Prospective Randomized Trial of Prone Accelerated Intensity Modulated Breast Radiotherapy with a Daily versus Weekly Boost to the Tumor Bed

Publication date: Available online 29 December 2015
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): B.T. Cooper, G.F. Formenti-Ujlaki, X. Li, S.M. Shin, M. Fenton-Kerimian, A. Guth, D.F. Roses, C.J. Hitchen, B.S. Rosenstein, J.K. Dewyngaert, J.D. Goldberg, S.C. Formenti
PurposeTo report the results of a prospective randomized trial comparing a daily versus weekly boost to the tumor cavity during the course of accelerated radiation to the breast in the prone position.Methods and MaterialsFrom 2009-2012, 400 stage 0-II breast cancer patients who had undergone segmental mastectomy participated in an IRB-approved trial testing prone breast radiotherapy to 40.5 Gy/15 fractions to the whole breast, five days a week after randomization to a concomitant daily boost to the tumor bed of 0.5 Gy, or a weekly boost of 2 Gy, on Friday. This non-inferiority trial tested the primary hypothesis that a weekly boost produced no more acute toxicity than a daily boost. Recurrence Free Survival (RFS) was estimated for both treatment arms using the Kaplan-Meier method; the relative risk of recurrence or death was estimated and the two arms were compared with the log-rank test.ResultsAt a median follow-up of 45 months, there were no deaths related to breast cancer. The weekly boost regimen produced no more grade ≥ 2 acute toxicity than the daily boost regimen (8.1% vs 10.4%; non-inferiority Z = -2.52; p = 0.006). There was no statistical difference in cumulative incidences of long term fibrosis or telangiectasia ≥2 between the two arms (log-rank p=0.923). There were 2 local and 2 distant recurrences in the daily arm. There were 3 local and 1 distant recurrences in the weekly arm, with no difference in 4-year RFS between the two arms (98% in both arms).ConclusionsA tumor bed boost delivered either daily or weekly is similarly tolerated during accelerated prone breast radiotherapy, with excellent control of disease and comparable cosmetic results.

Teaser

We conducted a prospective trial randomizing women with early stage breast cancer to accelerated prone, whole breast radiotherapy with a weekly versus daily boost to the tumor bed. At a median follow-up of 45 months, there was no difference in toxicity or efficacy between the two treatment arms. There was a trend towards more patients reporting good/excellent cosmesis among those treated with the weekly boost.


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A prospective comparison of the effects of interfractional variations on proton therapy and IMRT for prostate cancer

Publication date: Available online 29 December 2015
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): M. Moteabbed, A. Trofimov, G.C. Sharp, Y. Wang, A.L. Zietman, J. Efstathiou, H.-M. Lu
PurposeTo quantify and compare the impact of interfractional setup and anatomy variations on proton therapy (PT) and intensity modulated radiotherapy (IMRT) for prostate cancer.Methods and MaterialsTwenty patients with low- or intermediate-risk prostate cancer randomized to receive passive-scattering PT (n=10) and IMRT (n=10) were selected. For both modalities, clinical treatment plans included 50.4 Gy(RBE) to prostate and proximal seminal vesicles, and prostate-only boost to 79.2 Gy(RBE) in 1.8 Gy(RBE) per fraction. Implanted fiducials were used for prostate localization, and endorectal balloons for immobilization. Patients in PT and IMRT arms received weekly CT and cone-beam CT (CBCT) scans, respectively. The planned dose was re-calculated on each weekly image, scaled and mapped onto the planning CT using deformable registration. The resulting accumulated dose distribution over the entire treatment course was compared with the planned dose using dose-volume histogram (DVH) and gamma analysis.ResultsThe target conformity index remained acceptable after accumulation. The largest decrease in the average prostate D98 was 2.2 and 0.7 Gy for PT and IMRT, respectively. On average, the mean dose to bladder increased by 3.26±7.51 Gy and 1.97±6.84 Gy for PT and IMRT, respectively. These values were 0.74±2.37 and 0.56±1.90 for rectum. Differences between changes in DVH indices were not statistically significant between the two modalities. All volume indices remained within the protocol tolerances after accumulation. The average pass rate in gamma analysis, assuming tolerances of 3 mm and 3%, for PT/IMRT for CTV, bladder, rectum and whole patient were 100/100, 92.6/99, 99.2/100 and 97.2/99.4, respectively.ConclusionThe difference in target coverage and OAR dose deviations for PT and IMRT was not statistically significant under the guidelines of this protocol.

