The main objective of this study was to test whether pre-treatment coronary artery calcium (CAC) was associated with the cumulative incidence of acute coronary events (ACE) among breast cancer (BC) patients treated with postoperative radiotherapy (RT).
http://ift.tt/2gSvmLB
Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Σάββατο 28 Οκτωβρίου 2017
Is the coronary artery calcium score associated with acute coronary events in breast cancer patients treated with radiotherapy?
A custom-made mouthpiece incorporating tongue depressors and elevators to reduce radiation-induced tongue mucositis during carbon-ion radiotherapy for head and neck cancer
Source:Practical Radiation Oncology
Author(s): Hiroaki Ikawa, Masashi Koto, Daniel K Ebner, Ryo Takagi, Kazuhiko Hayashi, Hiroshi Tsuji, Tadashi Kamada
Here, we introduce a custom-made mouthpiece for carbon-ion radiotherapy for head and neck malignancy. The mouthpiece incorporates either a tongue depressor or elevator depending on tumor location. The risk of tongue mucositis may be reduced without compromising therapeutic efficacy through mouthpiece shaping.
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A custom-made mouthpiece incorporating tongue depressors and elevators to reduce radiation-induced tongue mucositis during carbon-ion radiotherapy for head and neck cancer
Source:Practical Radiation Oncology
Author(s): Hiroaki Ikawa, Masashi Koto, Daniel K Ebner, Ryo Takagi, Kazuhiko Hayashi, Hiroshi Tsuji, Tadashi Kamada
Here, we introduce a custom-made mouthpiece for carbon-ion radiotherapy for head and neck malignancy. The mouthpiece incorporates either a tongue depressor or elevator depending on tumor location. The risk of tongue mucositis may be reduced without compromising therapeutic efficacy through mouthpiece shaping.
http://ift.tt/2yb7N8d
Dengue hemorrhagic fever complicated with transient diabetic ketoacidosis: a case report
The increasing global prevalence of both dengue and diabetes may warrant closer observation for glycemic control and adapted fluid management to diminish the risk for a severe clinical presentation of dengue. ...
http://ift.tt/2xvRiPx
Disability in activities of daily living among adults with cancer: a systematic review and meta-analysis
Source:Cancer Treatment Reviews
Author(s): Josephine Neo, Lucy Fettes, Wei Gao, Irene J Higginson, Matthew Maddocks
IntroductionPeople with cancer frequently report limitation in Activities of Daily Living (ADLs); essential activities required to live independently within society. Although several studies have assessed ADL related disability, variability in assessment, setting, and population means evidence is difficult to interpret. We aimed to determine the prevalence of ADL related disability, overall and by setting, and the most commonly affected ADLs in people living with cancer.MethodsWe searched twelve databases to June 2016 for observational studies assessing ADL disability in adults with cancer. Data on study design, population, ADL instruments and disability (difficulty with or requiring assistance in ≥1 activity) were extracted, summarised, and pooled to estimate disability prevalence (with 95% confidence intervals, 95% CI) overall and by setting.ResultsForty-three studies comprising 19,246 patients were included. Overall, 36.7% (95% CI 29.8 to 44.3, 18 studies) and 54.6% (95% CI 46.5 to 62.3, 15 studies) of patients respectively reported disability relating to basic instrumental ADLs. Disability was marginally more prevalent in inpatient compared to outpatient settings. The Katz Index (18 studies) and Lawton IADL Scale (11 studies) were the most commonly used instruments. Across the activities studied, the most frequently affected basic ADLs were personal hygiene, walking and transfers, and instrumental ADLs were housework, shopping and transportation.ConclusionsAbout one-third and half of adults with cancer respectively have difficulty or require assistance to perform basic and instrumental ADLs. Our findings highlight the need for rehabilitation focused on functional independence. This underscores the importance of professionals skilled in occupational assessment and therapy in cancer services.
http://ift.tt/2yTM6qa
The clinical development of vaccines for HER2+ breast cancer: current landscape and future perspectives
Source:Cancer Treatment Reviews
Author(s): R.L.B. Costa, H. Soliman, B.J. Czierneicki
Human epidermal growth factor receptor 2 (HER2) is a tumor associated antigen over-expressed in 20-30% of cases of breast cancer. Passive immune therapy with HER2-directed monoclonal antibodies (mabs) has changed the natural history of this subset of breast tumors both in the localized and metastatic settings. The safety and efficacy of HER2 vaccines have been assessed in early phase clinical trials but to date clinically relevant results in late phase trials remain an elusive target. Here, we review the recent translational discoveries related to the interactions between the adaptive immune system and the HER2 antigen in breast cancer, results of published clinical trials, and future directions in the field of HER2 vaccine treatment development.
http://ift.tt/2iGV4TS
Primary High-Grade Non-Muscle-Invasive Bladder Cancer: High NFκB Expression in Tumor Specimens Distinguishes Patients Who are at Risk for Disease Progression
Abstract
To investigate the potential prognostic role of NFκB expression in primary high-grade non-muscle-invasive bladder cancer. Patients with primary high-grade non-muscle-invasive bladder cancer who received induction and maintenance BCG therapy were retrospectively included. Recurrence and progression were histologically proven. Intensity and extent of immunochemistry were assessed. The final evaluation of the NFκB staining was done by combining intensity and extent as ΄΄product΄΄ and expressing it as ΄΄low NFκΒ expression΄΄ or ΄΄high NFκB expression΄΄. Epidemiological, pathological, clinical parameters and NFκB expression were statistically analyzed for recurrence (REC), progression (PR), recurrence-free survival (RFS) and progression-free survival (PFS). NFκB is significantly associated with disease progression (p < 0,001 in univariate analysis and p = 0,001, Odds Ratio = 14,484, 95% Confidence Interval = 3187-65,821 in multivariate analysis), but not with recurrence. The median value of NFκB expression as ΄΄product΄΄ is significantly higher for the patients with progression in comparison to patients with recurrence only (p = 0,003) and patients without recurrence or progression (p = 0,001). Patients' age is significantly associated (p = 0,001 in univariate analysis and p = 0,003, Odds Ratio = 1273, 95% Confidence Interval = 1086–1492 in multivariate analysis) with disease recurrence. High NFκB expression in primary high-grade non-muscle-invasive bladder cancer, treated with postoperative intravesical BCG immunotherapy, could represent an unfavorable prognostic factor.
http://ift.tt/2gLkviC
MicroRNA Expression in Laser Micro-dissected Breast Cancer Tissue Samples – a Pilot Study
Abstract
Breast cancer continues to represent a significant public health burden despite outstanding research advances regarding the molecular mechanisms of cancer biology, biomarkers for diagnostics and prognostic and therapeutic management of this disease. The studies of micro RNAs in breast cancer have underlined their potential as biomarkers and therapeutic targets; however most of these studies are still done on largely heterogeneous whole breast tissue samples. In this pilot study we have investigated the expression of four micro RNAs (miR-21, 145, 155, 92) known to be involved in breast cancer, in homogenous cell populations collected by laser capture microdissection from breast tissue section slides. Micro RNA expression was assessed by real time PCR, and associations with clinical and pathological characteristics were also explored. Our results have confirmed previous associations of miR-21 expression with poor prognosis characteristics of breast cancers such as high stage, large and highly proliferative tumors. No statistically significant associations were found with the other micro RNAs investigated, possibly due to the small sample size of our study. Our results also suggest that miR-484 could be a suitable endogenous control for data normalization in breast tissues, these results needing further confirmation by future studies. In summary, our pilot study showed the feasibility of detecting micro RNAs expression in homogenous laser captured microdissected invasive breast cancer samples, and confirmed some of the previously reported associations with poor prognostic characteristics of breast tumors.
http://ift.tt/2ibsK88
Evaluation of Weekly Paclitaxel plus Carboplatin Followed by Anthracycline Chemotherapy on the Neoadjuvant Treatment of Patients with Triple-Negative Breast Cancer
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Aurelio B. Castrellon
ObjectiveTo evaluate the effectiveness and tolerability of neoadjuvant chemotherapy with weekly paclitaxel in combination with weekly carboplatin area under curve 2 followed by anthracycline chemotherapy.Patients and methodsThis is a retrospective review of electronic medical records of patients (N = 32) with stage 1c–III triple-negative breast cancer. Patients received neoadjuvant chemotherapy with paclitaxel 80 mg/m2 once per week for 12 weeks in combination with carboplatin area under curve 2 once per week for 12 weeks (wP + wCb), followed by a standard anthracycline regimen including either doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 or 3 weeks, or epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks for four cycles with myeloid growth factor support.ResultsMost patients (91%) received all 12 cycles of wP + wCb, and 88% received all four planned cycles of anthracycline chemotherapy. Of the patients, 84% completed all planned therapies. The complete pathologic response rate was 60%. In terms of hematologic toxicity, 96% of the patients experienced grade ≥ 3 leucopenia, 40% grade ≥ 3 anemia, and 15% grade ≥ 3 thrombocytopenia, and neutropenic fever was seen in 22% of the patients.ConclusionThe combination of neoadjuvant chemotherapy with wP + wCb before anthracycline chemotherapy can be tolerated by patients with triple-negative breast cancer. Complete pathologic response rates were comparable with those historically seen. Careful selection of patients is fundamental as this regimen is associated with a high incidence of hematologic toxicity.
http://ift.tt/2ibMWH8
Primary High-Grade Non-Muscle-Invasive Bladder Cancer: High NFκB Expression in Tumor Specimens Distinguishes Patients Who are at Risk for Disease Progression
Abstract
To investigate the potential prognostic role of NFκB expression in primary high-grade non-muscle-invasive bladder cancer. Patients with primary high-grade non-muscle-invasive bladder cancer who received induction and maintenance BCG therapy were retrospectively included. Recurrence and progression were histologically proven. Intensity and extent of immunochemistry were assessed. The final evaluation of the NFκB staining was done by combining intensity and extent as ΄΄product΄΄ and expressing it as ΄΄low NFκΒ expression΄΄ or ΄΄high NFκB expression΄΄. Epidemiological, pathological, clinical parameters and NFκB expression were statistically analyzed for recurrence (REC), progression (PR), recurrence-free survival (RFS) and progression-free survival (PFS). NFκB is significantly associated with disease progression (p < 0,001 in univariate analysis and p = 0,001, Odds Ratio = 14,484, 95% Confidence Interval = 3187-65,821 in multivariate analysis), but not with recurrence. The median value of NFκB expression as ΄΄product΄΄ is significantly higher for the patients with progression in comparison to patients with recurrence only (p = 0,003) and patients without recurrence or progression (p = 0,001). Patients' age is significantly associated (p = 0,001 in univariate analysis and p = 0,003, Odds Ratio = 1273, 95% Confidence Interval = 1086–1492 in multivariate analysis) with disease recurrence. High NFκB expression in primary high-grade non-muscle-invasive bladder cancer, treated with postoperative intravesical BCG immunotherapy, could represent an unfavorable prognostic factor.
