Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Σάββατο 2 Απριλίου 2016
Endostatin inhibits the growth and migration of 4T1 mouse breast cancer cells by skewing macrophage polarity toward the M1 phenotype
Abstract
The phenotypic diversity of tumor-associated macrophages (TAMs) increases with tumor development. One of the hallmarks of malignancy is the polarization of TAMs from a pro-immune (M1) phenotype to an immunosuppressive (M2) phenotype. However, the molecular basis of this process is still unclear. Endostatin is a powerful inhibitor of angiogenesis capable of suppressing tumor growth and metastasis. Here, we demonstrate that endostatin induces RAW264.7 cell polarization toward the M1 phenotype in vitro. Endostatin has no effect on TAM numbers in vivo, but results in an increased proportion of F4/80+Nos2+ cells and a decreased proportion of F4/80+CD206+ cells. Overexpression of endostatin in RAW264.7 cells resulted in a decrease in the phosphorylation of STAT3, an increase in expression of vascular endothelial growth factor A and placental growth factor, and an increase in the phosphorylation of STAT1, IκBα and p65 proteins compared with controls. These results indicate that endostatin regulates macrophage polarization, promoting the M1 phenotype by targeting NF-κB and STAT signaling.
from Cancer via ola Kala on Inoreader http://ift.tt/1MEfK79
via IFTTT
4-1BB agonism: adding the accelerator to cancer immunotherapy
Abstract
The success of checkpoint inhibitors has validated immunomodulatory agents as a valuable class of anticancer therapeutics. A promising co-stimulatory immunologic target is 4-1BB, or CD137, a member of the tumor necrosis factor receptor superfamily. Ligation of 4-1BB induces an activating signal in CD8+ T cells and natural killer cells, resulting in increased pro-inflammatory cytokine secretion, cytolytic function, and antibody-dependent cell-mediated cytotoxicity. Targeting 4-1BB with agonistic monoclonal antibody (mAb) therapy demonstrated potent antitumor effects in murine tumor models. While anti-4-1BB mAbs have entered clinical trials, optimal efficacy of 4-1BB-targeted agents will inevitably come from combination therapeutic strategies. Checkpoint blockade is a compelling combination partner for 4-1BB agonism. This novel immunotherapeutic approach has the potential to active antitumor immune effectors by a complementary mechanism: simultaneously "removing the brakes" via blocking inhibitory signaling and "stepping on the accelerator" via co-stimulation. While important considerations should be given to 4-1BB-mediated toxicities, the current understanding of 4-1BB biology suggests it may play a key role in advancing the capabilities of cancer combination therapy.
from Cancer via ola Kala on Inoreader http://ift.tt/1MEfIMP
via IFTTT
2′–5′ Oligoadenylate synthetase-like 1 (OASL1) deficiency in mice promotes an effective anti-tumor immune response by enhancing the production of type I interferons
Abstract
Type I interferon (IFN-I) plays a critical role in antiviral and antitumor defense. In our previous studies, we showed that IFN-I-inducible 2′–5′ oligoadenylate synthetase-like 1 (OASL1) negatively regulates IFN-I production upon viral infection by specifically inhibiting translation of the IFN-I-regulating master transcription factor, interferon regulatory factor 7 (IRF7). In this study, we investigated whether OASL1 plays a negative role in the anti-tumor immune response by using OASL1-deficient (Oasl1 −/−) mice and transplantable syngeneic tumor cell models. We found that Oasl1 −/− mice demonstrate enhanced resistance to lung metastatic tumors and subcutaneously implanted tumors compared to wild-type (WT) mice. Additionally, we found that cytotoxic effector cells such as CD8+ T cells (including tumor antigen-specific CD8+ T cells) and NK cells as well as CD8α+ DCs (the major antigen cross-presenting cells) were much more frequent (>fivefold) in the Oasl1 −/− mouse tumors. Furthermore, the cytotoxic effector cells in Oasl1 −/− mouse tumors seemed to be more functionally active. However, the proportion of immunosuppressive myeloid-derived suppressor cells within hematopoietic cells and of regulatory T cells within CD4+ T cells in Oasl1 −/− mouse tumors did not differ significantly from that of WT mice. Tumor-challenged Oasl1 −/− mice expressed increased levels of IFN-I and IRF7 protein in the growing tumor, indicating that the enhanced antitumor immune response observed in Oasl1 −/− mice was caused by higher IFN-I production in Oasl1 −/− mice. Collectively, these results show that OASL1 deficiency promotes the antitumor immune response, and thus, OASL1 could be a good therapeutic target for treating tumors.
from Cancer via ola Kala on Inoreader http://ift.tt/1SpmQJk
via IFTTT
Adoptive transfer of osteoclast-expanded natural killer cells for immunotherapy targeting cancer stem-like cells in humanized mice
Abstract
Based on data obtained from oral, pancreatic and lung cancers, glioblastoma, and melanoma, we have established that natural killer (NK) cells target cancer stem-like cells (CSCs). CSCs displaying low MHC class I, CD54, and PD-L1 are killed by cytotoxic NK cells and are differentiated by split anergized NK cells through both membrane bound and secreted forms of TNF-α and IFN-γ. NK cells select and differentiate both healthy and transformed stem-like cells, resulting in target cell maturation and shaping of their microenvironment. In our recent studies, we have observed that oral, pancreatic, and melanoma CSCs were capable of forming large tumors in humanized bone marrow, liver, thymus (hu-BLT) mice with fully reconstituted human immune system. In addition, major human immune subsets including NK cells, T cells, B cells, and monocytes were present in the spleen, bone marrow, peripheral blood, and tumor microenvironment. Similar to our previously published in vitro data, CSCs differentiated with split anergized NK cells prior to implantation in mice formed smaller tumors. Intravenous injection of functionally potent osteoclast-expanded NK cells inhibited tumor growth through differentiation of CSCs in humanized mice. In this review, we present current approaches, advances, and existing limitations in studying interactions of the immune system with the tumor, in particular NK cells with CSCs, using in vivo preclinical hu-BLT mouse model. In addition, we discuss the use of osteoclast-expanded NK cells in targeting cancer stem-like tumors in humanized mice—a strategy that provides a much-needed platform to develop effective cancer immunotherapies.
