A MALT lymphoma prognostic index Thieblemont, Catherine; Cascione, Luciano; Conconi, Annarita ...
Blood,
09/2017, Volume:
130, Issue:
12
Journal Article
Peer reviewed
Open access
There are no widely accepted prognostic indices for extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). This study aimed to develop and validate a specific prognostic tool ...to personalize and optimize treatment of patients with MALT lymphoma. A prognostic index was built by Cox regression (stepwise selection) using data from 401 patients enrolled in the international randomized International Extranodal Lymphoma Study Group 19 (IELSG-19) trial (NCT 00210353). A validation set, including 633 patients, was obtained by merging 3 independent cohorts of MALT lymphoma patients. The 3 individual features maintaining the greatest prognostic significance for event-free survival (EFS, the main endpoint of the IELSG-19 trial) were age ≥70 years (hazard ratio HR, 1.72; 95% confidence interval CI, 1.26-2.33), Ann Arbor stage III or IV (HR, 1.79; 95% CI ,1.35-2.38), and an elevated lactate dehydrogenase level (HR, 1.87; 95% CI, 1.27-2.77). The prognostic index (MALT-IPI) constructed using these 3 parameters identified 3 groups: low, intermediate, and high risk (corresponding to the presence of 0, 1, or ≥2 of these factors, respectively). The 5-year EFS rates in the low-, intermediate-, and high-risk groups were 70%, 56%, and 29%, respectively. The MALT-lymphoma International Prognostic Index (MALT-IPI) also significantly discriminated between patients with different progression-free, overall, and cause-specific survival. The prognostic utility was retained in gastric and nongastric lymphomas, in each treatment arm (chlorambucil, rituximab, and rituximab plus chlorambucil), and was confirmed in the validation set. The new index, MALT-IPI, is a simple, accessible, and effective tool to identify MALT lymphoma patients at risk of poor outcomes. It may help define appropriate treatment approaches for individual patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background.
The salivary gland is one of the most common sites involved by nongastric, extranodal marginal zone lymphomas of mucosa‐associated lymphoid tissue (MALT). A large series of patients with ...long‐term follow‐up has not been documented. This multicenter, international study sought to characterize the clinical characteristics, treatment, and natural history of salivary gland MALT lymphoma.
Methods.
Patients with biopsy‐confirmed salivary gland MALT lymphoma were identified from multiple international sites. Risk factors, treatment, and long‐term outcomes were evaluated.
Results.
A total of 247 patients were evaluated; 76% presented with limited‐stage disease. There was a history of autoimmune disorder in 41%, with Sjögren disease being the most common (83%). Fifty‐seven percent of patients were initially treated with local therapy with surgery, radiation, or both; 37 of patients were treated with systemic therapy initially, with 47% of those receiving rituximab; and 6% of patients were observed. The median overall survival (OS) was 18.3 years. The median progression‐free survival (PFS) following primary therapy was 9.3 years. There was no difference in the outcomes between patients receiving local or systemic therapy in first‐line management. On multivariate analysis, age <60 years and low to intermediate international prognostic index were associated with improved OS and PFS; Sjögren disease was associated with improved OS.
Conclusion.
Salivary gland MALT lymphoma has an excellent prognosis regardless of initial treatment, and patients with Sjögren disease have improved survival. Risks for long‐term complications must be weighed when determining initial therapy.
Implications for Practice:
Patients with salivary gland extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue (MALT) have an excellent prognosis, particularly those with associated Sjögren's disease. A wide range of available therapies may provide similar durable rates of disease control and survival. Therefore, an important goal in selection of therapy should be to minimize morbidity from treatment. When determining initial therapy for these patients, practitioners should consider the potential side effects and long‐term toxicities of treatment.
This multicenter, international study sought to characterize the clinical characteristics, treatment, and natural history of salivary gland MALT lymphoma in 247 patients. There was no difference in the outcomes between patients receiving local or systemic therapy in first‐line management. On multivariate analysis, age less than 60 years and low to intermediate international prognostic index were associated with improved overall survival and progression‐free survival; Sjögren disease was associated with improved overall survival.