http://ift.tt/2gLkviC
MicroRNA Expression in Laser Micro-dissected Breast Cancer Tissue Samples – a Pilot Study
Abstract
Breast cancer continues to represent a significant public health burden despite outstanding research advances regarding the molecular mechanisms of cancer biology, biomarkers for diagnostics and prognostic and therapeutic management of this disease. The studies of micro RNAs in breast cancer have underlined their potential as biomarkers and therapeutic targets; however most of these studies are still done on largely heterogeneous whole breast tissue samples. In this pilot study we have investigated the expression of four micro RNAs (miR-21, 145, 155, 92) known to be involved in breast cancer, in homogenous cell populations collected by laser capture microdissection from breast tissue section slides. Micro RNA expression was assessed by real time PCR, and associations with clinical and pathological characteristics were also explored. Our results have confirmed previous associations of miR-21 expression with poor prognosis characteristics of breast cancers such as high stage, large and highly proliferative tumors. No statistically significant associations were found with the other micro RNAs investigated, possibly due to the small sample size of our study. Our results also suggest that miR-484 could be a suitable endogenous control for data normalization in breast tissues, these results needing further confirmation by future studies. In summary, our pilot study showed the feasibility of detecting micro RNAs expression in homogenous laser captured microdissected invasive breast cancer samples, and confirmed some of the previously reported associations with poor prognostic characteristics of breast tumors.
http://ift.tt/2ibsK88
Clinical significance of tryptophan catabolism in Hodgkin lymphoma
Summary
Indoleamine 2,3-dioxygenase 1 (IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway. The purpose of the present study was to determine the clinical significance of Trp catabolism in newly-diagnosed Hodgkin Lymphoma (HL) patients. We quantified serum Trp and Kyn in 52 HL patients, and analyzed their associations with different clinical parameters including serum soluble CD30 (sCD30) concentration. IDO expression was evaluated in the patients′ affected lymph nodes. The enrolled patients comprised 22 males and 30 females (age range 15-81, median 45 years), with a 5-year overall survival (OS) of 88.6%. The OS was significantly shorter for patients with a high Kyn/Trp ratio (OS at 5 years, 60.0%-vs-92.2%), for those with stage IV disease, and for those with lymphocytopenia (< 600/mm3 and/or < 8% of the white blood cell [WBC] count). The latter two parameters are components of the international prognostic score for advanced HL. In contrast, there were no significant differences in OS according to age, serum albumin, hemoglobin, sex, WBC count, or serum sCD30 (≥ or < 285.6 ng/mL). Multivariate analysis using the three variables stage, lymphocytopenia and serum Kyn/Trp ratio demonstrated that only the latter significantly affected OS. IDO was produced by macrophages/dendritic cells, but not by HL tumor cells, and IDO levels determined by immunohistochemistry had a significant positive correlation with the serum Kyn/Trp ratio. In conclusion, quantification of serum Kyn and Trp is useful for predicting prognosis of individual HL patients.
This article is protected by copyright. All rights reserved.
http://ift.tt/2lpimOP
Clinical significance of tryptophan catabolism in Hodgkin lymphoma
Summary
Indoleamine 2,3-dioxygenase 1 (IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway. The purpose of the present study was to determine the clinical significance of Trp catabolism in newly-diagnosed Hodgkin Lymphoma (HL) patients. We quantified serum Trp and Kyn in 52 HL patients, and analyzed their associations with different clinical parameters including serum soluble CD30 (sCD30) concentration. IDO expression was evaluated in the patients′ affected lymph nodes. The enrolled patients comprised 22 males and 30 females (age range 15-81, median 45 years), with a 5-year overall survival (OS) of 88.6%. The OS was significantly shorter for patients with a high Kyn/Trp ratio (OS at 5 years, 60.0%-vs-92.2%), for those with stage IV disease, and for those with lymphocytopenia (< 600/mm3 and/or < 8% of the white blood cell [WBC] count). The latter two parameters are components of the international prognostic score for advanced HL. In contrast, there were no significant differences in OS according to age, serum albumin, hemoglobin, sex, WBC count, or serum sCD30 (≥ or < 285.6 ng/mL). Multivariate analysis using the three variables stage, lymphocytopenia and serum Kyn/Trp ratio demonstrated that only the latter significantly affected OS. IDO was produced by macrophages/dendritic cells, but not by HL tumor cells, and IDO levels determined by immunohistochemistry had a significant positive correlation with the serum Kyn/Trp ratio. In conclusion, quantification of serum Kyn and Trp is useful for predicting prognosis of individual HL patients.
This article is protected by copyright. All rights reserved.
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Survival benefit of postoperative radiation in papillary meningioma: Analysis of the National Cancer Data Base
Source:Reports of Practical Oncology & Radiotherapy, Volume 22, Issue 6
Author(s): Whitney A. Sumner, Arya Amini, Todd C. Hankinson, Nicholas K. Foreman, Laurie E. Gaspar, Brian D. Kavanagh, Sana D. Karam, Chad G. Rusthoven, Arthur K. Liu
Aim/BackgroundPapillary meningioma represents a rare subset of World Health Organization (WHO) Grade III meningioma that portends an overall poor prognosis. There is relatively limited data regarding the benefit of postoperative radiation therapy (PORT). We used the National Cancer Data Base (NCDB) to compare overall survival (OS) outcomes of surgically resected papillary meningioma cases undergoing PORT compared to post-operative observation.Materials and methodsThe NCDB was queried for patients with papillary meningioma, diagnosed between 2004 and 2013, who underwent upfront surgery with or without PORT. Overall survival (OS) was determined using the Kaplan–Meier method. Univariate (UVA) and multivariate (MVA) analyses were performed.ResultsIn total, 190 patients were identified; 89 patients underwent PORT, 101 patients were observed. Eleven patients received chemotherapy (6 with PORT, 5 without). 2-Year OS was significantly improved with PORT vs. no PORT (93.0% vs. 74.4%), as was 5-year OS (78.5% vs. 62.5%) (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.27–0.85; p=0.01). On MVA, patients receiving PORT had improved OS compared to observation (HR, 0.41; 95% CI, 0.22–0.76; p=0.005). On subset analysis by age group, the benefit of PORT vs. no PORT was significant in patients ≤18 years (n=13), with 2-year OS of 85.7% vs. 50.0% (HR, 0.08; 95% CI, 0.01–0.80; p=0.032) and for patients >18 years (n=184), with 2-year OS of 94.7% vs. 76.1% (HR, 0.55; 95% CI, 0.31–1.00; p=0.049), respectively.ConclusionsIn this large contemporary analysis, PORT was associated with improved survival for both adult and pediatric patients with papillary meningioma. PORT should be considered in those who present with this rare, aggressive tumor.
http://ift.tt/2xuOmCF
The Presence of ALK Alterations and Clinical Relevance of Crizotinib Treatment in Pediatric Solid Tumors
Abstract
Soft tissue sarcomas (STS) and neuroblastomas (NBL), are childhood malignancies still associated with poor prognoses despite the overall improvement in childhood tumor survival of the past decades. Anaplastic lymphoma kinase (ALK) inhibition is promising new strategy to improve the outcome of these pediatric tumors. Eighteen histologic samples of pediatric STS and 19 NBL patients were analyzed for ALK abnormalities using fluorescent in situ hybridization (FISH) with break-apart probes and immunohistochemistry (IHC). ALK alterations were presented in 20 of the 37 sections. The presence of ALK alteration in NBL samples were detected using IHC in 84,2% of all cases compared to 21,1% FISH positivity. In STS cases the results were less different (IHC 16,7% vs FISH 22,2%). The difference can be explained by the different type of molecular alterations. FISH method detected translocation and amplification, but not the point mutation of ALK gene. IHC confirmed the diagnosis by detecting the expression of ALK protein.After ALK positivity was proven, the effectiveness and safety of the crizotinib therapy was examined in 4 patients (1 alveolar rhabdomyosarcoma (RMA), 1 embryonal rhabdomyosarcoma (RME), 1 inflammatory myofibroblastic tumor (IMT), 1 NBL). We observed continuous remission of the IMT patient, all other cases the inhibitor treatment was not curative.Our findings underline the importance of screening the ALK status parallel with both IHC and FISH. Crizotinib treatment had a long-term effect in ALK positive IMT patients, however itwas only temporary efficient in relapsed, progressive STS and NBL.
http://ift.tt/2hhe4o7
The Presence of ALK Alterations and Clinical Relevance of Crizotinib Treatment in Pediatric Solid Tumors
Abstract
Soft tissue sarcomas (STS) and neuroblastomas (NBL), are childhood malignancies still associated with poor prognoses despite the overall improvement in childhood tumor survival of the past decades. Anaplastic lymphoma kinase (ALK) inhibition is promising new strategy to improve the outcome of these pediatric tumors. Eighteen histologic samples of pediatric STS and 19 NBL patients were analyzed for ALK abnormalities using fluorescent in situ hybridization (FISH) with break-apart probes and immunohistochemistry (IHC). ALK alterations were presented in 20 of the 37 sections. The presence of ALK alteration in NBL samples were detected using IHC in 84,2% of all cases compared to 21,1% FISH positivity. In STS cases the results were less different (IHC 16,7% vs FISH 22,2%). The difference can be explained by the different type of molecular alterations. FISH method detected translocation and amplification, but not the point mutation of ALK gene. IHC confirmed the diagnosis by detecting the expression of ALK protein.After ALK positivity was proven, the effectiveness and safety of the crizotinib therapy was examined in 4 patients (1 alveolar rhabdomyosarcoma (RMA), 1 embryonal rhabdomyosarcoma (RME), 1 inflammatory myofibroblastic tumor (IMT), 1 NBL). We observed continuous remission of the IMT patient, all other cases the inhibitor treatment was not curative.Our findings underline the importance of screening the ALK status parallel with both IHC and FISH. Crizotinib treatment had a long-term effect in ALK positive IMT patients, however itwas only temporary efficient in relapsed, progressive STS and NBL.
http://ift.tt/2hhe4o7
Combination chemotherapy with irinotecan and gemcitabine for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancer: a multicenter phase I/II trial (GOGO-Ov 6)
Abstract
Purpose
To develop a new therapeutic strategy for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers, we evaluated the feasibility and efficacy of irinotecan and gemcitabine combination chemotherapy.
Methods
Patients with taxane/platinum-resistant/refractory cancer received escalating doses of irinotecan and gemcitabine (level 1: 80 and 800 mg/m2, respectively; level 2: 100 and 1000 mg/m2) on days 1 and 8 on a 21-day cycle. Genotyping for UGT1A1*6 and *28 polymorphisms was performed for possible adverse irinotecan sensitivity.