Teaser

The impact of setup and anatomy variations on the dose distribution was compared between proton therapy and IMRT for prostate cancer. Although both modalities were robust to interfractional variations with no statistically significant differences, it is desirable to minimize the remaining sources of uncertainty mainly in setup accuracy and bladder size consistency.


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Clinicopathologic features of small cell glioblastomas

Abstract

Small cell glioblastoma (SCGBM) is a variant of glioblastomas characterized by a predominant population of small and monomorphic glial cells. The aim of the present study was to investigate clinical, neuroimaging, pathologic, and genetic features of SCGBM. The clinicopathologic and genetic features were evaluated in 14 patients with SCGBM. All cases were divided into multifocal and solitary type by MRI, and extent of microvascular proliferation, intratumoral necrosis, and perivascular lymphocytic accumulation were investigated. IDH1 mutations by immunohistochemistry (IDH1 R132H) and 1p 19q codeletion by fluorescence in situ hybridization were detected. Patients ranged from 23 to 92 years of age (median: 71 years), with three females and eleven males. The overall survival time of the patients ranged from 7 to 23 months (mean: 11 months). Nine patients (64 %) were the multifocal type. Pathologic study revealed that the microvascular proliferation, necrosis, and lymphocytic infiltration were limited in SCGBM. Immunohistochemically, tumor cells were negative for IDH1 R132H in all patients. FISH analysis demonstrated that no SCGBM had 1p/19q codeletion in informative patients. Our investigation suggested that an elderly onset and multifocal lesions were characteristics of SCGBM associated with degradation of the immune response, infiltrative feature of tumor cells, and an unfavorable prognosis.

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Combination treatment with fasudil and clioquinol produces synergistic anti-tumor effects in U87 glioblastoma cells by activating apoptosis and autophagy

Abstract

Survival of patients with glioblastoma (GBM) remains poor, and novel treatment methods are urgently needed. In this study, we tested the effects of a combination of fasudil, a ROCK inhibitor, and clioquinol, an 8-hydroxyquinoline derivative with antimicrobial properties, on human GBM U87 cells. Combination treatment synergistically inhibited the viability of glioma cells but not mouse normal neuron HT22 cells and significantly induced mitochondria-mediated apoptosis. Moreover, the combination was also found to trigger macro-autophagy (henceforth referred to as autophagy) by increasing the expression levels of several proteins involved in the induction of autophagy. Further studies showed that 3-methyladenine (3-MA) or chloroquine (CQ), two autophagy inhibitors, abrogated the cytotoxic effects of the combination treatment as well as the autophagy. Overall, we demonstrated that fasudil and clioquinol show synergistic anti-cancer effects, providing evidence for the further development of combination therapy for GBM.

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Associations among treatment-related neurological risk factors and neuropsychological functioning in survivors of childhood brain tumor

Abstract

Adverse neurological side effects associated with childhood brain tumors and their treatments contribute to long-term neurocognitive morbidity. Measures designed to quantify tumor-related risk factors are lacking. The neurological predictor scale (NPS) is designed to assess treatment-related neurological risks. Preliminary validation established associations between the NPS and global cognitive functioning in this population, though its associations with specific neurobehavioral domains has yet to be addressed. Participants referred for outpatient neuropsychological assessment completed performance-based measures of intellectual, attentional, working memory, motor speed, and executive abilities. Caregivers completed ratings of adaptive functioning. Neuropsychological and adaptive data were available for 100 brain tumor survivors (51 % female), ages 6 to 22 years (M = 12.83, SD = 4.37). Total NPS scores were generated via retrospective medical record review. Total NPS scores were significantly associated with several neurocognitive composite scores including verbal reasoning and working memory, after controlling for years post-diagnosis (ps < .05). NPS scores also were significantly associated with performance-based measures of attention, executive functioning, and cognitive efficiency (ps < .05). No significant relationship was demonstrated between NPS scores and caregiver-reported adaptive behavior skills (ps > .05). Results indicate that the NPS is associated with performance-based neurocognitive functioning and executive skills but not with functioning in specific caregiver-reported adaptive behavior domains. The NPS offers some value as a resource for understanding associations between treatment-related neurological risks and select aspects of neurocognitive morbidity. Future studies should examine whether the NPS can aid in planning appropriate therapeutic intervention as survivors progress into early adulthood.

