Prognostic significance of HLA class I and II expression in patients with diffuse large B cell lymphoma treated with standard chemoimmunotherapy

Abstract

Loss of tumor cell human leukocyte antigen (HLA) is an immune escape mechanism for malignancies. However, the effect of low HLA class I or class II expression in diffuse large B cell lymphoma (DLBCL) treated with chemoimmunotherapy with the monoclonal antibody rituximab is largely unknown. We retrospectively analyzed samples and other data from 144 patients with DLBCL who were newly diagnosed in our institution and treated with standard R-CHOP therapy. We used antibodies against pan-HLA class I and pan-HLA class II molecules to assess HLA expression and its effect on prognosis. In a multivariate analysis, loss of HLA class II expression was a significantly independent adverse factor for progression-free survival (PFS; hazard ratio 2.3; 95 % confidence interval 1.2–4.6; P = 0.01). Although HLA class I loss of expression did not correlate with prognosis, the combination of HLA class I⁺ with either low peripheral lymphocyte count or CD3⁺ lymphocyte count was an adverse prognostic factor for PFS. Loss of HLA class II is an International Prognostic Index (IPI)-independent adverse factor for PFS in patients with DLBCL treated with standard therapy. However, in contrast to other solid cancers, HLA class I loss was not solely a prognostic factor in DLBCL.

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Prognostic significance of HLA class I and II expression in patients with diffuse large B cell lymphoma treated with standard chemoimmunotherapy

Abstract

Loss of tumor cell human leukocyte antigen (HLA) is an immune escape mechanism for malignancies. However, the effect of low HLA class I or class II expression in diffuse large B cell lymphoma (DLBCL) treated with chemoimmunotherapy with the monoclonal antibody rituximab is largely unknown. We retrospectively analyzed samples and other data from 144 patients with DLBCL who were newly diagnosed in our institution and treated with standard R-CHOP therapy. We used antibodies against pan-HLA class I and pan-HLA class II molecules to assess HLA expression and its effect on prognosis. In a multivariate analysis, loss of HLA class II expression was a significantly independent adverse factor for progression-free survival (PFS; hazard ratio 2.3; 95 % confidence interval 1.2–4.6; P = 0.01). Although HLA class I loss of expression did not correlate with prognosis, the combination of HLA class I⁺ with either low peripheral lymphocyte count or CD3⁺ lymphocyte count was an adverse prognostic factor for PFS. Loss of HLA class II is an International Prognostic Index (IPI)-independent adverse factor for PFS in patients with DLBCL treated with standard therapy. However, in contrast to other solid cancers, HLA class I loss was not solely a prognostic factor in DLBCL.

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Health—exploring complexity: an interdisciplinary systems approach HEC2016

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Prognostic significance of HLA class I and II expression in patients with diffuse large B cell lymphoma treated with standard chemoimmunotherapy

Abstract

Loss of tumor cell human leukocyte antigen (HLA) is an immune escape mechanism for malignancies. However, the effect of low HLA class I or class II expression in diffuse large B cell lymphoma (DLBCL) treated with chemoimmunotherapy with the monoclonal antibody rituximab is largely unknown. We retrospectively analyzed samples and other data from 144 patients with DLBCL who were newly diagnosed in our institution and treated with standard R-CHOP therapy. We used antibodies against pan-HLA class I and pan-HLA class II molecules to assess HLA expression and its effect on prognosis. In a multivariate analysis, loss of HLA class II expression was a significantly independent adverse factor for progression-free survival (PFS; hazard ratio 2.3; 95 % confidence interval 1.2–4.6; P = 0.01). Although HLA class I loss of expression did not correlate with prognosis, the combination of HLA class I⁺ with either low peripheral lymphocyte count or CD3⁺ lymphocyte count was an adverse prognostic factor for PFS. Loss of HLA class II is an International Prognostic Index (IPI)-independent adverse factor for PFS in patients with DLBCL treated with standard therapy. However, in contrast to other solid cancers, HLA class I loss was not solely a prognostic factor in DLBCL.