from Cancer via ola Kala on Inoreader http://ift.tt/1qlsdmr
via IFTTT
Differential immunomodulatory activity of tumor cell death induced by cancer therapeutic toll-like receptor ligands
Abstract
Synthetic toll-like receptor (TLR) ligands stimulate defined immune cell subsets and are currently tested as novel immunotherapeutic agents against cancer with, however, varying clinical efficacy. Recent data showed the expression of TLR receptors also on tumor cells. In this study we investigated immunological events associated with the induction of tumor cell death by poly(I:C) and imiquimod. A human head and neck squamous cell carcinoma (HNSCC) cell line was exposed to poly(I:C) and imiquimod, which were delivered exogenously via culture medium or via electroporation. Cell death and cell biological consequences thereof were analyzed. For in vivo analyses, a human xenograft and a syngeneic immunocompetent mouse model were used. Poly(I:C) induced cell death only if delivered by electroporation into the cytosol. Cell death induced by poly(I:C) resulted in cytokine release and activation of monocytes in vitro. Monocytes activated by the supernatant of cancer cells previously exposed to poly(I:C) recruited significantly more Th1 cells than monocytes exposed to control supernatants. If delivered exogenously, imiquimod also induced tumor cell death and some release of interleukin-6, but cell death was not associated with release of Th1 cytokines, interferons, monocyte activation and Th1 recruitment. Interestingly, intratumoral injection of poly(I:C) triggered tumor cell death in tumor-bearing mice and reduced tumor growth independent of TLR signaling on host cells. Imiquimod did not affect tumor size. Our data suggest that common cancer therapeutic RNA compounds can induce functionally diverse types of cell death in tumor cells with implications for the use of TLR ligands in cancer immunotherapy.
from Cancer via ola Kala on Inoreader http://ift.tt/1SpmPFj
via IFTTT
Tumour infiltrating lymphocytes correlate with improved survival in patients with oesophageal adenocarcinoma
Abstract
Background
Oesophageal adenocarcinoma (OAC) is increasingly common in the west, and survival remains poor at 10–15 % at 5 years. Immune responses are increasingly implicated as a determining factor of tumour progression. The ability of lymphocytes to recognise tumour antigens provides a mechanism for a host immune attack against cancer providing a potential treatment strategy.
Materials and Methods
Tumour infiltrating lymphocytes (TILs: CD3+, CD4+, CD8+ and FOXp3+) were assessed by immunohistochemistry using tissue microarrays in a contemporary and homogeneous cohort of OAC patients (n = 128) undergoing curative treatment.
Results
Multivariate analysis identified three independent prognostic factors for improved cancer-specific survival (CSS): increased CD8+ TILs (p = 0.003), completeness of resection (p < 0.0001) and lower pathological N stage (p < 0.0001). Independent prognostic factors for favourable disease-free survival included surgery-only treatment (p = 0.015), completeness of resection (p = 0.001), increased CD8+ TILs (p < 0.0001) and reduced pathological N stage (p < 0.0001). Higher levels of TILs in the pathological specimen were associated with significant pathological response to neoadjuvant chemotherapy (NAC). On multivariate analysis increased levels of CD4+ (p = 0.017) and CD8+ TILs (p = 0.005) were associated with significant local tumour regression and lymph node downstaging, respectively.
Discussion
Our results establish an association of TILs and survival in OAC, as seen in other solid tumours, and identify particular TIL subsets that are present at higher levels in patients who responded to NAC compared to non-responders. These findings highlight potential therapeutic strategies in EAC based on utilising the host immunological response and highlight the immune responses biomarker potential.
from Cancer via ola Kala on Inoreader http://ift.tt/1ohP6Wg
via IFTTT
Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model
Abstract
Fibroblast activation protein α (FAPα) is a tumor stromal antigen overexpressed by cancer-associated fibroblasts (CAFs). CAFs are genetically more stable compared with the tumor cells and immunosuppressive components of the tumor microenvironment, rendering them excellent targets for cancer immunotherapy. DNA vaccines are widely applied due to their safety. To specifically destroy CAFs, we constructed and examined the immunogenicity and anti-tumor immune mechanism of a DNA vaccine expressing human FAPα. This vaccine successfully reduced 4T1 tumor growth through producing FAPα-specific cytotoxic T lymphocyte responses which could kill CAFs, and the decrease in FAPα-expressing CAFs resulted in markedly attenuated expression of collagen I and other stromal factors that benefit the tumor progression. Based on these results, a DNA vaccine targeting human FAPα may be an attractive and effective cancer immunotherapy strategy.
from Cancer via ola Kala on Inoreader http://ift.tt/1LVd4Sw
via IFTTT
Dosimetric predictors of acute hematologic toxicity during concurrent intensity-modulated radiotherapy and chemotherapy for anal cancer
Abstract
Purpose
This study aimed at investigating whether the irradiated volume of pelvic bone marrow (PBM) and specific subsites may predict the occurrence of acute hematologic toxicity (HT) in anal cancer patients undergoing concurrent chemo-radiation.
Methods
50 patients, submitted to IMRT and concurrent chemotherapy, were analyzed. Several bony structures were defined on planning-CT: PBM and lumbar-sacral (LSBM), lower pelvis (LPBM) and iliac (IBM) bone marrow. On dose-volume histograms, dosimetric parameters were taken. Endpoints included white blood-cell-count (WBC), absolute-neutrophil-count (ANC), hemoglobin (Hb) and platelet nadirs and acute hematologic toxicity (HT) according to RTOG scoring scale. Generalized linear modeling was used to find correlations between dosimetric variables and blood cell nadirs, while logistic regression analysis was used to test correlation with ≥G3 HT. Receiver Operating Characteristic (ROC) curve analysis was used to evaluate the optimal cut-off points for predictive dosimetric variables with the Youden method.