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Evaluation of chromosome 1q gain in intracranial ependymomas

Abstract

Ependymomas are relatively uncommon gliomas with poor prognosis despite recent advances in neurooncology. Molecular pathogenesis of ependymomas is not extensively studied. Lack of correlation of histological grade with patient outcome has directed attention towards identification of molecular alterations as novel prognostic markers. Recently, 1q gain has emerged as a potential prognostic marker, associated with decreased survival, especially in posterior fossa, high grade tumors. Cases of intracranial ependymomas were retrieved. Tumors were graded using objective criteria to supplement WHO grading. Fluorescence in situ hybridization for 1q gain was performed on formalin-fixed paraffin embedded sections. Eighty-one intracranial ependymomas were analyzed. Pediatric (76 %) and infratentorial (70 %) ependymomas constituted the majority. 1q gain was seen in 27 cases (33 %), was equally frequent in children (34 %) and adults (32 %), supratentorial (37 %) and infratentorial (32 %) location, grade II (33 %) and III (25 %) tumors. Recurrence was noted in 24 cases and death in 7 cases with 5-year progression-free and overall-survival rates of 37 % and 80 %, respectively. Grade II tumors had a better survival than grade III tumors; histopathological grade was the only prognostically significant marker. 1q gain had no prognostic significance. 1q gain is frequent in ependymomas in Indian patients, seen across all ages, sites and grades, and thus is likely an early event in pathogenesis. The prognostic value of 1q gain, remains uncertain, and multicentric pooling of data is required. A histopathological grading system using objective criteria correlates well with patient outcome and can serve as an economical option for prognostication of ependymomas.

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The cost-effectiveness of surgical resection and cesium-131 intraoperative brachytherapy versus surgical resection and stereotactic radiosurgery in the treatment of metastatic brain tumors

Abstract

This study aims to evaluate the cost-effectiveness of surgical resection (S) and Cesium-131 (Cs-131) [S + Cs-131] intraoperative brachytherapy versus S and stereotactic radiosurgery (SRS) [S + SRS] for the treatment of brain metastases. Treatment records as well as hospital and outpatient charts of 49 patients with brain metastases between 2008 and 2012 who underwent S + Cs-131 (n = 24) and S + SRS (n = 25) were retrospectively reviewed. Hospital charges were compared for the single treatment in question. Means and curves of survival time were defined by the Kaplan–Meier estimator, with the cost analysis focusing on the time period of the relevant treatment. Quality adjusted life years (QALY) and Incremental cost-effectiveness ratios (ICER) were calculated for each treatment option as a measure of cost-effectiveness. The direct hospital costs of treatments per patient were: S + Cs131 = $19,271 and S + SRS = $44,219. The median survival times of S + Cs-131 and S + SRS were 15.5 and 11.3 months, and the 12 month survival rates were 61 % and 49 % (P = 0.137). The QALY for S + SRS when compared to S + Cs-131 yielded a p < 0.0001, making it significantly more cost-effective. The ICER also revealed that when compared to S + Cs-131, S + SRS was significantly inferior (p < 0.0001). S + Cs-131 is more cost-effective compared with S + SRS based on hospital charges as well as QALYs and ICER. Cost effectiveness, in addition to efficacy and risk, should factor into the comparison between these two treatment modalities for patients with surgically resectable brain metastases.

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Increased expression of phosphatidylethanolamine-binding protein 4 (PEBP4) strongly associates with human gliomas grade

Abstract

Abnormal expression of phosphatidylethanolamine-binding protein 4 (PEBP4) has been found in various types of malignancies. However, the PEBP4 expression in human gliomas is still unclear. In this study, we aim to compare the expression of PEBP4 in tumor samples derived from 58 patients with different grades of gliomas with that in 5 non-neoplastic brain samples and to investigate the clinical significance of PEBP4 expression in gliomas. The mRNA and protein expressions of PEBP4 were measured by real-time quantitative polymerase chain reaction and western blot, respectively. The intracellular expressions of PEBP4 in samples were examined by immunohistochemistry. The association between PEBP4 expression and the clinicopathologic characteristics of gliomas patients were analyzed. Our results demonstrated that the mRNA and protein levels of PEBP4 were upregulated in gliomas tissues, especially in high-grade (World Health Organization Grades III and IV) gliomas, when compared to normal control (p < 0.01). Immunohistochemical analysis indicated that PEBP4 was highly expressed in 82.4 % (28/34) of high-grade gliomas, when compared to 41.7 % (10/24) of high expression in low-grade gliomas and 20.0 % (1/5) in non-neoplastic brain samples (p = 0.001). Multivariate Cox regression analysis revealed that increased PEBP4 expression was an independent prognostic factor for gliomas. Patients with low level of PEBP4 had longer survival time compared to those with high PEBP4 expression (p = 0.003). These data indicate a clinical significance of PEBP4 for predicting the tumor grade and the prognosis in patients with gliomas.

