Mickey, Paiman P. Ghoroghchian, Rupal S. Bhatt, Samuel D. Kaffenberger, Ronit Simantov, Toni K. Choueiri, Daniel Y.C. Heng
BackgroundA growing body of evidence has demonstrated the anti-neoplastic activity of statins. The objective of this study was to investigate the effect of statin use on survival in patients with metastatic renal cell carcinoma (mRCC) treated in the modern therapy era.Patients and methodsWe conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression and the Kaplan–Meier method.ResultsWe identified 4736 patients treated with sunitinib (n=1059), sorafenib (n=772), axitinib (n=896), temsirolimus (n=457), temsirolimus+interferon (IFN)-α (n=208), bevacizumab+temsirolimus (n=393), bevacizumab+IFN-α (n=391) or IFN-α (n=560), of whom 511 were statin users. Overall, statin users demonstrated an improved overall survival (OS) compared to non-users (25.6 versus 18.9 months, adjusted hazard ratio [aHR] 0.801, 95% confidence interval [CI] 0.659–0.972, p=0.025). When stratified by therapy type, a benefit in OS was demonstrated in statin users compared to non-users in individuals receiving therapy targeting vascular endothelial growth factor (28.4 versus 22.2 months, aHR 0.749, 95% CI 0.584–0.961, p=0.023) or mammalian target of rapamycin (18.6 versus 14.0 months, aHR 0.657, 95% CI 0.445–0.972, p=0.035) but not in those receiving IFN-α (15.6 versus 14.8 months, aHR 1.292, 95% CI 0.703–2.275, p=0.410). Adverse events were similar between users and non-users.ConclusionsWe demonstrate that statin use may be associated with improved survival in patients with mRCC treated in the targeted therapy era. Statins could represent an adjunct therapy for patients with mRCC; however, this is hypothesis generating and requires prospective evaluation.



from Cancer via ola Kala on Inoreader http://ift.tt/1Rg1oL8
via IFTTT

Long-term outcome of molecular subgroups of GIST patients treated with standard-dose imatinib in the BFR14 trial of the French Sarcoma Group

Publication date: January 2016
Source:European Journal of Cancer, Volume 52
Author(s): Anna Patrikidou, Julien Domont, Sylvie Chabaud, Isabelle Ray-Coquard, Jean-Michel Coindre, Binh Bui-Nguyen, Antoine Adenis, Maria Rios, François Bertucci, Florence Duffaud, Christine Chevreau, Didier Cupissol, David Pérol, Jean-François Emile, Jean-Yves Blay, Axel Le Cesne
BackgroundThe added value of tumoural genomic profiles to conventional clinico-biological factors to predict progression-free survival (PFS) and overall survival (OS) was prospectively investigated in patients with advanced gastrointestinal stromal tumours (GIST) treated in the BFR14 study.MethodsOf the 434 included patients, mutational analysis was performed in 322 patients. Survival analysis was performed in patients with validated mutational status.ResultsMutational status was validated in 228 patients. We identified 196 patients with tumours harbouring 200 KIT alterations (exon 11: 173 patients, exon 9: 22 patients, exon 17: 3 patients, exon 13: 2 patients; 4 patients had double KIT mutations), 6 patients with PDGFRA mutations and 26 patients with wild-type (WT) GIST genotype. On a median follow-up of 73 months, median PFS/OS were 12.3/54.9 months for WT GIST, 12.6/55 months for KIT exon 9, and 39.4 months/not reached (69.1% at 5 years) for KIT exon 11. Tumour size, female gender, KIT exon 11 mutations and CD34 positivity were independent prognostic factors for a higher PFS. A higher OS was predicted by performance status (PS) <2, low neutrophil and normal lymphocyte counts, KIT exon 11 mutations, non-advanced tumour and female gender. KIT exon 11 mutations at codons 557–558 showed better tumour response (p=0.028) but shorter PFS (p=0.0176).ConclusionsIn GIST patients, presence of a KIT exon 11 mutation is an independent prognostic factor for PFS and OS, along with gender, PS, tumour size, lymphocyte and neutrophil counts. Subsets of exon 11 mutations are associated with significantly different response patterns and PFS.



from Cancer via ola Kala on Inoreader http://ift.tt/1Rg1qCF
via IFTTT

Targeting acid ceramidase sensitises head and neck cancer to cisplatin

Publication date: January 2016
Source:European Journal of Cancer, Volume 52
Author(s): Jong-Lyel Roh, Jin Young Park, Eun Hye Kim, Hye Jin Jang
BackgroundAcid ceramidase (AC), a key enzyme in ceramide metabolism, plays a role in cancer progression and resistance to therapy. However, the role of AC in head and neck cancer (HNC) has not been addressed. Here, we investigate the effect of AC inhibition on the response to cisplatin-based chemotherapy for HNC.MethodsAC protein and messenger RNA (mRNA) expression were examined in primary tumours and paired normal tissues, and in HNC cell lines. The effects of genetic and pharmacological AC inhibition using small hairpin RNA (shRNA) and N-oleoyl-ethanolamine (NOE), alone and in combination with cisplatin, were assessed in human HNC cells by measuring cell viability, cell cycle progression, apoptosis, mRNA, and protein expression, and in preclinical tumour xenograft mouse models.FindingsAC overexpression was observed in four of six primary tumour tissues and six of nine HNC cell lines. Cisplatin sensitivity was significantly decreased by AC overexpression and significantly increased by AC downregulation in HNC cells (P<0.01). NOE or AC shRNA-mediated AC inhibition enhanced cisplatin-induced HNC cell death by increasing ceramide production and activating pro-apoptotic proteins, and these effects were abrogated by PUMA small interfering RNA transfection. AC inhibition promoted cisplatin-induced apoptosis of HNC cells in vitro and in vivo.InterpretationsAC overexpression is associated with cisplatin sensitivity, suggesting its potential role as a chemotherapeutic target for HNC. Genetic or pharmacological AC inhibition promotes cisplatin cytotoxicity in HNC cells.



from Cancer via ola Kala on Inoreader http://ift.tt/1jUAzxE
via IFTTT