Summary
The study included 1848 diffuse large B‐cell lymphoma (DLBCL)patients treated with chemotherapy/rituximab. The aims were to validate the National Comprehensive Cancer Network International ...Prognostic Index (NCCN‐IPI) and explore the effect of adding high Beta‐2 microglobulin (β2M), primary extranodal presentation and intense treatment to the NCCN‐IPI variables in order to develop an improved index. Comparing survival curves, NCCN‐IPI discriminated better than IPI, separating four risk groups with 5‐year overall survival rates of 93%, 83%, 67% and 49%, but failing to identify a true high‐risk population. For the second aim the series was split into training and validation cohorts: in the former the multivariate model identified age, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, Stage III‐IV, and β2M as independently significant, whereas the NCCN‐IPI‐selected extranodal sites, primary extranodal presentation and intense treatments were not. These results were confirmed in the validation cohort. The Grupo Español de Linfomas/Trasplante de Médula ósea (GELTAMO)‐IPI developed here, with 7 points, significantly separated four risk groups (0, 1–3, 4 or ≥5 points) with 11%, 58%, 17% and 14% of patients, and 5‐year overall survival rates of 93%, 79%, 66% and 39%, respectively. In the comparison GELTAMO IPI discriminated better than the NCCN‐IPI. In conclusion, GELTAMO‐IPI is more accurate than the NCCN‐IPI and has statistical and practical advantages in that the better discrimination identifies an authentic high‐risk group and is not influenced by primary extranodal presentation or treatments of different intensity.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Aims
The clinical implications of the programmed cell death 1 (PD1)/programmed cell death‐ligand 1 (PD‐L1) axis in patients with post‐transplant lymphoproliferative disorders are largely unknown, and ...its association with Epstein–Barr virus (EBV) status and PD‐L1 copy number alterations (CNAs) has not been thoroughly studied.
Methods and results
PD1/PD‐L1 expression was studied in 50 adult post‐transplant lymphoproliferative disorders, and the correlations with PD‐L1 CNAs, EBV, clinicopathological features and outcome were evaluated. Thirty‐seven (74%) cases were classified as diffuse large B‐cell lymphoma (DLBCL), nine (18%) cases were classified as polymorphic, and four (8%) cases were classified as classic Hodgkin lymphoma. Thirty‐four cases were EBV‐positive, with 29 of 34 (85%) having latency II or III, and 15 of 34 (44%) having viral replication. PD‐L1 expression in tumour cells and tumour‐associated macrophages was observed in 30 (60%) and 37 (74%) cases, respectively. PD1 positivity was seen in 16 (32%) cases. PD‐L1 expression was associated with EBV with latency II or III (P = 0.001) and organ rejection (P = 0.04), and, in DLBCL, with non‐germinal centre type DLBCL (P < 0.001). Cases with PD‐L1‐positive tumour cells showed a higher number of PD‐L1 CNAs than PD‐L1‐negative cases (P = 0.001). Patients with EBV/latency III/replication and simultaneous PD‐L1 expression showed the worst overall survival (P < 0.001).
Conclusions
The PD1/PD‐L1 axis is deregulated in post‐transplant lymphoproliferative disorders, with frequent PD‐L1 expression and PD1 negativity. PD‐L1 expression is associated with EBV latency II or III and PD‐L1 CNAs, and probably reflects a proinflammatory tumour microenvironment. The combined analysis of EBV status and PD‐L1 expression may help to identify deeply immunosuppressed patients who can benefit from immune reconstitution approaches.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Electronic cigarette (E-cigarettes) emissions present a potentially new hazard to neonates through inhalation, dermal and oral contact. Exposure to nicotine containing E-cigarettes may cause ...significant systemic absorption in neonates due to the potential for multi-route exposure. Systemic absorption of nicotine and constituents of E-cigarette emissions may adversely impact weight and lung development in the neonate. To address these questions we exposed neonatal mice to E-cigarette emissions and measured systemic cotinine levels and alveolar lung growth.