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Clinical outcome of gliosarcoma compared with glioblastoma multiforme: a clinical study in Chinese patients

Abstract

Gliosarcoma (GSM) is a rare biphasic neoplasms of the central nervous system composed of a glioblastoma multiforme (GBM) admixed with a sarcomatous component. In clinical practice GSM is generally managed similarly to GBM. However, there are conflicting reports regarding their clinical aggressiveness, cell line of origin and possible prognosis compared with those of GBM. The objective of this study was to compare clinic-pathological features in GSM patients with the GBM patients during the same study period. 518 patients with GBM were treated at our hospital between 2008 and 2013, among them 51 were GSM. In this series the GSMs represented 9.8 % of all GBMs and included 58.8 % male with a median age of 44.7 years. The locations, all supratentorial, included temporal in 41.2 %, frontal in 25.5 %, parietal in 19.6 %, and occipital in 13.7 %. All patients underwent tumor resection followed by post-operative radiation and adjuvant chemotherapy. The O6-methylguanine-DNA methyltransferase promoter methylation studies were significantly more frequent in the GBMs than GSMs (80.1 % vs. 44.7 %, P < 0.001). The median progression free survival and overall survival for the patients with GSM were 8.0 and 13.0 months, respectively, as compared with 9.0 and 14.0 months in the GBM group (log rank test P = 0.001 and 0.004, respectively). The Cox proportional hazards regression model indicated that the extent of tumor resection (HR = 1.518, P = 0.009) and pathological types (HR = 0.608, P = 0.002) were the significant prognostic factors in our own series. With regard to clinical features and outcomes, GSM and GBM cannot be distinguished clinically. GSM in China may be managed similarly to GBM, with maximal safe surgical resection followed by chemo-radiotherapy. Our study adds further evidence to support GSM as a unique clinical entity with a likely worse prognosis than GBM.

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Clinicopathologic features of small cell glioblastomas

Abstract

Small cell glioblastoma (SCGBM) is a variant of glioblastomas characterized by a predominant population of small and monomorphic glial cells. The aim of the present study was to investigate clinical, neuroimaging, pathologic, and genetic features of SCGBM. The clinicopathologic and genetic features were evaluated in 14 patients with SCGBM. All cases were divided into multifocal and solitary type by MRI, and extent of microvascular proliferation, intratumoral necrosis, and perivascular lymphocytic accumulation were investigated. IDH1 mutations by immunohistochemistry (IDH1 R132H) and 1p 19q codeletion by fluorescence in situ hybridization were detected. Patients ranged from 23 to 92 years of age (median: 71 years), with three females and eleven males. The overall survival time of the patients ranged from 7 to 23 months (mean: 11 months). Nine patients (64 %) were the multifocal type. Pathologic study revealed that the microvascular proliferation, necrosis, and lymphocytic infiltration were limited in SCGBM. Immunohistochemically, tumor cells were negative for IDH1 R132H in all patients. FISH analysis demonstrated that no SCGBM had 1p/19q codeletion in informative patients. Our investigation suggested that an elderly onset and multifocal lesions were characteristics of SCGBM associated with degradation of the immune response, infiltrative feature of tumor cells, and an unfavorable prognosis.

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Combination treatment with fasudil and clioquinol produces synergistic anti-tumor effects in U87 glioblastoma cells by activating apoptosis and autophagy

Abstract

Survival of patients with glioblastoma (GBM) remains poor, and novel treatment methods are urgently needed. In this study, we tested the effects of a combination of fasudil, a ROCK inhibitor, and clioquinol, an 8-hydroxyquinoline derivative with antimicrobial properties, on human GBM U87 cells. Combination treatment synergistically inhibited the viability of glioma cells but not mouse normal neuron HT22 cells and significantly induced mitochondria-mediated apoptosis. Moreover, the combination was also found to trigger macro-autophagy (henceforth referred to as autophagy) by increasing the expression levels of several proteins involved in the induction of autophagy. Further studies showed that 3-methyladenine (3-MA) or chloroquine (CQ), two autophagy inhibitors, abrogated the cytotoxic effects of the combination treatment as well as the autophagy. Overall, we demonstrated that fasudil and clioquinol show synergistic anti-cancer effects, providing evidence for the further development of combination therapy for GBM.