Results
Maximum detected acute HT comprised 38 % of ≥G3 leukopenia and 32 % of ≥G3 neutropenia. Grade 2 anemia was observed in 4 % of patients and ≥G3 thrombocytopenia in 10 %. On multivariate analysis a higher PBM-V 20 was associated with lower WBC nadir. Increased LSBM-V 40 was correlated with a higher likelihood to develop ≥G3 HT. A cut-off point at 41 % for LSBM-V 40 was found. Patients with LSBM-V 40 ≥41 % were more likely to develop ≥G3 HT (55.3 vs. 32.4 %; p < 0.01).
Conclusions
Increased low-dose to pelvic bony structures significantly predicted for WBC decrease. Medium–high dose to specific osseous subsites was associated with a higher probability of HT. LSBM-V 40 was a strong predictor of ≥G3 HT. A threshold at 41 % for LSBM-V 40 could be used to limit HT.
from Cancer via ola Kala on Inoreader http://ift.tt/1RU3JwQ
via IFTTT
Reduction in Hepatocyte Growth Factor Serum Levels is Associated with Improved Prognosis in Advanced Lung Adenocarcinoma Patients Treated with Afatinib: a Phase II Trial
Abstract
Background
C-met and its ligand, hepatocyte growth factor (HGF) have been associated with the resistance mechanism of EGFR-TKIs. HGF was evaluated as a clinical-marker of response in NSCLC patients treated with afatinib.
Methods
Sixty-six patients with stage IIIB/IV lung adenocarcinoma and progression to any-line chemotherapy received afatinib 40 mg/day. Mutational EGFR and HER2 status were assessed by RT-PCR. HER2 amplification was evaluated by FISH. Serum HGF content was measured by ELISA before and 2 months after the start of treatment. HGF levels were assessed with the objective response rate (ORR), progression-free-survival (PFS), and overall survival (OS). This trial was registered on ClinicalTrials.gov: NCT01542437.
Results
Fifty patients (75 %) were EGFR mutation positive. Response was achieved in 59 % of all patients and 78 % of EGFR mutated patients. Median PFS was 10 [95 % CI 6.8-13.1] and 14.5 months [10.9-18.9] for all and EGFR mutated patients, respectively. Median OS was 22.8 [17.5-28.1] and 32.4 months [18.3-46.6] for all and EGFR mutated patients, respectively. Patients with reduced serum HGF levels had improved ORR (75 % vs 44 %; p = 0.011), PFS (15.1 [2.9-27.3] vs 6.5 months [3.9-9.1]; p = 0.005) and OS (NR vs 14.5 months [7.8 - 21.3] p = 0.007). A reduction in serum HGF levels was an independent factor associated with longer PFS (HR 0.40; p = 0.021) and OS (HR 0.31; p = 0.006) in all and EGFR mutated patients.
Conclusions
A reduction in serum HGF levels was associated with improved outcomes in patients treated with afatinib. These results suggest HGF might have a role as a mechanism of resistance to EGFR-TKIs. HGF could represent a potential therapeutic target to prevent or reverse resistance particularly in EGFR mutated patients.
from Cancer via ola Kala on Inoreader http://ift.tt/1qeuZdx
via IFTTT
Dosimetric predictors of acute hematologic toxicity during concurrent intensity-modulated radiotherapy and chemotherapy for anal cancer
Abstract
Purpose
This study aimed at investigating whether the irradiated volume of pelvic bone marrow (PBM) and specific subsites may predict the occurrence of acute hematologic toxicity (HT) in anal cancer patients undergoing concurrent chemo-radiation.
Methods
50 patients, submitted to IMRT and concurrent chemotherapy, were analyzed. Several bony structures were defined on planning-CT: PBM and lumbar-sacral (LSBM), lower pelvis (LPBM) and iliac (IBM) bone marrow. On dose-volume histograms, dosimetric parameters were taken. Endpoints included white blood-cell-count (WBC), absolute-neutrophil-count (ANC), hemoglobin (Hb) and platelet nadirs and acute hematologic toxicity (HT) according to RTOG scoring scale. Generalized linear modeling was used to find correlations between dosimetric variables and blood cell nadirs, while logistic regression analysis was used to test correlation with ≥G3 HT. Receiver Operating Characteristic (ROC) curve analysis was used to evaluate the optimal cut-off points for predictive dosimetric variables with the Youden method.
Results
Maximum detected acute HT comprised 38 % of ≥G3 leukopenia and 32 % of ≥G3 neutropenia. Grade 2 anemia was observed in 4 % of patients and ≥G3 thrombocytopenia in 10 %. On multivariate analysis a higher PBM-V 20 was associated with lower WBC nadir. Increased LSBM-V 40 was correlated with a higher likelihood to develop ≥G3 HT. A cut-off point at 41 % for LSBM-V 40 was found. Patients with LSBM-V 40 ≥41 % were more likely to develop ≥G3 HT (55.3 vs. 32.4 %; p < 0.01).
Conclusions
Increased low-dose to pelvic bony structures significantly predicted for WBC decrease. Medium–high dose to specific osseous subsites was associated with a higher probability of HT. LSBM-V 40 was a strong predictor of ≥G3 HT. A threshold at 41 % for LSBM-V 40 could be used to limit HT.
from Cancer via ola Kala on Inoreader http://ift.tt/1RU3JwQ
via IFTTT
Early Sorafenib-Related Adverse Events Predict Therapy Response of TACE plus Sorafenib: A Multicenter Clinical Study of 606 HCC Patients
ABSTRACT
The purpose of our study was to test the hypothesis that sorafenib-related dermatologic adverse events (AEs) as an early biomarker can predict the long-term outcomes following the combination therapy of transarterial chemoembolization (TACE) plus sorafenib (CTACES). The intermediate-stage hepatocellular carcinoma patients who received either CTACES or TACE-alone treatment were consecutively included into analysis. In the CTACES group, patients with ≥ grade 2 dermatologic AEs within the first month of sorafenib initiation were defined as responders; whereas those with < grade 2 were defined as nonresponders. In the CTACES group, the median overall survival (OS) of the responders was significantly longer than that of nonresponders (28.9 months vs. 16.8 months, respectively; P = 0.004). Multivariate analysis demonstrated that nonresponders were significantly associated with an increased risk of death compared with responders (HR = 1.9; 95% confidence Interval-CI: 1.3-2.7; P = 0.001). The survival analysis showed that the median OS was 27.9 months (95% CI: 25.0-30.8) among responders treated with CTACES vs.18.3 months (95% CI: 14.5-22.1) among those who received TACE-alone (P = 0.046). The median time to progression was 13.1 months (95% CI: 4.4-21.8) in the CTACES group, a duration that was significantly longer than that in the TACE-alone group [5 months (95% CI: 6.4-13.3), P = 0.014]. This study demonstrated that sorafenib-related dermatologic AEs are clinical biomarkers to identify responders from all of the patients for CTACES therapy. Sorafenib-related dermatologic AEs, clinical biomarkers, can predict the efficacy of CTACES in future randomized controlled trials. This article is protected by copyright. All rights reserved.