Neonatal mice were exposed to E-cigarettes for the first 10 days of life. E-cigarette cartridges contained either 1.8% nicotine in propylene glycol (PG) or PG vehicle alone. Daily weights, plasma and urine cotinine levels and lung growth using the alveolar mean linear intercept (MLI) method were measured at 10 days of life and compared to room air controls. Mice exposed to 1.8% nicotine/PG had a 13.3% decrease in total body weight compared to room air controls. Plasma cotinine levels were found to be elevated in neonatal mice exposed to 1.8% nicotine/PG E-cigarettes (mean 62.34± 3.3 ng/ml). After adjusting for sex and weight, the nicotine exposed mice were found to have modestly impaired lung growth by MLI compared to room air control mice (p<.054 trial 1; p<.006 trial 2). These studies indicate that exposure to E-cigarette emissions during the neonatal period can adversely impact weight gain. In addition exposure to nicotine containing E-cigarettes can cause detectable levels of systemic cotinine, diminished alveolar cell proliferation and a modest impairment in postnatal lung growth.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Three-dimensional cell cultures have improved the evaluation of drugs for cancer therapy, due to their high similarity to solid tumors. In melanoma, autophagy appears to show a dual role depending on ...the progression of the disease. p62 protein has been proposed for the evaluation of autophagic flux since its expression is an indicator of the state of autophagy. Pentoxifylline (PTX) and Norcantharidin (NCTD) are drugs that have been shown to possess anticancer effects. In this work, we used B16F1 mouse melanoma cells in two-dimensional (2D) monolayer cultures and three-dimensional (3D) spheroids to test the effect of PTX and NCTD over the p62 expression. We analyzed the effect on p62 expression through Western blot and immunofluorescence assays. Our results indicate that PTX decreases p62 expression in both cell culture models, while Norcantharidin increases its expression in 3D cultures at 24 h. Therefore, these drugs could have a potential therapeutic use for the regulation of autophagy in melanoma, depending on the state of evolution of the disease.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Flows of US immigrants are concentrated at the extremes of the skill distribution. We develop a dynamic political economy model consistent with this observation. Individuals care about wages and the ...welfare of their children. Skill types are complementary in production. Voter support for immigration requires that the children of median-voter natives and of immigrants have sufficiently dissimilar skills. We estimate intergenerational transition matrices for skills, as measured by education, and find support for immigration at high and low skills, but not in the middle. In a version with guest worker programs, voters prefer high-skilled immigrants but low-skilled guest workers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•The acetylation helped to obtain biocomposites with improved functional properties.•Biocomposites mechanical properties were enhanced by increasing the fiber until 12%.•The acetylation of both ...starch and fiber improved the biocomposites water resistance.•All the treatments were biodegradable, but maintained their stability for 5 weeks.•Microstructural analysis evidenced the chemical modification and interactions.
Fiber-reinforced starch-based biocomposites provide an environmentally friendly alternative to replace petroleum-based plastics. Nevertheless, these materials present structural stability problems owing to their hydrophilicity. Therefore, a chemical modification is usually necessary. Hence, the aim of this research is to obtain biocomposites based on acetylated corn starch (AS), acetylated sugarcane fiber (AcSF) and glycerol. Also, to assess the AcSF content (FC, 0.0–20.0%) and glycerol content (GC, 20.0–30.0%) on their physical, mechanical and microstructural properties. A single-screw extruder and central composite rotatable design were employed. Due to acetylation and possible interaction between matrix-fiber, there was an improvement in water resistance; while the mechanical properties were enhanced by increasing FC up to 12.0%. Biodegradability recorded a range of 24.2–39.3%. Microstructural analysis evidenced the extrusion process effect, chemical modification and new interactions formation. It was found that an optimum blend was of FC = 12.0% and GC = 24.0%. The acetylation of both sugarcane fiber and corn starch allowed us to obtain eco-friendly materials with good mechanical properties and water resistance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aims
Mantle cell lymphoma (MCL) is a heterogeneous disease with an aggressive behaviour in most cases, which is associated with expression of sex determining region‐Y‐box11 (SOX11). Experimental ...studies have shown that SOX11 expression is associated with an angiogenic switch characterised by increased expression of angiogenic‐related signatures and vascularisation of murine tumours. However, the relationship between angiogenesis and SOX11 expression in primary tumours is not well understood. Therefore, the aim of this study was to evaluate the development of microvascular angiogenesis in primary MCL in relation to SOX11 expression and its potential prognostic value.