Results
A total of 35 patients were enrolled. The recommended dose was defined as 100 mg/m2 irinotecan and 1000 mg/m2 gemcitabine (level 2). The observed common grade 3/4 toxicities were neutropenia (60%), anemia (17.1%), diarrhea (8.6%), thrombocytopenia (5.7%) and nausea (5.7%). Groups homozygous for UGT1A1*6 or *28 were associated with grade 3/4 neutropenia and diarrhea. Objective responses were 20%, including one complete response and six partial responses. In 29 patients treated with the recommended dose, the median progression-free survival and overall survival were 3.8 months (95% CI 2.1–6.0 months) and 17.4 months (95% CI 9.9–21.9 months), respectively, while the 1-year survival rate was 58.6%.
Conclusions
Combination chemotherapy with irinotecan and gemcitabine represents a safe and effective treatment combination for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers.
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Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study
Abstract
Purpose
Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects.
Methods
Part 1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680 mg in eight subjects. Part 2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680 mg) on QT/QTc interval. 64 healthy subjects were planned to be enrolled. Baseline-adjusted QT (QTc) intervals for ibrutinib and moxifloxacin (assay sensitivity) were compared to placebo using linear mixed-effect model. A concentration-QTc analysis was also conducted.
Results
No clinically relevant safety observations were noted in Part 1. During Part 2, one subject experienced Grade 4 ALT/AST elevations with ibrutinib 1680 mg, leading to study termination and limiting the enrollment to 20 subjects. Ibrutinib demonstrated dose-dependent increases in exposure. The upper bounds of the 90% CIs for the mean difference in change from baseline in QTc between ibrutinib and placebo were < 10 ms at all timepoints and at supratherapeutic C max. Moxifloxacin showed the anticipated QTc effect, confirming assay sensitivity despite the early study termination. Ibrutinib caused a concentration-dependent mild shortening of QTc and mild PR prolongation, but these effects were not considered clinically meaningful.
Conclusions
Therapeutic and supratherapeutic concentrations of ibrutinib do not prolong the QTc interval.
Clinicaltrials.gov
NCT02271438.
from Cancer via ola Kala on Inoreader http://ift.tt/2hhOC20
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Combination chemotherapy with irinotecan and gemcitabine for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancer: a multicenter phase I/II trial (GOGO-Ov 6)
Abstract
Purpose
To develop a new therapeutic strategy for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers, we evaluated the feasibility and efficacy of irinotecan and gemcitabine combination chemotherapy.
Methods
Patients with taxane/platinum-resistant/refractory cancer received escalating doses of irinotecan and gemcitabine (level 1: 80 and 800 mg/m2, respectively; level 2: 100 and 1000 mg/m2) on days 1 and 8 on a 21-day cycle. Genotyping for UGT1A1*6 and *28 polymorphisms was performed for possible adverse irinotecan sensitivity.
Results
A total of 35 patients were enrolled. The recommended dose was defined as 100 mg/m2 irinotecan and 1000 mg/m2 gemcitabine (level 2). The observed common grade 3/4 toxicities were neutropenia (60%), anemia (17.1%), diarrhea (8.6%), thrombocytopenia (5.7%) and nausea (5.7%). Groups homozygous for UGT1A1*6 or *28 were associated with grade 3/4 neutropenia and diarrhea. Objective responses were 20%, including one complete response and six partial responses. In 29 patients treated with the recommended dose, the median progression-free survival and overall survival were 3.8 months (95% CI 2.1–6.0 months) and 17.4 months (95% CI 9.9–21.9 months), respectively, while the 1-year survival rate was 58.6%.
Conclusions
Combination chemotherapy with irinotecan and gemcitabine represents a safe and effective treatment combination for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers.
http://ift.tt/2yUrDSd
Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study
Abstract
Purpose
Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects.
Methods
Part 1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680 mg in eight subjects. Part 2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680 mg) on QT/QTc interval. 64 healthy subjects were planned to be enrolled. Baseline-adjusted QT (QTc) intervals for ibrutinib and moxifloxacin (assay sensitivity) were compared to placebo using linear mixed-effect model. A concentration-QTc analysis was also conducted.
Results
No clinically relevant safety observations were noted in Part 1. During Part 2, one subject experienced Grade 4 ALT/AST elevations with ibrutinib 1680 mg, leading to study termination and limiting the enrollment to 20 subjects. Ibrutinib demonstrated dose-dependent increases in exposure. The upper bounds of the 90% CIs for the mean difference in change from baseline in QTc between ibrutinib and placebo were < 10 ms at all timepoints and at supratherapeutic C max. Moxifloxacin showed the anticipated QTc effect, confirming assay sensitivity despite the early study termination. Ibrutinib caused a concentration-dependent mild shortening of QTc and mild PR prolongation, but these effects were not considered clinically meaningful.
Conclusions
Therapeutic and supratherapeutic concentrations of ibrutinib do not prolong the QTc interval.
Clinicaltrials.gov
NCT02271438.
http://ift.tt/2hhOC20
Combination chemotherapy with irinotecan and gemcitabine for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancer: a multicenter phase I/II trial (GOGO-Ov 6)
Abstract
Purpose
To develop a new therapeutic strategy for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers, we evaluated the feasibility and efficacy of irinotecan and gemcitabine combination chemotherapy.
Methods
Patients with taxane/platinum-resistant/refractory cancer received escalating doses of irinotecan and gemcitabine (level 1: 80 and 800 mg/m2, respectively; level 2: 100 and 1000 mg/m2) on days 1 and 8 on a 21-day cycle. Genotyping for UGT1A1*6 and *28 polymorphisms was performed for possible adverse irinotecan sensitivity.
Results
A total of 35 patients were enrolled. The recommended dose was defined as 100 mg/m2 irinotecan and 1000 mg/m2 gemcitabine (level 2). The observed common grade 3/4 toxicities were neutropenia (60%), anemia (17.1%), diarrhea (8.6%), thrombocytopenia (5.7%) and nausea (5.7%). Groups homozygous for UGT1A1*6 or *28 were associated with grade 3/4 neutropenia and diarrhea. Objective responses were 20%, including one complete response and six partial responses. In 29 patients treated with the recommended dose, the median progression-free survival and overall survival were 3.8 months (95% CI 2.1–6.0 months) and 17.4 months (95% CI 9.9–21.9 months), respectively, while the 1-year survival rate was 58.6%.
Conclusions
Combination chemotherapy with irinotecan and gemcitabine represents a safe and effective treatment combination for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers.
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Are community-based health worker interventions an effective approach for early diagnosis of cancer? A systematic review and meta-analysis
Abstract
Objective
This systematic review aimed to assess the effectiveness of community-based health worker (CBHW) interventions for early detection of cancer. Secondary aims were to consider the extent that interventions were based on theory, and potential moderators including behaviour change techniques (BCTs).
Methods
Six databases were searched for randomized controlled trials. Random-effects meta-analyses were applied to 30 eligible studies with a cancer screening outcome.
Results
Participation in CBHW interventions was associated with increased receipt of screening (OR =1.901, 95% CI: 1.60-2.26, p<0.001) for breast, cervical and bowel cancer. Larger effect sizes were observed in participants previously non-adherent with recommended schedules of cancer screening. 25/30 studies were conducted with ethnic minority groups. Only 15 (45%) studies explicitly reported a theoretical foundation for intervention. The number of BCTs used by CBHWs had a trend level association with observed effect size (p=0.08). Study quality was generally poor and common limitations were inadequate blinding and reliance on self-reported outcomes.
Conclusions
CBHW interventions are an effective resource for increasing uptake of all three types of cancer screening in ethnic minority groups. Those previously non-adherent with recommended schedules of cancer screening benefitted the most from the CBHW approach. However, better quality studies based on more explicit evidence-based theory are needed to optimise the effectiveness of CBHW interventions on screening uptake. Further research is needed to ascertain whether CBHWs can help promote symptom recognition and help-seeking behaviour to facilitate early diagnosis of cancer.
http://ift.tt/2zLAnJw
Are community-based health worker interventions an effective approach for early diagnosis of cancer? A systematic review and meta-analysis
Abstract
Objective
This systematic review aimed to assess the effectiveness of community-based health worker (CBHW) interventions for early detection of cancer. Secondary aims were to consider the extent that interventions were based on theory, and potential moderators including behaviour change techniques (BCTs).
Methods
Six databases were searched for randomized controlled trials. Random-effects meta-analyses were applied to 30 eligible studies with a cancer screening outcome.
Results
Participation in CBHW interventions was associated with increased receipt of screening (OR =1.901, 95% CI: 1.60-2.26, p<0.001) for breast, cervical and bowel cancer. Larger effect sizes were observed in participants previously non-adherent with recommended schedules of cancer screening. 25/30 studies were conducted with ethnic minority groups. Only 15 (45%) studies explicitly reported a theoretical foundation for intervention. The number of BCTs used by CBHWs had a trend level association with observed effect size (p=0.08). Study quality was generally poor and common limitations were inadequate blinding and reliance on self-reported outcomes.
Conclusions
CBHW interventions are an effective resource for increasing uptake of all three types of cancer screening in ethnic minority groups. Those previously non-adherent with recommended schedules of cancer screening benefitted the most from the CBHW approach. However, better quality studies based on more explicit evidence-based theory are needed to optimise the effectiveness of CBHW interventions on screening uptake. Further research is needed to ascertain whether CBHWs can help promote symptom recognition and help-seeking behaviour to facilitate early diagnosis of cancer.
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Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study
Abstract
Purpose
Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects.
Methods
Part 1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680 mg in eight subjects. Part 2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680 mg) on QT/QTc interval. 64 healthy subjects were planned to be enrolled. Baseline-adjusted QT (QTc) intervals for ibrutinib and moxifloxacin (assay sensitivity) were compared to placebo using linear mixed-effect model. A concentration-QTc analysis was also conducted.
Results
No clinically relevant safety observations were noted in Part 1. During Part 2, one subject experienced Grade 4 ALT/AST elevations with ibrutinib 1680 mg, leading to study termination and limiting the enrollment to 20 subjects. Ibrutinib demonstrated dose-dependent increases in exposure. The upper bounds of the 90% CIs for the mean difference in change from baseline in QTc between ibrutinib and placebo were < 10 ms at all timepoints and at supratherapeutic C max. Moxifloxacin showed the anticipated QTc effect, confirming assay sensitivity despite the early study termination. Ibrutinib caused a concentration-dependent mild shortening of QTc and mild PR prolongation, but these effects were not considered clinically meaningful.
Conclusions
Therapeutic and supratherapeutic concentrations of ibrutinib do not prolong the QTc interval.
Clinicaltrials.gov
NCT02271438.
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Delivery of care consistent with the psychosocial standards in pediatric cancer: Current practices in the United States
Abstract
Background
With published evidence-based Standards for Psychosocial Care for Children with Cancer and their Families, it is important to know the current status of their implementation. This paper presents data on delivery of psychosocial care related to the Standards in the United States.