from Cancer via ola Kala on Inoreader http://ift.tt/1Trqh7o
via IFTTT
First-line treatment with FOLFOXIRI for advanced pancreatic cancer in clinical practice: patients' outcome and analysis of prognostic factors
Abstract
FOLFIRINOX is a standard first-line treatment for advanced pancreatic cancer (aPC). The Gruppo Oncologico Nord Ovest (GONO) FOLFOXIRI regimen demonstrated efficacy in metastatic colorectal cancer. We aimed to evaluate activity and tolerability of FOLFOXIRI regimen in patients with aPC and to explore putative prognostic factors. 137 consecutive aPC patients were treated with FOLFOXIRI in our institution between 2008 and 2014. Clinical, laboratory and pathological data were collected and their association with activity, progression free survival (PFS) and overall survival (OS) was investigated. After a median follow up of 30 months, median PFS and OS were 8.0 months (95% CI 6.19-9.81) and 12 months (95%CI 9.75-14.25), respectively. Response rate was 38.6%, while disease-control rate 72.2%. At multivariate analysis liver metastases (p=0.019; Hazard Ratio, HR, 0.59, 95% Confidence Interval, CI, 0.38-0.96), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 (p=0.001; HR 2.26, 95%CI 1.42-3.59) and neutrophil-lymphocyte ratio (NLR)> 4 (p= 0.002; HR: 2.42; 95% CI 1.38- 4.25) were associated with poorer OS. We categorized 119 pts with complete available data as good-risk (0 factors, 38 pts), intermediate-risk (1 factor, 49 pts) and poor-risk (≥2 factors, 32 pts). Median OS for these 3 groups were 17.6, 11.1 and 7.4 months, respectively (p<0.001). FOLFOXIRI is active and feasible in aPC. Prognosis of aPC pts treated with FOLFOXIRI is influenced by easily available factors: our analysis revealed ECOG PS, liver metastases and NLR as the most important predictors of survival. These factors could be helpful for treatment decision and clinical trial design. This article is protected by copyright. All rights reserved.
from Cancer via ola Kala on Inoreader http://ift.tt/1X6VP1i
via IFTTT
Patients' perceptions of mortality risk for localized prostate cancer vary markedly depending on their treatment strategy
Abstract
Treatment choice for localized prostate cancer (PCa) is a controversial issue, and mortality risk is probably the most decisive factor in this regard. The study aimed to compare prostate-cancer-specific mortality risk estimates for different treatment options assigned by patients managed with active surveillance (AS), radical prostatectomy (RP), and patients who had discontinued AS (DAS). We matched patients initially managed with AS or RP (N = 370) according to length of therapy. Patients completed mailed questionnaires assessing their mortality risk estimates (in %) and prostate-cancer-specific anxiety. We analyzed differences in risk estimates among the three treatment groups using ANOVA, relationships of clinical and psychosocial variables with risk estimates using standard multiple regression. In all treatment groups, the prostate- cancer-specific mortality risk was overestimated. This applied whether it was the patient's own treatment or the alternative treatment option. RP patients assigned a mortality risk to AS that was almost three times higher than that assigned to RP (50.9±25.0 vs. 17.8±19.7, d = 1.48; p <.001). Anxiety was significantly associated with risk estimates for AS (p = .008) and RP (p = .001). Compared to clinical data that suggest that the prostate-cancer-specific mortality risk for AS is low and does not significantly differ from that for RP, patients strongly overestimated the mortality risk. This was most markedly so in RP patients, who drastically overestimated the benefits of RP compared to the risk of AS. This overestimation could increase overtreatment and should therefore be corrected by better patient education. This article is protected by copyright. All rights reserved.
from Cancer via ola Kala on Inoreader http://ift.tt/1TrqgjV
via IFTTT
Agreement between institutional measurements and treatment planning system calculations for basic dosimetric parameters as measured by IROC-Houston
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): James R. Kerns, David Followill, Jessica Lowenstein, Andrea Molineu, Paola Alvarez, Paige A. Taylor, Stephen F. Kry
PurposeWe compared radiation machine measurement data collected by the Imaging and Radiation Oncology Core at Houston (IROC-H) with institutional treatment planning system (TPS) values to identify parameters with large differences in agreement. The findings will help institutions focus their efforts to improve the accuracy of their TPS models.MethodsBetween 2000 and 2014, IROC-H visited more than 250 institutions and conducted independent measurements of machine dosimetric data points, including percentage depth dose, output factors, off-axis factors, multileaf collimator small fields, and wedge data. We compared these data with the institutional TPS values for the same points by energy, class, and parameter to identify differences and similarities using criteria involving both the medians and standard deviations for Varian linear accelerators. Distributions of differences between machine measurements and institutional TPS values were generated for basic dosimetric parameters.ResultsOn average, intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT)-style output factors and upper physical wedge output factors were the most problematic. Percentage depth dose, jaw output factors, and enhanced dynamic wedge output factors agreed best between the IROC-H measurements and the TPS values. Although small differences were shown between two common TPS systems, neither was superior to the other. Parameter agreement was constant over time from 2000 to 2014.ConclusionDifferences in basic dosimetric parameters between machine measurements and TPS values vary widely depending on the parameter, although agreement does not appear to vary by TPS and has not changed over time. IMRT-style output factors, SBRT-style output factors, and upper physical wedge output factors had the largest disagreement and should be carefully modeled to ensure accuracy.