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Associations among treatment-related neurological risk factors and neuropsychological functioning in survivors of childhood brain tumor

Abstract

Adverse neurological side effects associated with childhood brain tumors and their treatments contribute to long-term neurocognitive morbidity. Measures designed to quantify tumor-related risk factors are lacking. The neurological predictor scale (NPS) is designed to assess treatment-related neurological risks. Preliminary validation established associations between the NPS and global cognitive functioning in this population, though its associations with specific neurobehavioral domains has yet to be addressed. Participants referred for outpatient neuropsychological assessment completed performance-based measures of intellectual, attentional, working memory, motor speed, and executive abilities. Caregivers completed ratings of adaptive functioning. Neuropsychological and adaptive data were available for 100 brain tumor survivors (51 % female), ages 6 to 22 years (M = 12.83, SD = 4.37). Total NPS scores were generated via retrospective medical record review. Total NPS scores were significantly associated with several neurocognitive composite scores including verbal reasoning and working memory, after controlling for years post-diagnosis (ps < .05). NPS scores also were significantly associated with performance-based measures of attention, executive functioning, and cognitive efficiency (ps < .05). No significant relationship was demonstrated between NPS scores and caregiver-reported adaptive behavior skills (ps > .05). Results indicate that the NPS is associated with performance-based neurocognitive functioning and executive skills but not with functioning in specific caregiver-reported adaptive behavior domains. The NPS offers some value as a resource for understanding associations between treatment-related neurological risks and select aspects of neurocognitive morbidity. Future studies should examine whether the NPS can aid in planning appropriate therapeutic intervention as survivors progress into early adulthood.

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Evaluation of chromosome 1q gain in intracranial ependymomas

Abstract

Ependymomas are relatively uncommon gliomas with poor prognosis despite recent advances in neurooncology. Molecular pathogenesis of ependymomas is not extensively studied. Lack of correlation of histological grade with patient outcome has directed attention towards identification of molecular alterations as novel prognostic markers. Recently, 1q gain has emerged as a potential prognostic marker, associated with decreased survival, especially in posterior fossa, high grade tumors. Cases of intracranial ependymomas were retrieved. Tumors were graded using objective criteria to supplement WHO grading. Fluorescence in situ hybridization for 1q gain was performed on formalin-fixed paraffin embedded sections. Eighty-one intracranial ependymomas were analyzed. Pediatric (76 %) and infratentorial (70 %) ependymomas constituted the majority. 1q gain was seen in 27 cases (33 %), was equally frequent in children (34 %) and adults (32 %), supratentorial (37 %) and infratentorial (32 %) location, grade II (33 %) and III (25 %) tumors. Recurrence was noted in 24 cases and death in 7 cases with 5-year progression-free and overall-survival rates of 37 % and 80 %, respectively. Grade II tumors had a better survival than grade III tumors; histopathological grade was the only prognostically significant marker. 1q gain had no prognostic significance. 1q gain is frequent in ependymomas in Indian patients, seen across all ages, sites and grades, and thus is likely an early event in pathogenesis. The prognostic value of 1q gain, remains uncertain, and multicentric pooling of data is required. A histopathological grading system using objective criteria correlates well with patient outcome and can serve as an economical option for prognostication of ependymomas.

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The cost-effectiveness of surgical resection and cesium-131 intraoperative brachytherapy versus surgical resection and stereotactic radiosurgery in the treatment of metastatic brain tumors

Abstract

This study aims to evaluate the cost-effectiveness of surgical resection (S) and Cesium-131 (Cs-131) [S + Cs-131] intraoperative brachytherapy versus S and stereotactic radiosurgery (SRS) [S + SRS] for the treatment of brain metastases. Treatment records as well as hospital and outpatient charts of 49 patients with brain metastases between 2008 and 2012 who underwent S + Cs-131 (n = 24) and S + SRS (n = 25) were retrospectively reviewed. Hospital charges were compared for the single treatment in question. Means and curves of survival time were defined by the Kaplan–Meier estimator, with the cost analysis focusing on the time period of the relevant treatment. Quality adjusted life years (QALY) and Incremental cost-effectiveness ratios (ICER) were calculated for each treatment option as a measure of cost-effectiveness. The direct hospital costs of treatments per patient were: S + Cs131 = $19,271 and S + SRS = $44,219. The median survival times of S + Cs-131 and S + SRS were 15.5 and 11.3 months, and the 12 month survival rates were 61 % and 49 % (P = 0.137). The QALY for S + SRS when compared to S + Cs-131 yielded a p < 0.0001, making it significantly more cost-effective. The ICER also revealed that when compared to S + Cs-131, S + SRS was significantly inferior (p < 0.0001). S + Cs-131 is more cost-effective compared with S + SRS based on hospital charges as well as QALYs and ICER. Cost effectiveness, in addition to efficacy and risk, should factor into the comparison between these two treatment modalities for patients with surgically resectable brain metastases.