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Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases

Abstract

Introduction

Infiltration of cancers by T cells is associated with improved patient survival and response to immune therapies; however, optimal approaches to induce T cell infiltration of tumors are not known. This study was designed to assess whether topical treatment of melanoma metastases with the TLR7 agonist imiquimod plus administration of a multipeptide cancer vaccine will improve immune cell infiltration of melanoma metastases.

Patients and methods

Eligible patients were immunized with a vaccine comprised of 12 melanoma peptides and a tetanus toxoid-derived helper peptide, and imiquimod was applied topically to metastatic tumors daily. Adverse events were recorded, and effects on the tumor microenvironment were evaluated from sequential tumor biopsies. T cell responses were assessed by IFNγ ELIspot assay and T cell tetramer staining. Patient tumors were evaluated for immune cell infiltration, cytokine and chemokine production, and gene expression.

Results and conclusions

Four eligible patients were enrolled, and administration of imiquimod and vaccination were well tolerated. Circulating T cell responses to the vaccine was detected by ex vivo ELIspot assay in 3 of 4 patients. Treatment of metastases with imiquimod induced immune cell infiltration and favorable gene signatures in the patients with circulating T cell responses. This study supports further study of topical imiquimod combined with vaccines or other immune therapies for the treatment of melanoma.

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Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases

Abstract

Introduction

Optimal approaches to induce T cell infiltration of tumors are not known. Chemokines CXCL9, CXCL10, and CXCL11 support effector T cell recruitment and may be induced by IFN. This study tests the hypothesis that intratumoral administration of IFNγ will induce CXCL9–11 and will induce T cell recruitment and anti-tumor immune signatures in melanoma metastases.

Patients and methods

Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted melanoma peptides and received IFNγ intratumorally. Effects on the tumor microenvironment were evaluated in sequential tumor biopsies. Adverse events (AEs) were recorded. T cell responses to vaccination were assessed in PBMC by IFNγ ELISPOT assay. Tumor biopsies were evaluated for immune cell infiltration, chemokine protein expression, and gene expression.

Results

Vaccination and intratumoral administration of IFNγ were well tolerated. Circulating T cell responses to vaccine were detected in six of nine patients. IFNγ increased production of chemokines CXCL10, CXCL11, and CCL5 in patient tumors. Neither vaccination alone, nor the addition of IFNγ promoted immune cell infiltration or induced anti-tumor immune gene signatures.

Conclusion

The melanoma vaccine induced circulating T cell responses, but it failed to infiltrate metastases, thus highlighting the need for combination strategies to support T cell infiltration. A single intratumoral injection of IFNγ induced T cell-attracting chemokines; however, it also induced secondary immune regulation that may paradoxically limit immune infiltration and effector functions. Alternate dosing strategies or additional combinatorial treatments may be needed to promote trafficking and retention of tumor-reactive T cells in melanoma metastases.

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TCF-1 participates in the occurrence of dedifferentiated chondrosarcoma

Abstract

The present study demonstrated that T cell factor 1 (TCF-1) protein, a component of the canonical Wnt/β-catenin signaling pathway, can regulate the expression of runt-related transcription factor 2 (runx2) gene and Sry-related HMG box 9 (sox9) gene, which may participate in the differentiation of chondrosarcoma. Dedifferentiated chondrosarcoma (DDCS) is a special variant of conventional chondrosarcoma (CCS), associated with poor survival and high metastasis rate. However, little is known about the mechanism of its occurrence; thus, no effective treatment is available except surgery. Earlier, high expression of runx2 and low expression of sox9 were found in DDCS compared with CCS. Using Western blot to detect clinical tissue samples (including 8 CCS samples and 8 DDCS samples) and immunohistochemistry to detect 85 different-grade chondrosarcoma specimens, a high expression of TCF-1 in DDCS tissues was found compared with CCS tissues. This difference in expression was related to patients' prognosis. Results of luciferase, chromatin immunoprecipitation, and gel electrophoresis mobility shift assays demonstrated that TCF-1 protein could bind to the promoter of runx2 gene directly and sox9 gene indirectly. Hence, it could regulate expression of runx2 gene positively and sox9 gene negatively. Furthermore, in vitro and in vivo experiments showed that TCF-1 protein was closely related to the phenotype and aggressiveness of chondrosarcoma. In conclusion, this study proved that TCF-1 participates in the dedifferentiation of DDCS, which may be mediated by runx2 gene and sox9 gene. Also, TCF-1 can be of important prognostic value and a promising therapeutic target for DDCS patients.