Teaser
Measurements of more than 500 Varian linear accelerators were compared to their respective treatment planning system calculations (TPS) for simple dosimetric conditions. Analysis compared various parameters to identify those that, on average, performed poorly compared to the TPS. Troublesome parameters included small MLC fields and physical wedges. To improve accuracy, these parameters should be given special attention during TPS commissioning.from Cancer via ola Kala on Inoreader http://ift.tt/1qdQhYw
via IFTTT
Long term cancer outcomes from Study XXXX: A phase II study of accelerated partial breast irradiation with multicatheter brachytherapy following lumpectomy for early stage breast cancer
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Julia White, Kathryn Winter, Robert R. Kuske, John S. Bolton, Douglas W. Arthur, Troy Scroggins, Rachel A. Rabinovitch, Tracy Kelly, Leonard M. Toonkel, Frank A. Vicini, Beryl McCormick
PurposeAccelerated partial breast irradiation (APBI) has increasingly gained acceptance in clinical practice despite relatively limited long term data. Study XXXX is a multi-institutional prospective trial that studied one of the earliest methods of APBI, multicatheter brachytherapy (MCT), and can uniquely provide long term cancer outcomes.MethodsEligibility included stage I/II unifocal breast cancer < 3cm in size post lumpectomy with negative surgical margins and 0-3 positive axillary nodes without extracapsular extension. The APBI dose delivered was 34 Gy in 10 BID fractions over 5 days for High Dose Rate (HD); and 45 Gy in 3.5-5 days for Low Dose Rate (LDR) brachytherapy. The primary endpoint was HDR and LDR MCT reproducibility. This analysis focuses on long term ipsilateral breast recurrence (IBR), contralateral breast cancer events (CBE), regional recurrence (RR), and distant metastases (DM), disease-free (DFS), and overall survival (OS).ResultsThe median follow up is 12.1 years. 100 patients were accrued from 1997-2000; 98 were evaluable; 65 underwent HDR and 33 LDR MCT. Median age was 62; 88% had T1 tumors; 81% were p N0. 77% were estrogen (ER) and/or progesterone receptor (PR) positive; 33% received adjuvant chemotherapy and 64% antiendocrine therapy. There have been 4 isolated IBR and 1 IBR with RR, for 5.2% 10-year IBR without DM. There was 1 isolated RR, 1 with IBR, and 1 with a CBE, for 3.1% 10-year RR without DM. 10-year CBE was 4.2%, with 5 total events. Eleven patients have developed DM; 8 have died of breast cancer, and 22 have died from other causes. The 10-year DFS and OS are 69.8% and 78.0%, respectively.ConclusionThis multi-institutional Phase II trial studying MCT-APBI continues to report durable in breast cancer control rates with long term follow-up.
Teaser
Study XXXX, a phase II multi institutional single arm prospective trial, evaluated one of the earliest methods of accelerated partial breast irradiation (APBI), multicatheter brachytherapy (MCT), and accrued a total of 100 patients. This combined analysis of those who received low and high dose rate APBI demonstrates durable local control outcomes at a median follow up of 12.1 years.from Cancer via ola Kala on Inoreader http://ift.tt/1RUed93
via IFTTT
Validation of the web-based IBTR! 2.0 nomogram to predict for ipsilateral breast tumor recurrence after breast conserving therapy
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Isabelle Kindts, Annouschka Laenen, Stephanie Peeters, Hilde Janssen, Tom Depuydt, Ines Nevelsteen, Erik Van Limbergen, Caroline Weltens
PurposeA nomogram to predict the 10-year ipsilateral breast tumor recurrence (IBTR) after breast conserving therapy (BCT) with and without radiotherapy for breast cancer (BC) was developed based on seven literature-derived clinicopathologic variables with a concordance index (C-index) of 0.66 on independent validation. The aim of this study was to evaluate this IBTR! 2.0 model.Methods and MaterialsWe retrospectively identified 1898 BC cases, treated with BCT and radiotherapy at the XXX from 2000 to 2007 with requisite data for the nomogram variables. Clinicopathologic factors were assessed. Two definitions of IBTR were considered where simultaneous regional or distant recurrence were either censored (conform IBTR! 2.0) or included as event.Validity of the prediction algorithm was tested in terms of discrimination and calibration. Discrimination was assessed by the concordance probability estimate (CPE) and Harrell's C-index. The mean predicted and observed 10-year estimates were compared for the entire cohort and for four risk groups predefined by nomogram-predicted IBTR risks and a calibration plot was drawn.ResultsMedian follow-up was 10.9 years. The 10-year IBTR rates were 1.3 % and 2.1 %, according to the two definitions of IBTR.The validation cohort differed from the development cohort with respect to the administration of hormonal therapy, surgical section margins, lymphovascular invasion and tumor size. In univariable analysis, a younger age (p = 0.002) and a positive nodal status (p = 0.048) were significantly associated with IBTR with a trend for the omission of hormonal therapy (p = 0.061).The CPE and C-index varied between 0.57 to 0.67 for the two definitions of IBTR. In all four risk groups, the model overestimated the IBTR risk. In particular between the lowest-risk groups a limited differentiation was suggested by the calibration plot.ConclusionsThe IBTR! 2.0 predictive model for IBTR in BC patients shows substandard discriminative ability with an overestimation of the risk in all subgroups.
