Concept: Types of cancer
Increasing knowledge concerning the biology of hematologic malignancies as well as the role of the immune system in the control of these diseases has led to the development and approval of immunotherapies that are resulting in impressive clinical responses. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a hematologic malignancy Cancer Immunotherapy Guidelines panel consisting of physicians, nurses, patient advocates, and patients to develop consensus recommendations for the clinical application of immunotherapy for patients with multiple myeloma, lymphoma, and acute leukemia. These recommendations were developed following the previously established process based on the Institute of Medicine’s clinical practice guidelines. In doing so, a systematic literature search was performed for high-impact studies from 2004 to 2014 and was supplemented with further literature as identified by the panel. The consensus panel met in December of 2014 with the goal to generate consensus recommendations for the clinical use of immunotherapy in patients with hematologic malignancies. During this meeting, consensus panel voting along with discussion were used to rate and review the strength of the supporting evidence from the literature search. These consensus recommendations focus on issues related to patient selection, toxicity management, clinical endpoints, and the sequencing or combination of therapies. Overall, immunotherapy is rapidly emerging as an effective therapeutic strategy for the management of hematologic malignances. Evidence-based consensus recommendations for its clinical application are provided and will be updated as the field evolves.
Background Patients with diffuse large B-cell lymphoma or follicular lymphoma that is refractory to or that relapses after immunochemotherapy and transplantation have a poor prognosis. High response rates have been reported with the use of T cells modified by chimeric antigen receptor (CAR) that target CD19 in B-cell cancers, although data regarding B-cell lymphomas are limited. Methods We used autologous T cells that express a CD19-directed CAR (CTL019) to treat patients with diffuse large B-cell lymphoma or follicular lymphoma that had relapsed or was refractory to previous treatments. Patients were monitored for response to treatment, toxic effects, the expansion and persistence of CTL019 cells in vivo, and immune recovery. Results A total of 28 adult patients with lymphoma received CTL019 cells, and 18 of 28 had a response (64%; 95% confidence interval [CI], 44 to 81). Complete remission occurred in 6 of 14 patients with diffuse large B-cell lymphoma (43%; 95% CI, 18 to 71) and 10 of 14 patients with follicular lymphoma (71%; 95% CI, 42 to 92). CTL019 cells proliferated in vivo and were detectable in the blood and bone marrow of patients who had a response and patients who did not have a response. Sustained remissions were achieved, and at a median follow-up of 28.6 months, 86% of patients with diffuse large B-cell lymphoma who had a response (95% CI, 33 to 98) and 89% of patients with follicular lymphoma who had a response (95% CI, 43 to 98) had maintained the response. Severe cytokine-release syndrome occurred in 5 patients (18%). Serious encephalopathy occurred in 3 patients (11%); 2 cases were self-limiting and 1 case was fatal. All patients in complete remission by 6 months remained in remission at 7.7 to 37.9 months (median, 29.3 months) after induction, with a sustained reappearance of B cells in 8 of 16 patients and with improvement in levels of IgG in 4 of 10 patients and of IgM in 6 of 10 patients at 6 months or later and in levels of IgA in 3 of 10 patients at 18 months or later. Conclusions CTL019 cells can be effective in the treatment of relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. High rates of durable remission were observed, with recovery of B cells and immunoglobulins in some patients. Transient encephalopathy developed in approximately one in three patients and severe cytokine-release syndrome developed in one in five patients. (Funded by Novartis and others; ClinicalTrials.gov number, NCT02030834 .).
A number of constitutively activated signaling pathways play critical roles in the survival and growth of primary effusion lymphoma cells (PELs) including NFkB and PI3/AKT kinase cascades. NFkBis constitutively activated in a number of malignancies, including multiple myeloma, Burkitt’s lymphoma and diffuse large cell B-cell lymphoma. However, its role in primary effusion lymphoma has not been fully explored.
Ewing Sarcoma Family Tumours (ESFT) are rare in early childhood. The aim of this study was to report the clinical characteristics and outcome of children under 6 years of age affected by ESFT of the bone in Italy.
Hairy cell leukemia is a mature B-cell non-Hogkin lymphoma characterized by unique clinical, morphological and immunhistochemical features. Patients with hairy cell leukemia usually present with splenomegaly, progressive pancytopenia and a relative indolent clinical course. The diagnosis does not always indicate immediate treatment, as treatment depends on the clinical stage of the leukemia. Asymptomatic disease without progression requires a watchful waiting policy, while other categories usually need treatment. The treatment of choice is purin nucleosid analogues (pentostatin, cladribine) which can achieve complete remission even for decades. Interferon and monoclonal CD20 antibodies can also significantly prolong tevent free survival. Unfortunately, only the latter two therapies are easily available in Hungary. Splenectomy, which was suggested as first line treatment before the era of purin nucleosid analogues, is only recommended as ultimum refugium. Although hairy cell leukemia is a well-defined lymphoproliferative disease, sometimes it is difficult to differentiate it from other similar entities such as hairy cell leukema variant, splenic marginal zone lymphoma, small lymphocytic lymphoma etc. Making the correct diagnosis is of utmost importance because of the great difference in treatment modalities. Recently, a somatic mutation was found in all analysed hairy cell leukemia samples, but not in other splenic B-cell lymphomas. This article reviews the significance of this observation and presents the different types of methods for the detection of this mutation. Orv. Hetil., 2013, 154, 123-127.