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Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases

Abstract

Introduction

Infiltration of cancers by T cells is associated with improved patient survival and response to immune therapies; however, optimal approaches to induce T cell infiltration of tumors are not known. This study was designed to assess whether topical treatment of melanoma metastases with the TLR7 agonist imiquimod plus administration of a multipeptide cancer vaccine will improve immune cell infiltration of melanoma metastases.

Patients and methods

Eligible patients were immunized with a vaccine comprised of 12 melanoma peptides and a tetanus toxoid-derived helper peptide, and imiquimod was applied topically to metastatic tumors daily. Adverse events were recorded, and effects on the tumor microenvironment were evaluated from sequential tumor biopsies. T cell responses were assessed by IFNγ ELIspot assay and T cell tetramer staining. Patient tumors were evaluated for immune cell infiltration, cytokine and chemokine production, and gene expression.

Results and conclusions

Four eligible patients were enrolled, and administration of imiquimod and vaccination were well tolerated. Circulating T cell responses to the vaccine was detected by ex vivo ELIspot assay in 3 of 4 patients. Treatment of metastases with imiquimod induced immune cell infiltration and favorable gene signatures in the patients with circulating T cell responses. This study supports further study of topical imiquimod combined with vaccines or other immune therapies for the treatment of melanoma.

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Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases

Abstract

Introduction

Optimal approaches to induce T cell infiltration of tumors are not known. Chemokines CXCL9, CXCL10, and CXCL11 support effector T cell recruitment and may be induced by IFN. This study tests the hypothesis that intratumoral administration of IFNγ will induce CXCL9–11 and will induce T cell recruitment and anti-tumor immune signatures in melanoma metastases.

Patients and methods

Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted melanoma peptides and received IFNγ intratumorally. Effects on the tumor microenvironment were evaluated in sequential tumor biopsies. Adverse events (AEs) were recorded. T cell responses to vaccination were assessed in PBMC by IFNγ ELISPOT assay. Tumor biopsies were evaluated for immune cell infiltration, chemokine protein expression, and gene expression.

Results

Vaccination and intratumoral administration of IFNγ were well tolerated. Circulating T cell responses to vaccine were detected in six of nine patients. IFNγ increased production of chemokines CXCL10, CXCL11, and CCL5 in patient tumors. Neither vaccination alone, nor the addition of IFNγ promoted immune cell infiltration or induced anti-tumor immune gene signatures.

Conclusion

The melanoma vaccine induced circulating T cell responses, but it failed to infiltrate metastases, thus highlighting the need for combination strategies to support T cell infiltration. A single intratumoral injection of IFNγ induced T cell-attracting chemokines; however, it also induced secondary immune regulation that may paradoxically limit immune infiltration and effector functions. Alternate dosing strategies or additional combinatorial treatments may be needed to promote trafficking and retention of tumor-reactive T cells in melanoma metastases.

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Feasibility of dose-dense paclitaxel/carboplatin therapy in elderly patients with ovarian, fallopian tube, or peritoneal cancer

Abstract

Purpose

Weekly dose-dense paclitaxel (PTX) in combination with carboplatin (CBDCA) every 3 weeks (ddTC therapy) is a standard treatment for patients with advanced ovarian cancer. However, there is no detailed analysis of the feasibility of ddTC therapy in elderly patients with ovarian cancer.

Methods

We identified patients diagnosed with ovarian, fallopian tube, or peritoneal cancer who received ddTC therapy at the National Cancer Center Hospital from April 2003 to April 2013. We assessed the feasibility of ddTC therapy in elderly patients aged 70 years or older (elderly group), comparing relative dose intensity (RDI) for PTX, CBDCA, and ddTC; adverse events; and rate of chemotherapy discontinuation to those in patients below 70 years of age (younger group).