Teaser
Local failures after breast conserving therapy correlate with overall survival. Accurate prediction of these failures might alter therapeutic strategies. The IBTR! 2.0 nomogram predicts the 10-year ipsilateral breast tumor recurrence and has been made available in an online application. Our findings have validated the algorithm and conclude that it shows substandard discriminative ability with an overestimation of the risk in all subgroups.from Cancer via ola Kala on Inoreader http://ift.tt/1qdQgUt
via IFTTT
Pitfalls in prediction modelling for normal tissue toxicity in radiation therapy: an illustration with the ISE and MARIE cohorts
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Chamberlain Mbah, Hubert Thierens, Olivier Thas, Jan De Neve, Jenny Chang-Claude, Petra Seibold, Akke Botma, Catharine West, Kim De Ruyck
PurposeTo identify the main causes underlying the failure of prediction models for radiotherapy toxicity to replicate.MethodsData were used from two German cohorts ISE (n=418) and MARIE (n=409) of breast cancer patients with similar characteristics and radiotherapy treatments. The toxicity endpoint chosen was telangiectasia. The LASSO (Least Absolute Shrinkage and Selection Operator) logistic regression method was used to build a predictive model for a dichotomised endpoint (RTOG/EORTC score 0,1 or ≥2). Internal AUCs (inAUCs) were calculated by a naive approach where the training data (ISE) was also used for calculating the AUC. Cross validation was also applied to calculate the AUC within the same cohort, a second type of inAUC. InAUCs from cross validation were calculated within ISE and MARIE separately. Models trained on one dataset (ISE) were applied to a test dataset (MARIE) and AUCs calculated (exAUCs).ResultsInAUCs from the naive approach were generally larger than inAUCs from cross validation due to overfitting the training data. InAUCs from cross validation were also generally larger than the exAUCs, reflecting heterogeneity in the predictors between cohorts. The best models with largest inAUCs from cross validation within both cohorts had a number of common predictors: hypertension, normalised total boost and presence of estrogen receptors. Surprisingly the effect (coefficient in the prediction model) of hypertension on telangiectasia incidence was positive in ISE and negative in MARIE. Other predictors were also not common between the two cohorts illustrating that, overcoming overfitting does not solve the problem of replication failure of prediction models completely.ConclusionsOverfitting and cohort heterogeneity are the two main causes of replication failure of prediction models across cohorts. Cross validation and similar techniques (e.g. bootstrapping) cope with overfitting but the development of validated predictive models for radiotherapy toxicity requires strategies that deal with cohort heterogeneity.
Teaser
Overfitting and cohort heterogeneity are identified as the two main causes of replication failure of prediction models across cohorts. Cross validation and other resampling techniques (e.g. bootstrapping) can reduce the effect of overfitting. But the development of validated predictive models for radiotherapy toxicity requires strategies that deal with cohort heterogeneity.from Cancer via ola Kala on Inoreader http://ift.tt/1RUebOu
via IFTTT
Trends in mouth cancer incidence in Mumbai, India (1995–2009): An age-period-cohort analysis
Publication date: June 2016
Source:Cancer Epidemiology, Volume 42
Author(s): Krithiga Shridhar, Preetha Rajaraman, Shravani Koyande, Purvish M. Parikh, Pankaj Chaturvedi, Preet K. Dhillon, Rajesh P. Dikshit
IntroductionDespite tobacco control and health promotion efforts, the incidence rates of mouth cancer are increasing across most regions in India. Analysing the influence of age, time period and birth cohort on these secular trends can point towards underlying factors and help identify high-risk populations for improved cancer control programmes.MethodsWe evaluated secular changes in mouth cancer incidence among men and women aged 25–74 years in Mumbai between 1995 and 2009 by calculating age-specific and age-standardized incidence rates (ASR). We estimated the age-adjusted linear trend for annual percent change (EAPC) using the drift parameter, and conducted an age–period–cohort (APC) analysis to quantify recent time trends and to evaluate the significance of birth cohort and calendar period effects.ResultsOver the 15-year period, age-standardized incidence rates of mouth cancer in men in Mumbai increased by 2.7% annually (95% CI:1.9 to 3.4), p<0.0001) while rates among women decreased (EAPC=−0.01% (95% CI:−0.02 to −0.002), p=0.03). APC analysis revealed significant non-linear positive period and cohort effects in men, with higher effects among younger men (25–49 years). Non-significant increasing trends were observed in younger women (25–49 years).ConclusionsAPC analyses from the Mumbai cancer registry indicate a significant linear increase of mouth cancer incidence from 1995 to 2009 in men, which was driven by younger men aged 25–49 years, and a non-significant upward trend in similarly aged younger women. Health promotion efforts should more effectively target younger cohorts.
from Cancer via ola Kala on Inoreader http://ift.tt/1Y6nBvc
via IFTTT
The Uncontrolled Sialylation is Related to Chemoresistant Metastatic Breast Cancer
Abstract
Among the scientific communities, there is a convergence of results supporting a direct relationship between dysregulated sialylation and poor prognosis in many human cancers. For this reason, we have retrospectively investigated 169 cases of invasive ductal carcinoma of the breast, coming from female patients aged between 31 and 76 years old. The whole series was subdivided into two prognostic groups: the first group consisted of 138 patients, who showed a post-treatment survival time more than 5 years, while the second group was made up by 31 patients, died within 5 years despite of chemotherapy. All the surgical specimens were fixed in 10 % neutral buffered formalin, paraffin embedded and, then, submitted to routinely haematoxylin/eosin staining and to a further histochemical (Alcian Blue, DDD-Fast Blue B, Mercury Orange), immunohistochemical (ST3GAL5 sialyltransferase, Ki67, c-erbB2, ER, PR) and chemico-elemental characterization. In the 31 cases of breast cancer belonging to the second group, an overexpression of sialomucins and sialyltransferases has been detected. Our results lead us to support that in aggressive chemoresistant breast cancers, the altered expression of sialic acid, due to an uncontrolled sialylation, creates an excessive negative charge on cell membranes, which stimulates repulsion between neoplastic cells and their subsequent access into the blood stream. This event implies an early metastatization and a rapid disease progression with fatal outcome. The early application of Alcian Blue stain on diagnostic biopsies of breast cancer is able to cheaply reveal the sialomucin accumulations, providing for the disease course.
