Lymphopenia and tumor-associated macrophages are negative prognostic factors for survival in classical Hodgkin's lymphoma. We, therefore, studied whether the peripheral blood absolute lymphocyte ...count/absolute monocyte count ratio at diagnosis affects survival in classical Hodgkin's lymphoma.
We studied 476 consecutive patients with classical Hodgkin's lymphoma followed at the Mayo Clinic from 1974 to 2010. Receiver operating characteristic curves and area under the curve were used to determine cut-off values for the absolute lymphocyte count/absolute monocyte count ratio at diagnosis, while proportional hazards models were used to compare survival based on the absolute lymphocyte count/absolute monocyte count ratio at diagnosis.
The median follow-up period was 5.6 years (range, 0.1-33.7 years). An absolute lymphocyte count/absolute monocyte count ratio at diagnosis of 1.1 or more was the best cut-off value for survival with an area under the curve of 0.91 (95% confidence interval, 0.86 to 0.96), a sensitivity of 90% (95% confidence interval, 85% to 96%) and specificity of 79% (95% confidence interval, 73% to 88%). Absolute lymphocyte count/absolute monocyte count ratio at diagnosis was an independent prognostic factor for overall survival (hazard ratio, 0.18; 95% confidence interval, 0.08 to 0.38, P<0.0001); lymphoma-specific survival (hazard ratio, 0.10; 95% confidence interval, 0.04 to 0.25, P<0.0001); progression-free survival (hazard ratio, 0.35; 95% confidence interval, 0.18 to 0.66, P<0.002) and time to progression (hazard ratio, 0.27; 95% confidence interval, 0.17 to 0.57, P<0.0006).
The ratio of absolute lymphocyte count/absolute monocyte count at diagnosis is an independent prognostic factor for survival and provides a single biomarker to predict clinical outcomes in patients with classical Hodgkin's lymphoma.
Purpose
This study sought to characterize transformation incidence and outcome for patients with follicular lymphoma (FL) in a prospective observational series begun after diffusion of rituximab use.
...Patients and Methods
Patients with newly diagnosed FL were prospectively enrolled onto the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource from 2002 to 2009. Patients were actively followed for re-treatment, clinical or pathologic transformation, and death. Risk of transformation was analyzed via time to transformation by using death as a competing risk.
Results
In all, there were 631 patients with newly diagnosed grade 1 to 3a FL who had a median age at enrollment of 60 years. At a median follow-up of 60 months (range, 11 to 110 months), 79 patients had died, and 60 patients developed transformed lymphoma, of which 51 were biopsy proven. The overall transformation rate at 5 years was 10.7%, with an estimated rate of 2% per year. Increased lactate dehydrogenase was associated with increased risk of transformation. Transformation rate at 5 years was highest in patients who were initially observed and lowest in patients who initially received rituximab monotherapy (14.4% v 3.2%; P = .021). Median overall survival following transformation was 50 months and was superior in patients with transformation greater than 18 months after FL diagnosis compared with patients with earlier transformation (5-year overall survival, 66% v 22%; P < .001).
Conclusion
Follicular transformation rates in the immunochemotherapy era are similar to risk of death without transformation and may be lower than reported in older series. Post-transformation prognosis is substantially better than described in older series. Initial management strategies may influence the risk of transformation.
Bleomycin pulmonary toxicity (BPT) has been well described in Hodgkin's lymphoma (HL) patients treated with bleomycin-containing chemotherapy regimens. The influence of this pulmonary complication, ...along with the omission of bleomycin from further chemotherapy, on overall survival (OS) and progression-free survival (PFS) in HL remains unclear. We reviewed our experience with BPT in HL to better delineate outcome and appropriate treatment in these patients.
One hundred forty-one patients who were treated with bleomycin-containing chemotherapy for newly diagnosed HL between January 1986 and February 2003 were eligible for this retrospective review. BPT was defined by the presence of pulmonary symptoms, bilateral interstitial infiltrates, and no evidence of an infectious etiology.
BPT was observed in 18% of patients. Increasing age, doxorubicin, bleomycin, vinblastine, and dacarbazine as initial therapy, and granulocyte colony-stimulating factor use were associated with the development of BPT. Patients with BPT had a median 5-year OS rate of 63% v 90% (P = .001) in unaffected patients. The mortality rate from BPT was 4.2% in all patients and 24% in patients who developed the pulmonary syndrome. BPT incidence and mortality were highest in patients older than 40 years. The omission of bleomycin had no impact on obtaining a complete remission, PFS, or OS.
BPT results in a significant decrease in 5-year OS in patients who are treated for HL. Age > or = 40 years seems to add substantially to the risk. In patients who do not die from acute pulmonary toxicity, both OS and PFS seem equal, despite the omission of bleomycin.