Procedure
Pediatric oncologists, psychosocial leaders, and administrators in pediatric oncology from 144 programs completed an online survey. Participants reported on the extent to which psychosocial care consistent with the Standards was implemented and was comprehensive and state of the art. They also reported on specific practices and services for each Standard and the extent to which psychosocial care was integrated into broader medical care.
Results
Participants indicated that psychosocial care consistent with the Standards was usually or always provided at their center for most of the Standards. However, only half of the oncologists (55.6%) and psychosocial leaders (45.6%) agreed or strongly agreed that their psychosocial care was comprehensive and state of the art. Types of psychosocial care provided included evidence-based and less established approaches but were most often provided when problems were identified, rather than proactively. The perception of state of the art care was associated with practices indicative of integrated psychosocial care and the extent to which the Standards are currently implemented.
Conclusion
Many oncologists and psychosocial leaders perceive that the delivery of psychosocial care at their center is consistent with the Standards. However, care is quite variable, with evidence for the value of more integrated models of psychosocial services.
http://ift.tt/2zW6eZ7
Evaluation of patritumab with or without erlotinib in combination with standard cytotoxic agents against pediatric sarcoma xenograft models
Abstract
Background
Integrating molecularly targeted agents with cytotoxic drugs used in curative treatment of pediatric cancers is complex. An evaluation was undertaken with the ERBB3/Her3-specific antibody patritumab (P) either alone or with the ERBB1/epidermal growth factor receptor inhibitor erlotinib (E) in combination with standard cytotoxic agents, cisplatin, vincristine, and cyclophosphamide, in pediatric sarcoma xenograft models that express receptors and ligands targeted by these agents.
Procedures
Tumor models were selected based upon ERBB3 expression and phosphorylation, and ligand (heregulin) expression. Patritumab, E, or these agents combined was evaluated without or with concomitant cytotoxic agents using procedures developed by the Pediatric Preclinical Testing Program.
Results
Full doses of cytotoxic agents were tolerated when combined with P, whereas dose reductions of 25% (vincristine, cisplatin) or 50% (cyclophosphamide) were required when combined with P + E. Patritumab, E alone, or in combination did not significantly inhibit growth of any tumor model, except for Rh18 xenografts (E alone). Patritumab had no single-agent activity and marginally enhanced the activity of vincristine and cisplatin only in Ewing sarcoma ES-4. P + E did not increase the antitumor activity of vincristine or cisplatin, whereas dose-reduced cyclophosphamide was significantly less active than cyclophosphamide administered at its maximum tolerated dose when combined with P + E.
Conclusions
P had no single-agent activity, although it marginally potentiated the activity of vincristine and cisplatin in one of three models studied. However, the addition of E necessitated dose reduction of each cytotoxic agent, abrogating the enhancement observed with P alone.
http://ift.tt/2xvhSs3
Nutritional risk factors predict severe acute graft-versus-host disease and early mortality in pediatric allogeneic hematopoietic stem cell transplantation
Abstract
Background
Malnutrition is a pro-inflammatory state, yet data on nutritional risk factors and development of acute graft-versus-host disease (aGVHD) are extremely limited.
Procedure
We conducted a retrospective cohort analysis of pediatric patients up to age 21 years who underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the Children's Hospital of Philadelphia from January 2011 to September 2014 to determine whether malnutrition was associated with development of aGVHD and early mortality. We identified body mass index (BMI) percentile and serum albumin levels as potential markers of malnutrition and defined two composite nutritional risk variables as any of the following: albumin < 2.8 g/dl, weight loss ≥10% from baseline, and low BMI [<25th (NUT25) or <5th percentile (NUT5)]. Nutritional markers and GVHD grade were assessed at baseline, 30, 60, and 90 days post-HSCT, and patients were censored upon development of GVHD.
Results
BMI <25th or <5th percentile, NUT25, and NUT5 at the beginning of any 30-day period predicted a three- to fourfold risk of developing of severe (grade III–IV) aGVHD in the subsequent 30 days in models adjusted for age, sex, donor source, and degree of human leukocyte antigen matching. Mortality at day 100 was low, but NUT25 risk at baseline conferred an increased risk of death (7.9% vs. 1%, P = 0.035).
Conclusions
Malnutrition is a targetable risk factor in pediatric HSCT; prospective trials are needed to investigate this relationship further and identify effective nutritional interventions.
http://ift.tt/2zTP529
Delivery of care consistent with the psychosocial standards in pediatric cancer: Current practices in the United States
Abstract
Background
With published evidence-based Standards for Psychosocial Care for Children with Cancer and their Families, it is important to know the current status of their implementation. This paper presents data on delivery of psychosocial care related to the Standards in the United States.
Procedure
Pediatric oncologists, psychosocial leaders, and administrators in pediatric oncology from 144 programs completed an online survey. Participants reported on the extent to which psychosocial care consistent with the Standards was implemented and was comprehensive and state of the art. They also reported on specific practices and services for each Standard and the extent to which psychosocial care was integrated into broader medical care.
Results
Participants indicated that psychosocial care consistent with the Standards was usually or always provided at their center for most of the Standards. However, only half of the oncologists (55.6%) and psychosocial leaders (45.6%) agreed or strongly agreed that their psychosocial care was comprehensive and state of the art. Types of psychosocial care provided included evidence-based and less established approaches but were most often provided when problems were identified, rather than proactively. The perception of state of the art care was associated with practices indicative of integrated psychosocial care and the extent to which the Standards are currently implemented.
Conclusion
Many oncologists and psychosocial leaders perceive that the delivery of psychosocial care at their center is consistent with the Standards. However, care is quite variable, with evidence for the value of more integrated models of psychosocial services.
from Cancer via ola Kala on Inoreader http://ift.tt/2zW6eZ7
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Evaluation of patritumab with or without erlotinib in combination with standard cytotoxic agents against pediatric sarcoma xenograft models
Abstract
Background
Integrating molecularly targeted agents with cytotoxic drugs used in curative treatment of pediatric cancers is complex. An evaluation was undertaken with the ERBB3/Her3-specific antibody patritumab (P) either alone or with the ERBB1/epidermal growth factor receptor inhibitor erlotinib (E) in combination with standard cytotoxic agents, cisplatin, vincristine, and cyclophosphamide, in pediatric sarcoma xenograft models that express receptors and ligands targeted by these agents.
Procedures
Tumor models were selected based upon ERBB3 expression and phosphorylation, and ligand (heregulin) expression. Patritumab, E, or these agents combined was evaluated without or with concomitant cytotoxic agents using procedures developed by the Pediatric Preclinical Testing Program.
Results
Full doses of cytotoxic agents were tolerated when combined with P, whereas dose reductions of 25% (vincristine, cisplatin) or 50% (cyclophosphamide) were required when combined with P + E. Patritumab, E alone, or in combination did not significantly inhibit growth of any tumor model, except for Rh18 xenografts (E alone). Patritumab had no single-agent activity and marginally enhanced the activity of vincristine and cisplatin only in Ewing sarcoma ES-4. P + E did not increase the antitumor activity of vincristine or cisplatin, whereas dose-reduced cyclophosphamide was significantly less active than cyclophosphamide administered at its maximum tolerated dose when combined with P + E.
Conclusions
P had no single-agent activity, although it marginally potentiated the activity of vincristine and cisplatin in one of three models studied. However, the addition of E necessitated dose reduction of each cytotoxic agent, abrogating the enhancement observed with P alone.
from Cancer via ola Kala on Inoreader http://ift.tt/2xvhSs3
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Nutritional risk factors predict severe acute graft-versus-host disease and early mortality in pediatric allogeneic hematopoietic stem cell transplantation
Abstract
Background
Malnutrition is a pro-inflammatory state, yet data on nutritional risk factors and development of acute graft-versus-host disease (aGVHD) are extremely limited.
Procedure
We conducted a retrospective cohort analysis of pediatric patients up to age 21 years who underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the Children's Hospital of Philadelphia from January 2011 to September 2014 to determine whether malnutrition was associated with development of aGVHD and early mortality. We identified body mass index (BMI) percentile and serum albumin levels as potential markers of malnutrition and defined two composite nutritional risk variables as any of the following: albumin < 2.8 g/dl, weight loss ≥10% from baseline, and low BMI [<25th (NUT25) or <5th percentile (NUT5)]. Nutritional markers and GVHD grade were assessed at baseline, 30, 60, and 90 days post-HSCT, and patients were censored upon development of GVHD.
Results
BMI <25th or <5th percentile, NUT25, and NUT5 at the beginning of any 30-day period predicted a three- to fourfold risk of developing of severe (grade III–IV) aGVHD in the subsequent 30 days in models adjusted for age, sex, donor source, and degree of human leukocyte antigen matching. Mortality at day 100 was low, but NUT25 risk at baseline conferred an increased risk of death (7.9% vs. 1%, P = 0.035).
Conclusions
Malnutrition is a targetable risk factor in pediatric HSCT; prospective trials are needed to investigate this relationship further and identify effective nutritional interventions.
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Atypical meningioma: progression-free survival in 161 cases treated at our institution with surgery versus surgery and radiotherapy
Abstract
Although atypical meningioma recurs frequently in spite of total resection and/or radiotherapy, no consensus on optimal adjuvant management was found. However, several retrospective studies analysed the additional effect of adjuvant radiotherapy in atypical meningioma with inconsistent results. Therefrom, the purpose of this study was to evaluate prognostic factors influencing the recurrence/progression and progression-free survival (PFS) rates of atypical meningioma, particularly focused on the role of postoperative adjuvant radiotherapy. Between February 2001 and March 2015, 161 atypical meningioma resections were performed in our Department of Neurosurgery, of which, 128 cases underwent surgical treatment alone and 33 cases underwent surgery and radiotherapy. Kaplan–Meier analysis was used to provide median point estimates and PFS rates. The Cox-regression model was used in the univariate and multivariate analysis to identify significant factors associated with treatment. The extent of resection (Simpson grade I and II) significantly influenced the risk of recurrence (hazard ratio = 1.8, CI (95%) 1.3–2.6, p-value = 0.0004). There was no significant benefit for progression-free survival after adjuvant radiotherapy (hazard ratio = 1.48, CI (95%) 0.76–2.86, p-value = 0.22). Additionally, meningioma located at the anterior and posterior fossa showed a significantly longer PFS compared to other locations (p-value = 0.03). Adjuvant postoperative radiotherapy had no significant impact on recurrence/progression rate or PFS. The extent of resection according to Simpson grade remains the most important prognostic factor associated with lower recurrence/progression rates and longer PFS in patients with atypical meningioma. The location of the tumours at the anterior or posterior fossa was an independent factor associated with improved PFS.