from Cancer via ola Kala on Inoreader http://ift.tt/1PNHvF0
via IFTTT
Prospective validation of two mathematical models to calculate the risk of endometrial malignancy in patients with postmenopausal bleeding and sonographic endometrial thickness ≥4.5 mm
Publication date: May 2016
Source:European Journal of Cancer, Volume 59
Author(s): Povilas Sladkevicius, Lil Valentin
AimTo prospectively validate two mathematical models for calculating the likelihood of endometrial malignancy in patients with postmenopausal bleeding (PMPB), sonographic endometrial thickness (ET) ≥4.5 mm and no fluid in the uterine cavity.MethodsThis is a prospective observational diagnostic validation study performed in a PMPB clinic in a university hospital. Of 860 consecutive patients, 350 fulfilled our inclusion criteria. A standardized history was taken, clinical and transvaginal grey scale and power Doppler ultrasound examinations were performed following a research protocol. The percentage vascularized area of the endometrium at power Doppler examination (VI) was calculated using computer software. The colour content of the endometrial scan was estimated subjectively on a visual analogue scale (VAS). Gold standard was the histological diagnosis of the endometrium. Main outcome measures were area under the receiver operating characteristic curve (AUC), sensitivity and specificity when using the cut-offs suggested in the original study, and calibration curves.ResultsEighty (23%) patients had malignant endometrium. The performance of the models was similar to that in the original study. The model including patient's age, use of hormone therapy, ET and VAS performed best (AUC 0.91; 95% confidence interval [CI] 0.87–0.95; sensitivity 70%, specificity 93%). The model including ET, VI, patient's age and hormone therapy use had AUC 0.89 (95% CI 0.84–0.93; sensitivity 79%; specificity 81%). ET had AUC 0.83 (95% CI 0.78–0.88). The models were reasonably well calibrated.ConclusionOn prospective validation both models retained their diagnostic performance. This suggests that they are robust and potentially clinically useful for individualized patient management.
from Cancer via ola Kala on Inoreader http://ift.tt/1SuLpEO
via IFTTT
Prognostic instrument for survival outcome in melanoma patients: based on data from the population-based Swedish Melanoma Register
Publication date: May 2016
Source:European Journal of Cancer, Volume 59
Author(s): J. Lyth, R. Mikiver, K. Nielsen, K. Isaksson, C. Ingvar
BackgroundSeveral major analyses have identified a consistent set of independent risk factors for cutaneous malignant melanoma (CMM). A few prognostic models have been presented but some are based on a limited number of patients and others are based on selected groups of patients referred to major institutions. No nationwide population-based prognostic instrument for survival of CMM has been presented. The Swedish Melanoma Register (SMR) database covers 99% of CMM diagnosed in Sweden and includes today >50,000 cases.ObjectivesTo create a prognostic instrument based on SMR data to give highly reliable risk profiles for patients diagnosed with localised CMM.MethodsClinicopathological data were linked to the cause of death registry for calculation of CMM-specific survival. A generalised gamma method was used to derive 1, 5 and 10year probabilities of death for each combination of patient and tumour data: age, sex, tumour site, tumour thickness, tumour ulceration, Clark's level of invasion and when applicable also outcome of sentinel node biopsy (SNB).ResultsTumour thickness had the highest prognostic impact, explaining 77% of the model. Women had 30% lower risk of death because of CMM than men. Presence of ulceration nearly doubled the risk. If the patient had a positive SNB status the risk of death due to CMM increased three times versus a negative SNB status.ConclusionThis unique population-based prognostic model for primary CMM shows better survival than the American Joint Commission on Cancer prognostic model widely used. The reason is probably that the referral bias is eliminated in a population-based cohort.
from Cancer via ola Kala on Inoreader http://ift.tt/1TqQvqA
via IFTTT
Issue Contents
Publication date: April 2016
Source:Cancer/Radiothérapie, Volume 20, Issue 2
from Cancer via ola Kala on Inoreader http://ift.tt/1RE3S1Y
via IFTTT
Editorial Board
Publication date: April 2016
Source:Cancer/Radiothérapie, Volume 20, Issue 2
from Cancer via ola Kala on Inoreader http://ift.tt/1RT59rs
via IFTTT
Radiation-enhancing effect of sodium glycididazole in patients suffering from non-small cell lung cancer with multiple brain metastases: A randomized, placebo-controlled study
Publication date: Available online 1 April 2016
Source:Cancer/Radiothérapie
Author(s): Y.C. Zeng, R. Wu, R. Xing, F. Chi, S.L. Wang, X.D. Chen, Y. Xuan, L.N. Wu, Q.Y. Duan, M.Y. Tang, N. Niu, Y.N. Sun, G.L. Fan, H.M. Wang
PurposeMedian survival of patients with brain metastases from non-small cell lung cancer is poor. This study was to investigate the radiation-enhancing effect of sodium glycididazole combined with whole-brain radiotherapy of multiple brain metastases from non-small cell lung cancer.Patients and methodsSixty-four patients with multiple brain metastases from non-small cell lung cancer were included: the study group (n=32) received whole-brain radiotherapy combined with sodium glycididazole at a dose of 700mg/m2 intravenous infusion 30minutes before radiotherapy, three times a week; the control group (n=32) only received whole-brain radiotherapy. The primary end point was central nervous system (CNS) progression-free survival and overall survival. The treatment-related toxicity was also recorded.ResultsThe CNS disease control rate was better (90.6% vs 65.6%, P=0.016) in the study group than in the control group at 3 month of follow-up. The median CNS progression-free survival time was longer in the study group than in the control group (7.0 months vs 4.0 months, P=0.038). There was no significant difference of the median overall survival time between the study group and the control group (11.0 months vs 9.0 months, P=0.418). On the other hand, the treatment-related toxicity showed no statistically significant difference between these two groups (P>0.05).ConclusionsThe study indicated that sodium glycididazole was an effective, promising radiation-enhancing agent that improved CNS disease control rate, extended the median CNS progression-free survival time and was well tolerated in patients suffering from non-small cell lung cancer with multiple brain metastases.