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Increased expression of phosphatidylethanolamine-binding protein 4 (PEBP4) strongly associates with human gliomas grade

Abstract

Abnormal expression of phosphatidylethanolamine-binding protein 4 (PEBP4) has been found in various types of malignancies. However, the PEBP4 expression in human gliomas is still unclear. In this study, we aim to compare the expression of PEBP4 in tumor samples derived from 58 patients with different grades of gliomas with that in 5 non-neoplastic brain samples and to investigate the clinical significance of PEBP4 expression in gliomas. The mRNA and protein expressions of PEBP4 were measured by real-time quantitative polymerase chain reaction and western blot, respectively. The intracellular expressions of PEBP4 in samples were examined by immunohistochemistry. The association between PEBP4 expression and the clinicopathologic characteristics of gliomas patients were analyzed. Our results demonstrated that the mRNA and protein levels of PEBP4 were upregulated in gliomas tissues, especially in high-grade (World Health Organization Grades III and IV) gliomas, when compared to normal control (p < 0.01). Immunohistochemical analysis indicated that PEBP4 was highly expressed in 82.4 % (28/34) of high-grade gliomas, when compared to 41.7 % (10/24) of high expression in low-grade gliomas and 20.0 % (1/5) in non-neoplastic brain samples (p = 0.001). Multivariate Cox regression analysis revealed that increased PEBP4 expression was an independent prognostic factor for gliomas. Patients with low level of PEBP4 had longer survival time compared to those with high PEBP4 expression (p = 0.003). These data indicate a clinical significance of PEBP4 for predicting the tumor grade and the prognosis in patients with gliomas.

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Clinical outcome of gliosarcoma compared with glioblastoma multiforme: a clinical study in Chinese patients

Abstract

Gliosarcoma (GSM) is a rare biphasic neoplasms of the central nervous system composed of a glioblastoma multiforme (GBM) admixed with a sarcomatous component. In clinical practice GSM is generally managed similarly to GBM. However, there are conflicting reports regarding their clinical aggressiveness, cell line of origin and possible prognosis compared with those of GBM. The objective of this study was to compare clinic-pathological features in GSM patients with the GBM patients during the same study period. 518 patients with GBM were treated at our hospital between 2008 and 2013, among them 51 were GSM. In this series the GSMs represented 9.8 % of all GBMs and included 58.8 % male with a median age of 44.7 years. The locations, all supratentorial, included temporal in 41.2 %, frontal in 25.5 %, parietal in 19.6 %, and occipital in 13.7 %. All patients underwent tumor resection followed by post-operative radiation and adjuvant chemotherapy. The O6-methylguanine-DNA methyltransferase promoter methylation studies were significantly more frequent in the GBMs than GSMs (80.1 % vs. 44.7 %, P < 0.001). The median progression free survival and overall survival for the patients with GSM were 8.0 and 13.0 months, respectively, as compared with 9.0 and 14.0 months in the GBM group (log rank test P = 0.001 and 0.004, respectively). The Cox proportional hazards regression model indicated that the extent of tumor resection (HR = 1.518, P = 0.009) and pathological types (HR = 0.608, P = 0.002) were the significant prognostic factors in our own series. With regard to clinical features and outcomes, GSM and GBM cannot be distinguished clinically. GSM in China may be managed similarly to GBM, with maximal safe surgical resection followed by chemo-radiotherapy. Our study adds further evidence to support GSM as a unique clinical entity with a likely worse prognosis than GBM.

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Acknowledgement of reviewers 2014

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PD-L1-specific T cells

Abstract

Recently, there has been an increased focus on the immune checkpoint protein PD-1 and its ligand PD-L1 due to the discovery that blocking the PD-1/PD-L1 pathway with monoclonal antibodies elicits striking clinical results in many different malignancies. We have described naturally occurring PD-L1-specific T cells that recognize both PD-L1-expressing immune cells and malignant cells. Thus, PD-L1-specific T cells have the ability to modulate adaptive immune reactions by reacting to regulatory cells. Thus, utilization of PD-L1-derived T cell epitopes may represent an attractive vaccination strategy for targeting the tumor microenvironment and for boosting the clinical effects of additional anticancer immunotherapy. This review summarizes present information about PD-L1 as a T cell antigen, depicts the initial findings about the function of PD-L1-specific T cells in the adjustment of immune responses, and discusses future opportunities.

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Utilization of Subcutaneous Methotrexate in Rheumatoid Arthritis Patients After Failure or Intolerance to Oral Methotrexate: A Multicenter Cohort Study

Abstract

Introduction

Low-dose weekly methotrexate (MTX) is the mainstay in the therapy of rheumatoid arthritis (RA). It can be given via oral, intramuscular or subcutaneous (SC) route. This study sought to determine the real-world pattern of treatment with SC MTX in Portuguese adult patients with active RA.