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Clinical implications of in silico mathematical modeling for glioblastoma: a critical review
Abstract
Glioblastoma remains a clinical challenge in spite of years of extensive research. Novel approaches are needed in order to integrate the existing knowledge. This is the potential role of mathematical oncology. This paper reviews mathematical models on glioblastoma from the clinical doctor's point of view, with focus on 3D modeling approaches of radiation response of in vivo glioblastomas based on contemporary imaging techniques. As these models aim to provide a clinically useful tool in the era of personalized medicine, the integration of the latest advances in molecular and imaging science and in clinical practice by the in silico models is crucial for their clinical relevance. Our aim is to indicate areas of GBM research that have not yet been addressed by in silico models and to point out evidence that has come up from in silico experiments, which may be worth considering in the clinic. This review examines how close these models have come in predicting the outcome of treatment protocols and in shaping the future of radiotherapy treatments.
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MicroRNA-378 enhances radiation response in ectopic and orthotopic implantation models of glioblastoma
Abstract
Glioblastoma multiforme (GBM) is the most common and highly malignant primary brain tumor, which is virtually incurable due to its therapeutic resistance to radiation and chemotherapy. To develop novel therapeutic approaches for treatment of GBM, we examined the role of miR-378 on tumor growth, angiogenesis, and radiation response in ectopic and orthotopic U87 glioblastoma models. Cell and tumor growth rates, in vitro and in vivo radiation sensitivities, and tumor vascular density were evaluated in U87-GFP and U87-miR-378 tumor lines. Ectopic tumor response to radiation was evaluated under normal blood flow and clamp hypoxic conditions. Results show that in vitro, miR-378 expression moderately increased cell growth rate and plating efficiency, but did not alter radiation sensitivity. U87-miR-378 tumors exhibited a higher transplantation take rate than U87-GFP tumors. In vivo, under oxygenated condition, subcutaneous U87-miR-378 tumors receiving 25 Gy showed a tendency for longer tumor growth delay (TGD) than control U87-GFP tumors. In contrast, under hypoxic condition, U87-miR-378 xenografts exhibited substantially shorter TGD than U87-GFP tumors, indicating that under normal blood flow conditions, U87-miR-378 tumors were substantially more oxygenated than U87-GFP tumors. Intracranial multi-photon laser-scanning microscopy demonstrated increased vascular density of U87-miR-378 versus control U87-GFP tumors. Finally, miR-378 increased TGD following 12 Gy irradiation in U87 intracranial xenografts, and significantly prolonged survival of U87-miR-378 tumor-bearing mice (P = 0.04). In conclusion, higher miR-378 expression in U87-miR-378 cells promotes tumor growth, angiogenesis, radiation-induced TGD, and prolongs survival of orthotopic tumor-bearing hosts. Regulation of VEGFR2 by miR-378 significantly increased vascular density and oxygenation in U87 xenografts.
from Cancer via ola Kala on Inoreader http://ift.tt/2zczeyo
via IFTTT
Atypical meningioma: progression-free survival in 161 cases treated at our institution with surgery versus surgery and radiotherapy
Abstract
Although atypical meningioma recurs frequently in spite of total resection and/or radiotherapy, no consensus on optimal adjuvant management was found. However, several retrospective studies analysed the additional effect of adjuvant radiotherapy in atypical meningioma with inconsistent results. Therefrom, the purpose of this study was to evaluate prognostic factors influencing the recurrence/progression and progression-free survival (PFS) rates of atypical meningioma, particularly focused on the role of postoperative adjuvant radiotherapy. Between February 2001 and March 2015, 161 atypical meningioma resections were performed in our Department of Neurosurgery, of which, 128 cases underwent surgical treatment alone and 33 cases underwent surgery and radiotherapy. Kaplan–Meier analysis was used to provide median point estimates and PFS rates. The Cox-regression model was used in the univariate and multivariate analysis to identify significant factors associated with treatment. The extent of resection (Simpson grade I and II) significantly influenced the risk of recurrence (hazard ratio = 1.8, CI (95%) 1.3–2.6, p-value = 0.0004). There was no significant benefit for progression-free survival after adjuvant radiotherapy (hazard ratio = 1.48, CI (95%) 0.76–2.86, p-value = 0.22). Additionally, meningioma located at the anterior and posterior fossa showed a significantly longer PFS compared to other locations (p-value = 0.03). Adjuvant postoperative radiotherapy had no significant impact on recurrence/progression rate or PFS. The extent of resection according to Simpson grade remains the most important prognostic factor associated with lower recurrence/progression rates and longer PFS in patients with atypical meningioma. The location of the tumours at the anterior or posterior fossa was an independent factor associated with improved PFS.
http://ift.tt/2iFuNFr
Clinical implications of in silico mathematical modeling for glioblastoma: a critical review
Abstract
Glioblastoma remains a clinical challenge in spite of years of extensive research. Novel approaches are needed in order to integrate the existing knowledge. This is the potential role of mathematical oncology. This paper reviews mathematical models on glioblastoma from the clinical doctor's point of view, with focus on 3D modeling approaches of radiation response of in vivo glioblastomas based on contemporary imaging techniques. As these models aim to provide a clinically useful tool in the era of personalized medicine, the integration of the latest advances in molecular and imaging science and in clinical practice by the in silico models is crucial for their clinical relevance. Our aim is to indicate areas of GBM research that have not yet been addressed by in silico models and to point out evidence that has come up from in silico experiments, which may be worth considering in the clinic. This review examines how close these models have come in predicting the outcome of treatment protocols and in shaping the future of radiotherapy treatments.
http://ift.tt/2iblJ7s
MicroRNA-378 enhances radiation response in ectopic and orthotopic implantation models of glioblastoma
Abstract
Glioblastoma multiforme (GBM) is the most common and highly malignant primary brain tumor, which is virtually incurable due to its therapeutic resistance to radiation and chemotherapy. To develop novel therapeutic approaches for treatment of GBM, we examined the role of miR-378 on tumor growth, angiogenesis, and radiation response in ectopic and orthotopic U87 glioblastoma models. Cell and tumor growth rates, in vitro and in vivo radiation sensitivities, and tumor vascular density were evaluated in U87-GFP and U87-miR-378 tumor lines. Ectopic tumor response to radiation was evaluated under normal blood flow and clamp hypoxic conditions. Results show that in vitro, miR-378 expression moderately increased cell growth rate and plating efficiency, but did not alter radiation sensitivity. U87-miR-378 tumors exhibited a higher transplantation take rate than U87-GFP tumors. In vivo, under oxygenated condition, subcutaneous U87-miR-378 tumors receiving 25 Gy showed a tendency for longer tumor growth delay (TGD) than control U87-GFP tumors. In contrast, under hypoxic condition, U87-miR-378 xenografts exhibited substantially shorter TGD than U87-GFP tumors, indicating that under normal blood flow conditions, U87-miR-378 tumors were substantially more oxygenated than U87-GFP tumors. Intracranial multi-photon laser-scanning microscopy demonstrated increased vascular density of U87-miR-378 versus control U87-GFP tumors. Finally, miR-378 increased TGD following 12 Gy irradiation in U87 intracranial xenografts, and significantly prolonged survival of U87-miR-378 tumor-bearing mice (P = 0.04). In conclusion, higher miR-378 expression in U87-miR-378 cells promotes tumor growth, angiogenesis, radiation-induced TGD, and prolongs survival of orthotopic tumor-bearing hosts. Regulation of VEGFR2 by miR-378 significantly increased vascular density and oxygenation in U87 xenografts.
http://ift.tt/2zczeyo
Cancers, Vol. 9, Pages 148: Novel Molecular Challenges in Targeting Anaplastic Lymphoma Kinase in ALK-Expressing Human Cancers
Cancers, Vol. 9, Pages 148: Novel Molecular Challenges in Targeting Anaplastic Lymphoma Kinase in ALK-Expressing Human Cancers
Cancers doi: 10.3390/cancers9110148
Authors: Abdulraheem Alshareef
Targeting anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase receptor initially identified as a potent oncogenic driver in anaplastic large-cell lymphoma (ALCL) in the form of nucleophosmin (NPM)-ALK fusion protein, using tyrosine kinase inhibitors has shown to be a promising therapeutic approach for ALK-expressing tumors. However, clinical resistance to ALK inhibitors invariably occurs, and the molecular mechanisms are incompletely understood. Recent studies have clearly shown that clinical resistance to ALK inhibitors is a multifactorial and complex mechanism. While few of the mechanisms of clinical resistance to ALK inhibitors such as gene mutation are well known, there are others that are not well covered. In this review, the molecular mechanisms of cancer stem cells in mediating resistance to ALK inhibitors as well as the current understanding of the molecular challenges in targeting ALK in ALK-expressing human cancers will be discussed.
http://ift.tt/2zN9oNF
Cancers, Vol. 9, Pages 148: Novel Molecular Challenges in Targeting Anaplastic Lymphoma Kinase in ALK-Expressing Human Cancers
Cancers, Vol. 9, Pages 148: Novel Molecular Challenges in Targeting Anaplastic Lymphoma Kinase in ALK-Expressing Human Cancers
Cancers doi: 10.3390/cancers9110148
Authors: Abdulraheem Alshareef
Targeting anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase receptor initially identified as a potent oncogenic driver in anaplastic large-cell lymphoma (ALCL) in the form of nucleophosmin (NPM)-ALK fusion protein, using tyrosine kinase inhibitors has shown to be a promising therapeutic approach for ALK-expressing tumors. However, clinical resistance to ALK inhibitors invariably occurs, and the molecular mechanisms are incompletely understood. Recent studies have clearly shown that clinical resistance to ALK inhibitors is a multifactorial and complex mechanism. While few of the mechanisms of clinical resistance to ALK inhibitors such as gene mutation are well known, there are others that are not well covered. In this review, the molecular mechanisms of cancer stem cells in mediating resistance to ALK inhibitors as well as the current understanding of the molecular challenges in targeting ALK in ALK-expressing human cancers will be discussed.
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Clinical implications of in silico mathematical modeling for glioblastoma: a critical review
Abstract
Glioblastoma remains a clinical challenge in spite of years of extensive research. Novel approaches are needed in order to integrate the existing knowledge. This is the potential role of mathematical oncology. This paper reviews mathematical models on glioblastoma from the clinical doctor's point of view, with focus on 3D modeling approaches of radiation response of in vivo glioblastomas based on contemporary imaging techniques. As these models aim to provide a clinically useful tool in the era of personalized medicine, the integration of the latest advances in molecular and imaging science and in clinical practice by the in silico models is crucial for their clinical relevance. Our aim is to indicate areas of GBM research that have not yet been addressed by in silico models and to point out evidence that has come up from in silico experiments, which may be worth considering in the clinic. This review examines how close these models have come in predicting the outcome of treatment protocols and in shaping the future of radiotherapy treatments.
from Cancer via ola Kala on Inoreader http://ift.tt/2iblJ7s
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Reirradiation of Skull Base Tumors With Advanced Highly Conformal Techniques
Abstract
Purpose of Review
Skull base reirradiation is challenging due to complex anatomy, enrichment of treatment-resistant clonogens, and increased risk of severe treatment complications. Without local therapy, early mortality is certain and tumor progression can result in debilitating symptoms. Modern radiotherapy advancements, such as image-guided radiation therapy (IGRT), intensity-modulated radiation therapy (IMRT), particle therapy, and stereotactic radiation therapy (SRT), are attractive for skull base reirradiation.