from Cancer via ola Kala on Inoreader http://ift.tt/1RE3RLx
via IFTTT
Reducing understaging of bladder cancer with the aid of photodynamic cystoscopy
Publication date: Available online 1 April 2016
Source:Journal of the Egyptian National Cancer Institute
Author(s): K. Sfetsas, D. Mitropoulos
BackgroundThe authors evaluated the role of photodynamic cystoscopy in the detection of additional urothelial lesions, mainly carcinoma in situ, that would not be detected solely with white light cystoscopy, leading to disease understaging.MethodsFrom 2009 to 2011, 70 patients underwent white light cystoscopy, followed by photodynamic cystoscopy (blue light system, Karl Storz, Tuttlingen, Germany). Preoperatively they were instilled intravesically with 50ml of Hexvix (Hexaminolevulinate hexylester). We recorded all lesions found with white light cystoscopy and the additional lesions revealed by blue light cystoscopy. Afterward all lesions were removed and sent for pathologic evaluation.ResultsSeventeen patients (24.3%) had primary tumors while 53 patients (75.7%) had recurrent disease. In 53 out of 70 patients (75.7%) white light cystoscopy revealed urothelial lesions. In the rest 17 patients who had no findings with white light cystoscopy, blue light cystoscopy revealed 7 cases of Cis (41.2%) and 8 cases of dysplasia (47%). In the group of patients with visible lesions in white light cystoscopy photodynamic cystoscopy revealed additional carcinoma in situ in 22 patients. Altogether additional carcinoma in situ cases found with the aid of photodynamic cystoscopy were 29 out of 70 cases (41.4%).ConclusionsPhotodynamic cystoscopy is the most efficient diagnostic procedure for flat urothelial lesions and especially for carcinoma in situ. It is significantly more sensitive than conventional white light cystoscopy in Cis diagnosis, thus reducing understaging of the disease and consequently improving recurrence and progression rates.
from Cancer via ola Kala on Inoreader http://ift.tt/1RT59aW
via IFTTT
[What's next in glioblastoma treatment: Tumor-targeted or immune-targeted therapies?]
[What's next in glioblastoma treatment: Tumor-targeted or immune-targeted therapies?]
Bull Cancer. 2016 Mar 28;
Authors: Schernberg A, Marabelle A, Massard C, Armand JP, Dumont S, Deutsch E, Dhermain F
Abstract
INTRODUCTION: Glioblastoma (GBM) is associated with a poor prognosis. This review will discuss different directions of treatment, mostly regarding immunotherapies and combinatorial approaches.
DEVELOPMENT: Standard treatment for newly diagnosed GBM is maximal and safe surgical resection followed by concurrent radiochemotherapy (RCT) based on temozolomide, allowing 14.6 months median survival. Nowadays, no combination with molecular-targeted therapy had significantly improved prognosis. Phases I and II data are emerging, highlighting the potential efficacy of associations with other therapies. Studies have suggested the potential of targeting tumor stem cells, at less partially responsible for resistance to RCT. There is now some evidence that immunotherapy is also relevant for brain tumors. Treatment strategies have mainly explored vaccines strategies, such as the dendritic cell, heat shock protein or EGFRvIII vaccines. Of the work initiated in melanoma, immune checkpoints inhibitors have exhibited stimulating results. Others trials have demonstrated potential of autologous stimulated lymphocytes. Moreover, strong data indicates that radiation therapy has the potential to promote immunogenicity and create a sort of in situ personalized vaccine.
CONCLUSION: These data provide strong evidence to support the potential of associating combinatorial targeted and/or immunotherapeutic regimens in patients with GBM that may change patient outcome.
PMID: 27032303 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/1qcNtem
via IFTTT
Optimal combination of gemcitabine, sorafenib, and S-1 shows increased efficacy in treating cholangiocarcinoma in vitro and in vivo.
Cholangiocarcinoma (CCA) is one of the most difficult cancers to treat and lacks an established standard chemotherapy regimen. This study evaluated the effects of different combinations of gemcitabine, sorafenib, and S-1 on CCA cells to identify the optimal drug combination. A fractional factorial design method was applied in drug combination experiments to determine the optimal combination of these three drugs (gemcitabine=1.4 mmol/l, sorafenib=0.03 mmol/l, S-1=0.185 mmol/l). We constructed a mathematical model with a small number of runs (Y=1.14-0.377A-23.0B-1.81C+0.084A2+109B2+6.06C2+3.83AB+0.175AC-40.4BC) to predict the efficacy of combinations of the drugs. The optimal combination can significantly inhibit the AKT/mTOR pathway, and thus CCA cell proliferation, and can induce cell apoptosis. In vivo, this combination (gemcitabine=1.4 mmol/l, sorafenib=0.03 mmol/l, S-1=0.185 mmol/l) can significantly inhibit tumor growth. The present study showed that the mathematical model was reliable and could predict the efficacy of the different drug combinations. The optimal combination of these drugs may aid the development of a promising standard chemotherapy regimen for CCA. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
from Cancer via ola Kala on Inoreader http://ift.tt/1N3iE08
via IFTTT
from Cancer via ola Kala on Inoreader http://ift.tt/1N3iE08
via IFTTT
IL-6 blockade in K-ras mutant lung cancer
Activating mutations of K-ras are the most common oncogenic alterations found in lung cancer. Unfortunately, attempts to target K-ras mutant lung tumors have thus far failed, clearly indicating the need for new approaches in patients with this molecular profile. We have previously shown NF-κB activation, release of IL-6, and activation of its responsive transcription factor STAT3 in K-ras mutant lung tumors, which was further amplified by the tumor enhancing effect of chronic obstructive pulmonary disease (COPD)-type airway inflammation. These findings suggest an essential role for this inflammatory pathway in K-ras mutant lung tumorigenesis and its enhancement by COPD. Therefore, here we blocked IL-6 using a monoclonal anti-IL-6 antibody in a K-ras mutant mouse model of lung cancer in the absence or presence of COPD-type airway inflammation. IL-6 blockade significantly inhibited lung cancer promotion, tumor cell intrinsic STAT3 activation, tumor cell proliferation, and angiogenesis markers. Moreover, IL-6 inhibition reduced expression of pro-tumor type 2 molecules (Arginase 1, Fizz 1, Mgl, and IDO), number of M2 type macrophages and G-MDSCs, and pro-tumor T-regulatory/T helper 17 cell responses. This was accompanied by increased expression of anti-tumor type 1 molecule (Nos2), and anti-tumor T helper 1/CD8 T cell responses. Our study demonstrates that IL-6 blockade not only has direct intrinsic inhibitory effect on tumor cells, but also re-educates the lung microenvironment toward an anti-tumor phenotype by altering the relative proportion between pro-tumor and anti-tumor immune cells. This information introduces IL-6 as a potential druggable target for prevention and treatment of K-ras mutant lung tumors.
from Cancer via ola Kala on Inoreader http://ift.tt/22Xz7zC
via IFTTT
Εγγραφή σε:
Αναρτήσεις (Atom)