Methods

Utilization of Metoject^® in Rheumatoid Arthritis (UMAR) was a non-interventional, cohort multicenter study with retrospective data collection. Eligible patients had active RA, at least 18 years of age, and started SC MTX treatment in 2009 or 2010 after failure or intolerance to oral MTX. Data were collected from patient's clinical records. Both non-parametric and parametric survival methods were used to obtain a detailed understanding of SC MTX treatment duration.

Result

Fifty patients were included, of which only 9 discontinued SC MTX during the study follow-up period. The probability of discontinuation after 1, 2, and 3 years of treatment of SC MTX treatment is expected to be 6.10%, 8.50%, and 23.20%, respectively. The extrapolated median duration of SC MTX using an exponential model was 106.4 months/8.87 years. Mean dose of SC MTX was 18.36 mg. The reasons for treatment discontinuation were occurrence of adverse events in six patients and lack of efficacy in three.

Conclusion

The long treatment duration of SC MTX highlights its excellent tolerability compared to oral MTX, especially concerning the frequent adverse gastrointestinal events of MTX. Furthermore, long MTX treatment duration provides the opportunity to postpone or even avoid expensive therapies with biologics. The results obtained from the UMAR study provide important information for the utilization and public financing of SC MTX in Portugal.

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Healthcare Costs Among Adults with Type 2 Diabetes Initiating DPP-4 Inhibitors

Abstract

Introduction

Oral antidiabetes medications, including dipeptidyl peptidase-4 inhibitors (DPP-4is) saxagliptin and sitagliptin, are used for the treatment of type 2 diabetes (T2D). The study objective was to compare all-cause and diabetes-related costs following initiation of saxagliptin or sitagliptin.

Methods

Patients aged ≥18 years initiating saxagliptin or sitagliptin between January 1, 2009 and January 31, 2012 in the Truven Health MarketScan Commercial and Medicare Supplemental databases were identified. Patients were required to have continuous enrollment for ≥365 days before and ≥365 days after the index date (date of the first saxagliptin or sitagliptin claim). Additionally, patients were required to have a claim with a T2D diagnosis (ICD-9-CM 250.×0, 250.×2) and no claims for a DPP-4i medication before the index date. All-cause and diabetes-related medical costs and total costs (including pharmacy costs) were captured over the 1-year follow-up period. Generalized linear models with log link and gamma distribution were fit to compare costs between the two cohorts using cost ratios, controlling for patient baseline characteristics. Recycled prediction methods were used to generate adjusted predicted costs and confidence intervals.

Results

The final sample comprised 3354 saxagliptin initiators and 26,895 sitagliptin initiators. The average age of saxagliptin and sitagliptin initiators was 57 years and just over 50% were males. After adjusting for baseline characteristics, saxagliptin patients had significantly lower average all-cause medical costs (cost ratio = 0.901, P < 0.001; predicted mean costs: $8687 vs. $9646) compared with sitagliptin patients over the 1-year follow-up. Findings were consistent for diabetes-related medical costs (cost ratio = 0.890, P < 0.001; predicted mean costs: $2180 vs. $2450). Total costs were also lower for saxagliptin initiators (cost ratio = 0.950, P = 0.002; predicted mean costs: $13,911 vs. $14,651) over the 1-year follow-up period.

Conclusion

Initiation of treatment with saxagliptin was associated with lower medical costs over 1 year compared with initiation of sitagliptin among adults with T2D.

Funding

AstraZeneca.

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PD-L1-specific T cells

Abstract

Recently, there has been an increased focus on the immune checkpoint protein PD-1 and its ligand PD-L1 due to the discovery that blocking the PD-1/PD-L1 pathway with monoclonal antibodies elicits striking clinical results in many different malignancies. We have described naturally occurring PD-L1-specific T cells that recognize both PD-L1-expressing immune cells and malignant cells. Thus, PD-L1-specific T cells have the ability to modulate adaptive immune reactions by reacting to regulatory cells. Thus, utilization of PD-L1-derived T cell epitopes may represent an attractive vaccination strategy for targeting the tumor microenvironment and for boosting the clinical effects of additional anticancer immunotherapy. This review summarizes present information about PD-L1 as a T cell antigen, depicts the initial findings about the function of PD-L1-specific T cells in the adjustment of immune responses, and discusses future opportunities.