Results

A total of 143 patients (elderly group, 22; younger group, 121) was analyzed. A comparison of RDI between these two groups showed no significant differences for PTX, CBDCA, and ddTC. Nonhematological and hematological toxicity profiles of the elderly and younger groups were similar, except that severe peripheral neuropathy (Grade 2 or higher) was more common in the elderly group. There was no significant difference in the rate of chemotherapy discontinuation (elderly group, 13.6 % vs. younger group, 7.4 %, p = 0.397).

Conclusions

Our study showed that ddTC therapy was feasible for elderly patients. However, to prevent severe neuropathy, PTX dose reduction deserves consideration.

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Radiothérapie des cancers des cavités nasosinusiennes

Publication date: Available online 12 August 2016
Source:Cancer/Radiothérapie
Author(s): G. Peyraga, C. Lafond, Y. Pointreau, P. Giraud, P. Maingon
Les tumeurs nasosinusiennes sont rares (10 % des tumeurs de la tête et du cou) et sont principalement représentées par les carcinomes épidermoïdes des fosses nasales ou du sinus maxillaire et les adénocarcinomes de l'ethmoïde (maladie professionnelle, poussière de bois). Le signe clinique le plus fréquent est l'obstruction nasale, mais on peut aussi retrouver une rhinorrhée et/ou une épistaxis (signes à présentation le plus souvent unilatérale). Une imagerie par résonance magnétique du massif facial est systématique dans le bilan initial avant traitement. La prise en charge consiste en une chirurgie première si le patient est opérable et la tumeur résécable. Si ce n'est pas le cas, le traitement consiste en une radiothérapie associée à une chimiothérapie, en fonction des données initiales (stade T3/T4 ou atteinte ganglionnaire). Après chirurgie première, une radiothérapie est indiquée (sauf si stade T1N0 avec résection complète), associée à une chimiothérapie en fonction des données postopératoires (rupture capsulaire ou résection incomplète). Une irradiation ganglionnaire est à discuter au cas par cas, mais est indiquée devant tout envahissement ganglionnaire. La radiothérapie doit être délivrée avec modulation d'intensité (RCMI), statique ou dynamique, et guidée par l'imagerie (IGRT). Selon le rapport 83 de l'International Commission on Radiation Units and Measurements (ICRU), les doses reçues par les organes à risque et les volumes cibles doivent être rapportées. Enfin, après une imagerie de référence post-thérapeutique entre 2 et 4 mois, le suivi est alterné avec le chirurgien ORL tous les 2 à 3 mois pendant 2ans, puis tous les 4 à 6 mois pour 5ans au minimum.The nasal cavity and parasinusal cancer are rare (10% of tumors of the head and neck) and are mainly represented by squamous cell carcinoma of the nasal cavity or the maxillary sinus and adenocarcinoma of the ethmoid sinus (occupational disease, wood dust). The most common clinical sign is nasal obstruction, but tumors can also manifest as rhinorrhea and/or epistaxis (usually unilateral signs). A magnetic resonance imaging of the facial structure is systematic for staging before treatment. The treatment consists of a first surgery if the patient is operable with a resectable tumor. If it is not the case, the treatment consists of radiotherapy (RT) associated with chemotherapy (CT) according to the initial data (T3/T4 or N+). After first surgery, RT is indicated (except T1N0 with complete resection) associated with a CT based on postoperative data (capsular effraction or incomplete resection). Lymph node irradiation is considered case by case, but is indicated in any nodal involvement. RT must be an intensity modulated RT (IMRT), static or dynamic, and must be imagery guided (IGRT). According to ICRU 83, doses to organs at risk and target volumes must be carried. Finally, after a post-treatment baseline imaging between 2 and 4 months, monitoring will be alternated with the ENT surgeon every 2 or 3 months for 2 years, then every 4 to 6 months for 5 years.



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