Recent Findings
Although limited by their retrospective nature and heterogeneous patient populations, several studies have demonstrated that reirradiation with these highly conformal techniques is feasible. Compared to IMRT or particle therapy reirradiation, SRT reirradiation appears promising with lower toxicity and increased convenience.
Summary
Here, we provide thorough explanations for each technology and summarize the most relevant and recent studies, with particular attention to efficacy and toxicity. Skull base reirradiation using these extremely conformal therapy techniques requires meticulous treatment planning and should be delivered by experienced teams.
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Dysfunction of GABAergic neurons in the parafacial zone mediates sleep disturbances in a streptozotocin-induced rat model of sporadic Alzheimer’s disease
Abstract
Sleep disturbances are prevalent among patients with Alzheimer's disease (AD) and often precede the onset and progression of dementia. However, there are no reliable animal models for investigating sleep disturbances in patients with sporadic AD (sAD), which accounts for more than 90% of all AD cases. In the present study, we characterize the sleep/wake cycles and explore a potential mechanism underlying sleep disturbance in a rat model of sAD induced via intracerebroventricular (icv) injection of streptozotocin (STZ). STZ-icv rats exhibited progressive decreases in slow wave sleep (SWS) during the light phase and throughout the light/dark cycle beginning from 7 days after STZ-icv. Additionally, increased wakefulness and decreased rapid-eye-movement (REM) and non-REM (NREM) sleep were observed from 14 days after STZ-icv. Beginning on day 7, STZ-icv rats exhibited significant decreases in delta (0.5–4.0 Hz) power accompanied by increased power in the beta (12–30 Hz) and low gamma bands (30–50 Hz) during NREM sleep, resembling deficits in sleep quality observed in patients with AD. Immunohistochemical staining revealed a significant reduction in the ratio of c-Fos-positive GABAergic neurons in the parafacial zone (PZ) beginning from day 7 after STZ-icv. These results suggest that the STZ-icv rat model is useful for evaluating sleep disturbances associated with AD, and implicate the dysregulation of GABAergic neuronal activity in the PZ is associated with sleep disturbance induced by STZ.
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Treatment for Malignant Pheochromocytomas and Paragangliomas: 5 Years of Progress
Abstract
Purpose of Review
The purpose of this manuscript is to review the progress in the field of therapeutics for malignant pheochromocytomas and sympathetic paraganglioma (MPPG) over the past 5 years.
Recent Findings
The manuscript will describe the clinical predictors of survivorship and their influence on the first TNM staging classification for pheochromocytomas and sympathetic paragangliomas, the treatment of hormonal complications, and the rationale that supports the resection of the primary tumor and metastases in patients with otherwise incurable disease. Therapeutic options for patients with bone metastasis to the spine will be presented. The manuscript will also review chemotherapy and propose a maintenance regimen with dacarbazine for patients initially treated with cyclophosphamide, vincristine, and dacarbazine. Finally, the manuscript will review preliminary results of several phase 2 clinical trials of novel radiopharmaceutical agents and tyrosine kinase inhibitors.
Summary
MPPGs are very rare neuroendocrine tumors. MPPGs are usually characterized by a large tumor burden, excessive secretion of catecholamines, and decreased overall survival. Recent discoveries have enhanced our knowledge of the pathogenesis and phenotypes of MPPG. This knowledge is leading to a better understanding of the indications and limitations of the currently available localized and systemic therapies as well as the development of phase 2 clinical trials for novel medications.
from Cancer via ola Kala on Inoreader http://ift.tt/2hi4mSy
via IFTTT
Dysfunction of GABAergic neurons in the parafacial zone mediates sleep disturbances in a streptozotocin-induced rat model of sporadic Alzheimer’s disease
Abstract
Sleep disturbances are prevalent among patients with Alzheimer's disease (AD) and often precede the onset and progression of dementia. However, there are no reliable animal models for investigating sleep disturbances in patients with sporadic AD (sAD), which accounts for more than 90% of all AD cases. In the present study, we characterize the sleep/wake cycles and explore a potential mechanism underlying sleep disturbance in a rat model of sAD induced via intracerebroventricular (icv) injection of streptozotocin (STZ). STZ-icv rats exhibited progressive decreases in slow wave sleep (SWS) during the light phase and throughout the light/dark cycle beginning from 7 days after STZ-icv. Additionally, increased wakefulness and decreased rapid-eye-movement (REM) and non-REM (NREM) sleep were observed from 14 days after STZ-icv. Beginning on day 7, STZ-icv rats exhibited significant decreases in delta (0.5–4.0 Hz) power accompanied by increased power in the beta (12–30 Hz) and low gamma bands (30–50 Hz) during NREM sleep, resembling deficits in sleep quality observed in patients with AD. Immunohistochemical staining revealed a significant reduction in the ratio of c-Fos-positive GABAergic neurons in the parafacial zone (PZ) beginning from day 7 after STZ-icv. These results suggest that the STZ-icv rat model is useful for evaluating sleep disturbances associated with AD, and implicate the dysregulation of GABAergic neuronal activity in the PZ is associated with sleep disturbance induced by STZ.
http://ift.tt/2zMSWgH
Reirradiation of Skull Base Tumors With Advanced Highly Conformal Techniques
Abstract
Purpose of Review
Skull base reirradiation is challenging due to complex anatomy, enrichment of treatment-resistant clonogens, and increased risk of severe treatment complications. Without local therapy, early mortality is certain and tumor progression can result in debilitating symptoms. Modern radiotherapy advancements, such as image-guided radiation therapy (IGRT), intensity-modulated radiation therapy (IMRT), particle therapy, and stereotactic radiation therapy (SRT), are attractive for skull base reirradiation.
Recent Findings
Although limited by their retrospective nature and heterogeneous patient populations, several studies have demonstrated that reirradiation with these highly conformal techniques is feasible. Compared to IMRT or particle therapy reirradiation, SRT reirradiation appears promising with lower toxicity and increased convenience.
Summary
Here, we provide thorough explanations for each technology and summarize the most relevant and recent studies, with particular attention to efficacy and toxicity. Skull base reirradiation using these extremely conformal therapy techniques requires meticulous treatment planning and should be delivered by experienced teams.
http://ift.tt/2zM6fhk
Treatment for Malignant Pheochromocytomas and Paragangliomas: 5 Years of Progress
Abstract
Purpose of Review
The purpose of this manuscript is to review the progress in the field of therapeutics for malignant pheochromocytomas and sympathetic paraganglioma (MPPG) over the past 5 years.
Recent Findings
The manuscript will describe the clinical predictors of survivorship and their influence on the first TNM staging classification for pheochromocytomas and sympathetic paragangliomas, the treatment of hormonal complications, and the rationale that supports the resection of the primary tumor and metastases in patients with otherwise incurable disease. Therapeutic options for patients with bone metastasis to the spine will be presented. The manuscript will also review chemotherapy and propose a maintenance regimen with dacarbazine for patients initially treated with cyclophosphamide, vincristine, and dacarbazine. Finally, the manuscript will review preliminary results of several phase 2 clinical trials of novel radiopharmaceutical agents and tyrosine kinase inhibitors.
Summary
MPPGs are very rare neuroendocrine tumors. MPPGs are usually characterized by a large tumor burden, excessive secretion of catecholamines, and decreased overall survival. Recent discoveries have enhanced our knowledge of the pathogenesis and phenotypes of MPPG. This knowledge is leading to a better understanding of the indications and limitations of the currently available localized and systemic therapies as well as the development of phase 2 clinical trials for novel medications.
http://ift.tt/2hi4mSy
MicroRNA-378 enhances radiation response in ectopic and orthotopic implantation models of glioblastoma
Abstract
Glioblastoma multiforme (GBM) is the most common and highly malignant primary brain tumor, which is virtually incurable due to its therapeutic resistance to radiation and chemotherapy. To develop novel therapeutic approaches for treatment of GBM, we examined the role of miR-378 on tumor growth, angiogenesis, and radiation response in ectopic and orthotopic U87 glioblastoma models. Cell and tumor growth rates, in vitro and in vivo radiation sensitivities, and tumor vascular density were evaluated in U87-GFP and U87-miR-378 tumor lines. Ectopic tumor response to radiation was evaluated under normal blood flow and clamp hypoxic conditions. Results show that in vitro, miR-378 expression moderately increased cell growth rate and plating efficiency, but did not alter radiation sensitivity. U87-miR-378 tumors exhibited a higher transplantation take rate than U87-GFP tumors. In vivo, under oxygenated condition, subcutaneous U87-miR-378 tumors receiving 25 Gy showed a tendency for longer tumor growth delay (TGD) than control U87-GFP tumors. In contrast, under hypoxic condition, U87-miR-378 xenografts exhibited substantially shorter TGD than U87-GFP tumors, indicating that under normal blood flow conditions, U87-miR-378 tumors were substantially more oxygenated than U87-GFP tumors. Intracranial multi-photon laser-scanning microscopy demonstrated increased vascular density of U87-miR-378 versus control U87-GFP tumors. Finally, miR-378 increased TGD following 12 Gy irradiation in U87 intracranial xenografts, and significantly prolonged survival of U87-miR-378 tumor-bearing mice (P = 0.04). In conclusion, higher miR-378 expression in U87-miR-378 cells promotes tumor growth, angiogenesis, radiation-induced TGD, and prolongs survival of orthotopic tumor-bearing hosts. Regulation of VEGFR2 by miR-378 significantly increased vascular density and oxygenation in U87 xenografts.
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Progesterone-only contraception is associated with a shorter progression-free survival in premenopausal women with WHO Grade I meningioma
Abstract
The hormonally active nature of intracranial meningioma has prompted research examining the risk of tumorigenesis in patients using hormonal contraception. Studies exploring estrogen-only and estrogen/progesterone combination contraceptives have failed to demonstrate a consistent increased risk of meningioma. By contrast, the few trials examining progesterone-only contraceptives have shown higher odds ratios for risk of meningioma. With progesterone-only contraception on the rise, the risk of tumor recurrence with these specific medications warrants closer study. We sought to determine whether progesterone-only contraception increases recurrence rate and decreases progression-free survival in pre-menopausal women with surgically resected WHO Grade I meningioma. Comparative analysis of 67 pre-menopausal women taking hormone-based contraceptives (progesterone-only medication, n = 21; estrogen-only or estrogen/progesterone combination medication, n = 46) who underwent surgical resection of WHO Grade I intracranial meningioma was performed. Differences in demographics, degree of resection, adjuvant therapy and time to recurrence were compared between the two groups. Compared to patients taking combination or estrogen-only contraception, those taking progesterone-only contraception demonstrated a greater recurrence rate (33.3 vs. 19.6%) with a reduced time to recurrence (18 vs. 32 months, p = 0.038) despite a significantly shorter follow-up (p = 0.014). There were no significant demographic or treatment related differences. The results from this study suggest that exogenous progesterone-only medications may represent a specific contraceptive subgroup that should be avoided in patients with meningioma.