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Acknowledgement of reviewers 2014

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PD-L1-specific T cells

Abstract

Recently, there has been an increased focus on the immune checkpoint protein PD-1 and its ligand PD-L1 due to the discovery that blocking the PD-1/PD-L1 pathway with monoclonal antibodies elicits striking clinical results in many different malignancies. We have described naturally occurring PD-L1-specific T cells that recognize both PD-L1-expressing immune cells and malignant cells. Thus, PD-L1-specific T cells have the ability to modulate adaptive immune reactions by reacting to regulatory cells. Thus, utilization of PD-L1-derived T cell epitopes may represent an attractive vaccination strategy for targeting the tumor microenvironment and for boosting the clinical effects of additional anticancer immunotherapy. This review summarizes present information about PD-L1 as a T cell antigen, depicts the initial findings about the function of PD-L1-specific T cells in the adjustment of immune responses, and discusses future opportunities.

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PD-L1-specific T cells

Abstract

Recently, there has been an increased focus on the immune checkpoint protein PD-1 and its ligand PD-L1 due to the discovery that blocking the PD-1/PD-L1 pathway with monoclonal antibodies elicits striking clinical results in many different malignancies. We have described naturally occurring PD-L1-specific T cells that recognize both PD-L1-expressing immune cells and malignant cells. Thus, PD-L1-specific T cells have the ability to modulate adaptive immune reactions by reacting to regulatory cells. Thus, utilization of PD-L1-derived T cell epitopes may represent an attractive vaccination strategy for targeting the tumor microenvironment and for boosting the clinical effects of additional anticancer immunotherapy. This review summarizes present information about PD-L1 as a T cell antigen, depicts the initial findings about the function of PD-L1-specific T cells in the adjustment of immune responses, and discusses future opportunities.

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Cancers, Vol. 8, Pages 6: Pharmacokinetics of Selected Anticancer Drugs in Elderly Cancer Patients: Focus on Breast Cancer

Background: Elderly patients receiving anticancer drugs may have an increased risk to develop treatment-related toxicities compared to their younger peers. However, a potential pharmacokinetic (PK) basis for this increased risk has not consistently been established yet. Therefore, the objective of this study was to systematically review the influence of age on the PK of anticancer agents frequently administered to elderly breast cancer patients. Methods: A literature search was performed using the PubMed electronic database, Summary of Product Characteristics (SmPC) and available drug approval reviews, as published by EMA and FDA. Publications that describe age-related PK profiles of selected anticancer drugs against breast cancer, excluding endocrine compounds, were selected and included. Results: This review presents an overview of the available data that describe the influence of increasing age on the PK of selected anticancer drugs used for the treatment of breast cancer. Conclusions: Selected published data revealed differences in the effect and magnitude of increasing age on the PK of several anticancer drugs. There may be clinically-relevant, age-related PK differences for anthracyclines and platina agents. In the majority of cases, age is not a good surrogate marker for anticancer drug PK, and the physiological state of the individual patient may better be approached by looking at organ function, Charlson Comorbidity Score or geriatric functional assessment.

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Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial

Publication date: January 2016
Source:European Journal of Cancer, Volume 53
Author(s): P.H. Cashin, H. Mahteme, N. Spång, I. Syk, J.E. Frödin, M. Torkzad, B. Glimelius, W. Graf
BackgroundFirst-line treatment of isolated resectable colorectal peritoneal metastases remains unclear. This study (the Swedish peritoneal study) compares cytoreductive surgery and intraperitoneal chemotherapy (surgery arm) with systemic chemotherapy (chemotherapy arm).MethodsPatients deemed resectable preoperatively were randomised to surgery and intraperitoneal 5-fluorouracil 550 mg/m²/d for 6 d with repeated courses every month or to systemic oxaliplatin and 5-fluorouracil regimen every second week. Both treatments continued for 6 months. Primary end-point was overall survival (OS) and secondary end-points were progression-free survival (PFS), and morbidity.ResultsThe study terminated prematurely when 48 eligible patients (24/arm) were included due to recruitment difficulties. Two-year OS was 54% in the surgery arm and 38% in the chemotherapy arm (p = 0.04). After 5 years, 8 versus 1 patient were alive, respectively (p = 0.02). Median OS was 25 months versus 18 months, respectively, hazard ratio 0.51 (95% confidence interval: 0.27–0.96, p = 0.04). PFS in the surgery arm was 12 months versus 11 months in the chemotherapy arm (p = 0.16) with 17% versus 0% 5-year PFS. Grade III–IV morbidity was seen in 42% and 50% of the patients, respectively. No mortalities.ConclusionsCytoreductive surgery with intraperitoneal chemotherapy may be superior to systemic oxaliplatin-based treatment of colorectal cancer with resectable isolated peritoneal metastases.(ClinicalTrials.gov nr:NCT01524094).



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