Soft tissue sarcomas comprise approximately 1% of all adult solid malignancies. While chemotherapy is the mainstay of treatment for patients with metastatic or inoperable disease, overall survival for these patients is approximately 12 months, highlighting the need for novel agents. Both laboratory and clinical data have suggested that antiangiogenic agents may have a role in the treatment of soft tissue sarcomas. Pazopanib is a multitargeted receptor tyrosine kinase inhibitor with antiangiogenic activity. The randomized, double-blind, placebo-controlled, Phase III PALETTE (pazopanib for metastatic soft-tissue sarcoma) study demonstrated improved progression-free survival in patients receiving pazopanib compared with placebo. In this review, we discuss the rationale and clinical evidence for the use of pazopanib in the treatment of metastatic and inoperable soft tissue sarcomas.
We introduce a novel computational framework to enable automated identification of texture and shape features of lesions on (18)F-FDG-PET images through a graph-based image segmentation method. The proposed framework predicts future morphological changes of lesions with high accuracy. The presented methodology has several benefits over conventional qualitative and semi-quantitative methods, due to its fully quantitative nature and high accuracy in each step of (i) detection, (ii) segmentation, and (iii) feature extraction. To evaluate our proposed computational framework, thirty patients received 2 (18)F-FDG-PET scans (60 scans total), at two different time points. Metastatic papillary renal cell carcinoma, cerebellar hemongioblastoma, non-small cell lung cancer, neurofibroma, lymphomatoid granulomatosis, lung neoplasm, neuroendocrine tumor, soft tissue thoracic mass, nonnecrotizing granulomatous inflammation, renal cell carcinoma with papillary and cystic features, diffuse large B-cell lymphoma, metastatic alveolar soft part sarcoma, and small cell lung cancer were included in this analysis. The radiotracer accumulation in patients' scans was automatically detected and segmented by the proposed segmentation algorithm. Delineated regions were used to extract shape and textural features, with the proposed adaptive feature extraction framework, as well as standardized uptake values (SUV) of uptake regions, to conduct a broad quantitative analysis. Evaluation of segmentation results indicates that our proposed segmentation algorithm has a mean dice similarity coefficient of 85.75±1.75%. We found that 28 of 68 extracted imaging features were correlated well with SUV(max) (p<0.05), and some of the textural features (such as entropy and maximum probability) were superior in predicting morphological changes of radiotracer uptake regions longitudinally, compared to single intensity feature such as SUV(max). We also found that integrating textural features with SUV measurements significantly improves the prediction accuracy of morphological changes (Spearman correlation coefficient = 0.8715, p<2e-16).
The prognosis for fit patients with mantle cell lymphoma has improved with intensive strategies. Currently, the role of maintenance/consolidation approaches is being tested as relapses continue appearing. In this trial we evaluated the feasibility, safety and efficacy of R-Hyper-CVAD alternating with R-MtxAraC followed by consolidation with 90Y-Ibritumomab-Tiuxetan. Patients received 6 cycles followed by a single dose of 90Y-Ibritumomab-Tiuxetan. Thirty patients were enrolled. Median age was 59 years. Twenty four patients finished the induction treatment, 23 achieved complete remission (77%, 95% confidence interval 60-93) and one patient had progressive disease (3%). Eighteen patients (60%), all in complete remission, received consolidation. In the intent- to- treat population, failure free, progression free and overall survival at 4 years were 40 % (95% confidence interval 20.4-59.6), 52% (95% confidence interval 32.4-71.6) and 81% (95% confidence interval 67.28-94.72), respectively. For patients who received consolidation, failure free and overall survival were 55% (95% confidence interval 31.48&-78.52) and 87% (95% confidence interval 70-100), respectively. Hematological toxicity was significant during induction and responsible for one death (3.3%). After consolidation, grade 3-4 neutropenia and thrombocytopenia were observed in 72% and 83% of patients, with median duration of 5 and 12 weeks, respectively. Six (20%) patients died, 3 due to secondary malignancies (myelodisplastic syndrome and bladder and rectum carcinomas). In conclusion, our experience with R-Hyper-CVAD/R-MtxAraC followed by consolidation with 90Y-Ibritumomab-Tiuxetan is efficacious although less feasible than expected. The unacceptable toxicity observed, specially secondary malignancies, advise against the indication of this strategy. Trial registration: clinical.gov identifier: NCT2005-004400-37.
The tumor suppressor genes MGMT and DAPK1 become methylated in several cancers including diffuse large B-cell lymphoma (DLBCL). However, allelic methylation patterns have not been investigated in DLBCL. We developed a fast and cost-efficient method for the analysis of allelic methylation based on pyrosequencing of methylation specific PCR (MSP) products including a SNP. Allelic methylation patterns were reliably analyzed in standards of known allelic methylation status even when diluted in unmethylated DNA to below 1% methylation. When studying 148 DLBCL patients MGMT and DAPK1 methylation was observed in 19% and 89%, respectively, and among methylated and heterozygous patients 29% and 55%, respectively, were biallelically methylated. An association between the T-allele of the rs16906252 SNP and MGMT methylation was observed (p-value = 0.04), and DAPK1 methylation of the A-allele was associated with shorter overall survival (p-value = 0.006). In future cancer research allelic MSP-pyrosequencing may be used to study a wide range of other loci.
The chemokine receptor CCR7 mediates lymphoid dissemination of many cancers, including lymphomas and epithelial carcinomas, thus representing an attractive therapeutic target. Previous results have highlighted the potential of the anti-CCR7 monoclonal antibodies to inhibit migration in transwell assays. The present study aimed to evaluate the in vivo therapeutic efficacy of an anti-CCR7 antibody in a xenografted human mantle cell lymphoma model.