Methods and results
Fifty‐six patients diagnosed with MCL, 38 SOX11‐positive and 18 SOX11‐negative, were studied. The relative intratumoral microvascular area (MVA) and microvessel density (MVD) (number of intratumoral microvessels/μm2) were measured on CD34‐stained slides using a computerised image analysis system. SOX11‐positive MCL showed a significant higher microvascular development than negative tumours (median MVA = 14.5 × 10−3 versus 5.0 × 10−3 P < 0.001; median MVD = 18.6/μm2 versus 14.2/μm2, P = 0.021). Analysing the MVA and MVD as continuous variables, a high MVD was associated with shorter overall survival (P = 0.004), and a similar tendency was observed for high MVA (P = 0.064). The microvascular development was not related to the Ki‐67 proliferative index or 17p/TP53, 9p or 11q alterations.
Conclusions
These findings suggest that SOX11 promotes an angiogenic phenotype in primary MCL, which may contribute to the more aggressive behaviour of these tumours.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Locally advanced rectal cancers are treated with neoadjuvant chemoradiation therapy followed by surgery. In a minority (~20%) of patients, no tumor is present at the time of surgery; these patients ...with a complete pathologic response (pathCR) to neoadjuvant therapy have better treatment outcomes. Unfortunately, the inherent radioresistance of colorectal cancer (CRC) cells dictates that the majority of patients do not achieve a pathCR. Efforts to improve these odds have fueled the search for novel, relatively less‐toxic radiosensitizers with distinct molecular mechanism(s) and broad‐spectrum anticancer activities. Here, we use zerumbone, a sesquiterpene from the edible ginger (Zingiber zerumbet Smith), to enhance radiosensitivity of CRC cells. Short exposure to zerumbone (7 h) profoundly sensitized CRC cells, independent of their p53 or k‐RAS status. Zerumbone enhanced radiation‐induced cell cycle arrest (G2/M), increased radiation‐induced apoptosis, but induced little apoptosis by itself. Zerumbone significantly enhanced radiation‐induced DNA damage, as evident by delayed resolution of post‐irradiation nuclear γH2AX foci, whereas zerumbone treatment alone did not induce γH2AX foci formation. Zerumbone pretreatment inhibited radiation‐induced nuclear expression of DNA repair proteins ataxia‐telangiectasia mutated (ATM) and DNA‐PKcs. Interestingly, zerumbone‐mediated radiosensitization did not involve reactive oxygen species (ROS), but was mediated through depletion of cellular glutathione (GSH). Ability of only thiol‐based antioxidants to abrogate zerumbone‐mediated radiosensitization further corroborated this hypothesis. The α,β‐unsaturated carbonyl group in zerumbone was found to be essential for its bioactivity as zerumbone analog α‐Humulene that lacks this functional group, could neither radiosensitize CRC cells, nor deplete cellular GSH. Our studies elucidate novel mechanism(s) of zerumbone's ability to enhance CRC radiosensitivity.
Though sesquiterpene zerumbone has been shown to have antiproliferative and anticarcinogenic activities in colorectal cancer (CRC); no reports document its potential for and mechanism of CRC radiosensitization. Our studies, for the first time show potent radiosensitizing properties of zerumbone in CRC cells, and also for the first time report zerumbone's ability to enhance radiation‐induced DNA damage. This study suggests a novel cellular glutathione‐dependent mechanism of radiosensitization that is independent of reactive oxygen species generation.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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