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Atypical meningioma: progression-free survival in 161 cases treated at our institution with surgery versus surgery and radiotherapy
Abstract
Although atypical meningioma recurs frequently in spite of total resection and/or radiotherapy, no consensus on optimal adjuvant management was found. However, several retrospective studies analysed the additional effect of adjuvant radiotherapy in atypical meningioma with inconsistent results. Therefrom, the purpose of this study was to evaluate prognostic factors influencing the recurrence/progression and progression-free survival (PFS) rates of atypical meningioma, particularly focused on the role of postoperative adjuvant radiotherapy. Between February 2001 and March 2015, 161 atypical meningioma resections were performed in our Department of Neurosurgery, of which, 128 cases underwent surgical treatment alone and 33 cases underwent surgery and radiotherapy. Kaplan–Meier analysis was used to provide median point estimates and PFS rates. The Cox-regression model was used in the univariate and multivariate analysis to identify significant factors associated with treatment. The extent of resection (Simpson grade I and II) significantly influenced the risk of recurrence (hazard ratio = 1.8, CI (95%) 1.3–2.6, p-value = 0.0004). There was no significant benefit for progression-free survival after adjuvant radiotherapy (hazard ratio = 1.48, CI (95%) 0.76–2.86, p-value = 0.22). Additionally, meningioma located at the anterior and posterior fossa showed a significantly longer PFS compared to other locations (p-value = 0.03). Adjuvant postoperative radiotherapy had no significant impact on recurrence/progression rate or PFS. The extent of resection according to Simpson grade remains the most important prognostic factor associated with lower recurrence/progression rates and longer PFS in patients with atypical meningioma. The location of the tumours at the anterior or posterior fossa was an independent factor associated with improved PFS.
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Relationships of depressive behavior and sertraline treatment with walking speed and activity in older female nonhuman primates
Abstract
Depression is the most common mental health problem in aging persons and is a leading risk factor for physical disability, especially in women. Though antidepressant drugs such as serotonin reuptake inhibitors (SSRI) are commonly prescribed, epidemiological evidence reveals mixed effects of long-term antidepressant use on physical function and activity, possibly depending on depressive status. The purpose of this preclinical trial was to determine the relationships of depressive behavior and the potential for an SSRI treatment to modulate walking speed and activity patterns in older adult female cynomolgus monkeys (Macaca fascicularis). We evaluated the effects of depression and a commonly prescribed SSRI, sertraline HCl (20 mg/kg/day p.o.), on (a) walking speed, (b) accelerometry-derived activity (counts) and sedentariness (daytime 60-s sedentary epochs), and (c) observed locomotor and sedentary behaviors (% time) in adult female depressed and nondepressed monkeys (n = 42; 17.2 ± 1.8 years) during an 18 month pre-treatment phase and an 18 month treatment phase using a longitudinal, stratified placebo–control study design. Monkeys that were depressed prior to treatment (19/42) subsequently had slower walking speeds (F D [1, 38] = 4.14; p ≤ 0.05) and tended to be more sedentary during the daytime (F D [1, 38] = 3.63; p ≤ 0.06). Sertraline did not affect depressive behaviors, walking speed, accelerometry-derived physical activity or sedentariness, or time observed in total locomotor or sedentary behavior (all p > 0.10). This study provides the first experimental demonstration of relationships between nonhuman primate behavioral depression and walking speed, activity, and sedentariness and provides evidence for a lack of an effect of SSRI treatment on these phenotypes.
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A Randomized Phase 3 Study Evaluating the Efficacy of Single-dose NEPA, a Fixed Antiemetic Combination of Netupitant and Palonosetron, Versus an Aprepitant Regimen for Prevention of Chemotherapy-induced Nausea and Vomiting (CINV) in Patients Receiving Highly Emetogenic Chemotherapy (HEC)
Abstract
Background
Co-administration of multiple antiemetics that inhibit several molecular pathways involved in emesis is required to optimize CINV control in patients receiving highly emetogenic chemotherapy (HEC). NEPA, a fixed combination of a highly selective NK1 receptor antagonist (RA), netupitant (300 mg), and the pharmacologically distinct 5-HT3RA, palonosetron (PALO 0.50 mg), has shown superior CINV prevention compared to PALO in cisplatin and anthracycline/cyclophosphamide-based settings. This study is the first head-to-head comparison of NEPA versus an aprepitant (APR)/granisetron (GRAN) regimen. Patients and methods
This randomized, double-blind Phase 3 study conducted in Asia was designed with the primary objective to demonstrate non-inferiority of a single oral dose of NEPA compared with a 3-day oral APR/GRAN regimen in chemotherapy-naïve patients receiving cisplatin-based HEC. All patients also received oral dexamethasone (DEX) on days 1-4. The primary efficacy endpoint was complete response (CR: no emesis/no rescue medication) during the overall (0-120 h) phase. Non-inferiority was defined as a lower 95% CI greater than the non-inferiority margin set at -10%. Secondary efficacy endpoints included no emesis, no rescue medication, and no significant nausea (NSN). Results
Treatment groups were comparable for the 828 patients analyzed: predominantly male (71%); mean age 54.5 years; ECOG 0-1 (98%); lung cancer (58%). NEPA demonstrated non-inferiority to APR/GRAN for overall CR [NEPA 73.8% vs APR/GRAN 72.4%, 95%CI (-4.5%, 7.5%)]. No emesis [NEPA 75.0% vs APR/GRAN 74.0%, 95%CI (-4.8%, 6.9%)] and NSN rates [NEPA 75.7% vs APR/GRAN 70.4%, 95%CI (-0.6%, 11.4%)] were similar between groups, but significantly more NEPA patients did not take rescue medication [NEPA 96.6% vs APR/GRAN 93.5%, 95%CI (0.2%, 6.1%)]. NEPA was well tolerated with a similar safety profile to APR/GRAN. Conclusions
In this first study comparing NK1RA regimens and DEX, NEPA administered only on day 1 was non-inferior to a 3-day oral APR/GRAN regimen in preventing CINV associated with HEC.http://ift.tt/2yYg9z3
Safety and efficacy of alternating treatment with EP2006, a filgrastim biosimilar, and reference filgrastim: a phase 3, randomised, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy
Abstract
Background
In 2015, the biosimilar filgrastim EP2006 became the first biosimilar approved by the US Food and Drug Administration (FDA) for commercial use in the United States, marketed as Zarxio®. This phase 3 randomised, double-blind registration study in patients with breast cancer receiving (neo)adjuvant myelosuppressive chemotherapy (TAC; docetaxel+doxorubicin+cyclophosphamide) compares reference filgrastim, Neupogen®, with two groups receiving alternating treatment with reference and biosimilar every other cycle. Patients and methods
A total of 218 patients receiving 5 µg/kg/day filgrastim over six chemotherapy cycles were randomised 1:1:1:1 into four arms. Two arms received only one product, biosimilar or reference (unswitched), and two arms (switched) received alternating treatments every other cycle (biosimilar then reference or vice versa over six cycles). Since the switch occurred from Cycle 2 onwards, this analysis compared pooled switched groups to the unswitched reference group for efficacy during Cycles 2─6. Safety was also assessed. Non-inferiority in febrile neutropenia (FN) rates between groups for Cycles 2─6 was shown if 95% confidence intervals (CIs) were within a pre-defined margin of –15%. Results
A total of 109 patients switched treatment, and 52 patients received reference in all cycles. Baseline characteristics were similar between groups. The incidence of FN was 0% (reference) versus 3.4% (n=3, switched) across Cycles 2–6, with a difference of –3.4% (95% CI: –9.65–4.96), showing non-inferiority. Infections occurred in 9.3% (switched) versus 9.9% (reference). Hospitalisation due to FN was low (one patient in Cycle 6; switched). Adverse events related to filgrastim were reported in 42.1% (switched) versus 39.2% (reference) (all cycles). Musculoskeletal/connective tissue disorders related to filgrastim occurred in 35.5% (switched) versus 39.2% (reference) (all cycles), including bone pain (30.8% versus 33.3%). No neutralising antibodies were detected. Conclusions
There were no clinically meaningful results regarding efficacy, safety or immunogenicity when switching from reference to biosimilar filgrastim/EP2006, or vice versa.http://ift.tt/2yVHUGJ
Characterization of male breast cancer: Results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program
Abstract
Background
Male breast cancer (BC) is rare, managed by extrapolation from female BC. The International Male BC Program aims to better characterize and manage this disease. We report the results of part 1, a retrospective-joint-analysis of cases diagnosed during a 20-year-period. Methods
Patients with follow-up and tumor samples, treated between 1990-2010, in 93 centers/nine countries. Samples were centrally analyzed in three labs (UK, NL, US). Results
Of 1822 patients enrolled, 1483 were analyzed; 63.5% were diagnosed between 2001-2010, 57 (5.1%) had metastatic disease (M1). Median age at diagnosis: 68.4 years. Of 1054 M0 cases, 56.2% were node-negative (N0) and 48.5% had T1 tumors; 4% had breast conserving surgery (BCS), 18% sentinel lymph-node biopsy; half received adjuvant radiotherapy; 29.8% (neo)adjuvant chemotherapy and 76.8% adjuvant endocrine therapy (ET), mostly tamoxifen (88.4%). Per central pathology, for M0 tumors: 84.8% ductal invasive carcinomas, 51.5% grade 2; 99.3% ER-positive; 81.9% PR-positive; 96.9% AR-positive (ER, PgR or AR Allred score ≥3); 61.1% Ki67 expression low (<14% positive cells); using IHC surrogates, 41.9% were Luminal-A-like, 48.6% Luminal-B-like/HER-2-negative, 8.7% HER-2-positive, 0.3% triple negative. Median follow-up: 8.2 years (0·0-23·8) for all, 7.2 years (0·0 -23·2), for M0, 2.6 years (0·0-12·7) for M1 patients. A significant improvement over time was observed in age-corrected-breast-cancer-mortality. Breast-cancer-specific-mortality was higher for men <50 years. Better OS and RFS were observed for highly-ER + (p = 0·001), highly-PR + (p = 0·002), highly-AR+ disease (p = 0·019). There was no association between OS/RFS and HER-2 status, Ki67, IHC subtypes nor grade. Conclusions
Male BC is usually ER, PR, and AR positive, Luminal B-like/HER2-negative. 56% patients had T1 tumors but only 4% had BCS. ER was highly positive in > 90% of cases but only 77% received adjuvant ET. ER, PR, and AR were associated with OS and RFS, while grade, Ki67, and IHC surrogates were not. Significant improvement in survival over time was observed.http://ift.tt/2yYg0vv
Combined treatment with pemetrexed and vinflunine in patients with metastatic urothelial cell carcinoma after prior platinum-containing chemotherapy – results of an exploratory phase I study
Summary
Vinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination. Pemetrexed was added to vinflunine dosed at 280 mg/m2 on day 1 of a 21-day cycle. Three levels of pemetrexed were planned starting at 400 mg/m2. Four patients were enrolled with a mean age of 66 years and with a mean number of prior GC-cycles of 6,8. Two DLT's were observed at the lowest dose-level in cohort 1. One patient experienced grade 4 thrombocytopenia and a second demonstrated hepatobiliary toxicity grade 3 with an increase in alanine aminotransaminase. Most common grade 3 and 4 adverse events were anemia, thrombocytopenia and neutropenia. Three out of four patients received 3 cycles of pemetrexed and vinflunine, all had progressive disease. Based on these observations and due to protocol design, the study was interrupted at dose level 1 for safety reasons. The combined therapy of vinflunine (Javlor®, Pierre Fabre Pharma) and pemetrexed (Alimta®, Eli Lilly) is poorly tolerated in metastatic UCC patients. The combination cannot be recommended for further investigations in metastatic UCC.
http://ift.tt/2gOL7TA
Ganoderic acid, lanostanoid triterpene: a key player in apoptosis
Summary
Cancer is a multifactorial disease, causing behavioral and metabolic alterations, leading to uncontrolled cell proliferation with collateral weakening of immune system. Crucial balance between cell proliferation and cell death determines the fate of a cell, which might progress towards survival or apoptosis. Apoptosis is a complex, programmed, and highly regulated process causing dramatic morphological and biochemical perturbations in the cellular machinery. Ganoderma lucidum is a basidiomycetes, polypore mushroom known for its pharmacological properties in cancer. The major bioconstituents in G. lucidum are terpenoids, polysaccharides, and proteins that target cancer-signaling factors like plasma membrane receptors proteins and adapter molecules. Of all constituents, the major terpenoid, i.e. Ganoderic acid is reported to interact with membrane receptors mainly, receptor tyrosine kinase (RTKs). Ganoderic acid interacts and modulates the signaling network in IR, IGFR-1, IGFR-2, VEGFR-1, VEFGR-2, and EGFR in cancer signaling pathways. It primarily targets NF-κB, RAS-MAPK, PI3K/Akt/mTOR, and cell cycle resulting in apoptosis. This review highlights the role of ganoderic acid in apoptosis and modulations of various signaling proteins in cancer.
http://ift.tt/2ySRFru
A Randomized Phase 3 Study Evaluating the Efficacy of Single-dose NEPA, a Fixed Antiemetic Combination of Netupitant and Palonosetron, Versus an Aprepitant Regimen for Prevention of Chemotherapy-induced Nausea and Vomiting (CINV) in Patients Receiving Highly Emetogenic Chemotherapy (HEC)
Abstract
Background
Co-administration of multiple antiemetics that inhibit several molecular pathways involved in emesis is required to optimize CINV control in patients receiving highly emetogenic chemotherapy (HEC). NEPA, a fixed combination of a highly selective NK1 receptor antagonist (RA), netupitant (300 mg), and the pharmacologically distinct 5-HT3RA, palonosetron (PALO 0.50 mg), has shown superior CINV prevention compared to PALO in cisplatin and anthracycline/cyclophosphamide-based settings. This study is the first head-to-head comparison of NEPA versus an aprepitant (APR)/granisetron (GRAN) regimen. Patients and methods
This randomized, double-blind Phase 3 study conducted in Asia was designed with the primary objective to demonstrate non-inferiority of a single oral dose of NEPA compared with a 3-day oral APR/GRAN regimen in chemotherapy-naïve patients receiving cisplatin-based HEC. All patients also received oral dexamethasone (DEX) on days 1-4. The primary efficacy endpoint was complete response (CR: no emesis/no rescue medication) during the overall (0-120 h) phase. Non-inferiority was defined as a lower 95% CI greater than the non-inferiority margin set at -10%. Secondary efficacy endpoints included no emesis, no rescue medication, and no significant nausea (NSN). Results
Treatment groups were comparable for the 828 patients analyzed: predominantly male (71%); mean age 54.5 years; ECOG 0-1 (98%); lung cancer (58%). NEPA demonstrated non-inferiority to APR/GRAN for overall CR [NEPA 73.8% vs APR/GRAN 72.4%, 95%CI (-4.5%, 7.5%)]. No emesis [NEPA 75.0% vs APR/GRAN 74.0%, 95%CI (-4.8%, 6.9%)] and NSN rates [NEPA 75.7% vs APR/GRAN 70.4%, 95%CI (-0.6%, 11.4%)] were similar between groups, but significantly more NEPA patients did not take rescue medication [NEPA 96.6% vs APR/GRAN 93.5%, 95%CI (0.2%, 6.1%)]. NEPA was well tolerated with a similar safety profile to APR/GRAN. Conclusions
In this first study comparing NK1RA regimens and DEX, NEPA administered only on day 1 was non-inferior to a 3-day oral APR/GRAN regimen in preventing CINV associated with HEC.from Cancer via ola Kala on Inoreader http://ift.tt/2yYg9z3
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Safety and efficacy of alternating treatment with EP2006, a filgrastim biosimilar, and reference filgrastim: a phase 3, randomised, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy
Abstract
Background
In 2015, the biosimilar filgrastim EP2006 became the first biosimilar approved by the US Food and Drug Administration (FDA) for commercial use in the United States, marketed as Zarxio®. This phase 3 randomised, double-blind registration study in patients with breast cancer receiving (neo)adjuvant myelosuppressive chemotherapy (TAC; docetaxel+doxorubicin+cyclophosphamide) compares reference filgrastim, Neupogen®, with two groups receiving alternating treatment with reference and biosimilar every other cycle. Patients and methods
A total of 218 patients receiving 5 µg/kg/day filgrastim over six chemotherapy cycles were randomised 1:1:1:1 into four arms. Two arms received only one product, biosimilar or reference (unswitched), and two arms (switched) received alternating treatments every other cycle (biosimilar then reference or vice versa over six cycles). Since the switch occurred from Cycle 2 onwards, this analysis compared pooled switched groups to the unswitched reference group for efficacy during Cycles 2─6. Safety was also assessed. Non-inferiority in febrile neutropenia (FN) rates between groups for Cycles 2─6 was shown if 95% confidence intervals (CIs) were within a pre-defined margin of –15%. Results
A total of 109 patients switched treatment, and 52 patients received reference in all cycles. Baseline characteristics were similar between groups. The incidence of FN was 0% (reference) versus 3.4% (n=3, switched) across Cycles 2–6, with a difference of –3.4% (95% CI: –9.65–4.96), showing non-inferiority. Infections occurred in 9.3% (switched) versus 9.9% (reference). Hospitalisation due to FN was low (one patient in Cycle 6; switched). Adverse events related to filgrastim were reported in 42.1% (switched) versus 39.2% (reference) (all cycles). Musculoskeletal/connective tissue disorders related to filgrastim occurred in 35.5% (switched) versus 39.2% (reference) (all cycles), including bone pain (30.8% versus 33.3%). No neutralising antibodies were detected. Conclusions
There were no clinically meaningful results regarding efficacy, safety or immunogenicity when switching from reference to biosimilar filgrastim/EP2006, or vice versa.from Cancer via ola Kala on Inoreader http://ift.tt/2yVHUGJ
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Characterization of male breast cancer: Results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program
Abstract
Background
Male breast cancer (BC) is rare, managed by extrapolation from female BC. The International Male BC Program aims to better characterize and manage this disease. We report the results of part 1, a retrospective-joint-analysis of cases diagnosed during a 20-year-period. Methods
Patients with follow-up and tumor samples, treated between 1990-2010, in 93 centers/nine countries. Samples were centrally analyzed in three labs (UK, NL, US). Results
Of 1822 patients enrolled, 1483 were analyzed; 63.5% were diagnosed between 2001-2010, 57 (5.1%) had metastatic disease (M1). Median age at diagnosis: 68.4 years. Of 1054 M0 cases, 56.2% were node-negative (N0) and 48.5% had T1 tumors; 4% had breast conserving surgery (BCS), 18% sentinel lymph-node biopsy; half received adjuvant radiotherapy; 29.8% (neo)adjuvant chemotherapy and 76.8% adjuvant endocrine therapy (ET), mostly tamoxifen (88.4%). Per central pathology, for M0 tumors: 84.8% ductal invasive carcinomas, 51.5% grade 2; 99.3% ER-positive; 81.9% PR-positive; 96.9% AR-positive (ER, PgR or AR Allred score ≥3); 61.1% Ki67 expression low (<14% positive cells); using IHC surrogates, 41.9% were Luminal-A-like, 48.6% Luminal-B-like/HER-2-negative, 8.7% HER-2-positive, 0.3% triple negative. Median follow-up: 8.2 years (0·0-23·8) for all, 7.2 years (0·0 -23·2), for M0, 2.6 years (0·0-12·7) for M1 patients. A significant improvement over time was observed in age-corrected-breast-cancer-mortality. Breast-cancer-specific-mortality was higher for men <50 years. Better OS and RFS were observed for highly-ER + (p = 0·001), highly-PR + (p = 0·002), highly-AR+ disease (p = 0·019). There was no association between OS/RFS and HER-2 status, Ki67, IHC subtypes nor grade. Conclusions
Male BC is usually ER, PR, and AR positive, Luminal B-like/HER2-negative. 56% patients had T1 tumors but only 4% had BCS. ER was highly positive in > 90% of cases but only 77% received adjuvant ET. ER, PR, and AR were associated with OS and RFS, while grade, Ki67, and IHC surrogates were not. Significant improvement in survival over time was observed.from Cancer via ola Kala on Inoreader http://ift.tt/2yYg0vv
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Combined treatment with pemetrexed and vinflunine in patients with metastatic urothelial cell carcinoma after prior platinum-containing chemotherapy – results of an exploratory phase I study
Summary
Vinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination. Pemetrexed was added to vinflunine dosed at 280 mg/m2 on day 1 of a 21-day cycle. Three levels of pemetrexed were planned starting at 400 mg/m2. Four patients were enrolled with a mean age of 66 years and with a mean number of prior GC-cycles of 6,8. Two DLT's were observed at the lowest dose-level in cohort 1. One patient experienced grade 4 thrombocytopenia and a second demonstrated hepatobiliary toxicity grade 3 with an increase in alanine aminotransaminase. Most common grade 3 and 4 adverse events were anemia, thrombocytopenia and neutropenia. Three out of four patients received 3 cycles of pemetrexed and vinflunine, all had progressive disease. Based on these observations and due to protocol design, the study was interrupted at dose level 1 for safety reasons. The combined therapy of vinflunine (Javlor®, Pierre Fabre Pharma) and pemetrexed (Alimta®, Eli Lilly) is poorly tolerated in metastatic UCC patients. The combination cannot be recommended for further investigations in metastatic UCC.
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