Everolimus is an oral agent that targets the mammalian target of rapamycin (mTOR) pathway. This study investigated mTOR pathway activation in T-cell lymphoma (TCL) cell lines and assessed antitumor ...activity in patients with relapsed/refractory TCL in a phase 2 trial. The mTOR pathway was activated in all 6 TCL cell lines tested and everolimus strongly inhibited malignant T-cell proliferation with minimal cytotoxic effects. Everolimus completely inhibited phosphorylation of ribosomal S6, a raptor/mTOR complex 1 (mTORC1) target, without a compensatory activation of the rictor/mTORC2 target Akt (S475). In the clinical trial, 16 patients with relapsed TCL were enrolled and received everolimus 10 mg by mouth daily. Seven patients (44%) had cutaneous (all mycosis fungoides); 4 (25%) had peripheral T cell not otherwise specified; 2 (13%) had anaplastic large cell; and 1 each had extranodal natural killer/T cell, angioimmunoblastic, and precursor T-lymphoblastic leukemia/lymphoma types. The overall response rate was 44% (7/16; 95% confidence interval CI: 20% to 70%). The median progression-free survival was 4.1 months (95% CI, 1.5-6.5) and the median overall survival was 10.2 months (95% CI, 2.6-44.3). The median duration of response for the 7 responders was 8.5 months (95% CI, 1.0 to not reached). These studies indicate that everolimus has antitumor activity and provide proof-of-concept that targeting the mTORC1 pathway in TCL is clinically relevant. This trial was registered at www.clinicaltrials.gov as #NCT00436618.
•The mTOR pathway is constitutively activated in the TCL cells and is responsible for TCL proliferation.•This is first trial to demonstrate that mTORC1 inhibitors (everolimus) have substantial antitumor activity (44% overall response rate) in patients with relapsed TCL.
Renal proximal tubule injury is induced by agents/conditions known to cause endoplasmic reticulum (ER) stress, including cyclosporine A (CsA), an immunosuppressant drug with nephrotoxic effects. ...However, the underlying mechanism by which ER stress contributes to proximal tubule cell injury is not well understood. In this study, we report lipid accumulation, sterol regulatory element-binding protein-2 (SREBP-2) expression, and ER stress in proximal tubules of kidneys from mice treated with the classic ER stressor tunicamycin (Tm) or in human renal biopsy specimens showing CsA-induced nephrotoxicity. Colocalization of ER stress markers 78-kDa glucose regulated protein (GRP78), CHOP with SREBP-2 expression and lipid accumulation was prominent within the proximal tubule cells exposed to Tm or CsA. Prolonged ER stress resulted in increased apoptotic cell death of lipid-enriched proximal tubule cells with colocalization of GRP78, SREBP-2, and Ca(2+)-independent phospholipase A(2) (iPLA(2)β), an SREBP-2 inducible gene with proapoptotic characteristics. In cultured HK-2 human proximal tubule cells, CsA- and Tm-induced ER stress caused lipid accumulation and SREBP-2 activation. Furthermore, overexpression of SREBP-2 or activation of endogenous SREBP-2 in HK-2 cells stimulated apoptosis. Inhibition of SREBP-2 activation with the site-1-serine protease inhibitor AEBSF prevented ER stress-induced lipid accumulation and apoptosis. Overexpression of the ER-resident chaperone GRP78 attenuated ER stress and inhibited CsA-induced SREBP-2 expression and lipid accumulation. In summary, our findings suggest that ER stress-induced SREBP-2 activation contributes to renal proximal tubule cell injury by dysregulating lipid homeostasis.
Abstract
A limitation of the prognostic factor peripheral blood absolute lymphocyte/monocyte ratio (ALC/AMC) at diagnosis in diffuse large B-cell lymphoma (DLBCL) is its inability to sequentially ...assess the host/tumor microenvironment interaction and clinical outcomes during treatment. Therefore, we studied the ALC/AMC ratio at each rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) cycle as a predictor for survival. We studied 107 consecutive patients with DLBCL diagnosed, treated only with R-CHOP and followed at the Mayo Clinic. Unsupervised hierarchical clustering identified four clusters based on the patterns of ALC/AMC ratio recovery during cycles. The most inferior survival was seen in the cluster with ALC/AMC ratio < 1.1 in all cycles. By multivariate analysis, ALC/AMC ratio < 1.1 during all cycles was an independent predictor for inferior overall survival and progression-free survival. The ALC/AMC ratio during R-CHOP cycles predicts survival and provides a platform to develop therapeutic modalities to manipulate the ALC/AMC ratio during R-CHOP cycles to improve DLBCL clinical outcomes.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Low-density lipoprotein cholesterol (LDL-C) is an important indicator in the development and management of atherosclerotic cardiovascular disease (ASCVD). Herein, we describe the management of LDL-C ...with lipid-lowering therapy, among patients diagnosed with clinical ASCVD in Alberta, Canada.
A retrospective study was conducted by linking multiple health system databases to examine clinical characteristics, treatments, and LDL-C assessments. Patients with ASCVD were identified using a specific case definition on the basis of International Classification of Diseases, Ninth Revision, Clinical Modification/International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Canada codes between 2011 and 2015. LDL-C was assessed at the first measurement (index test) and second measurement (follow-up test) during the study period. LDL-C levels were evaluated on the basis of the 2016 Canadian Cardiovascular Society guideline recommendations for achieving < 2.0 mmol/L or a 50% reduction. Statin therapies were categorized as low-, moderate-, and high-intensity.
Among the 281,665 individuals identified with ASCVD during the study period, 219,488 (77.9%) had an index LDL-C test, whereas 120,906 (55.1%) and 144,607 (65.9%) were prescribed lipid-lowering therapy before and after their index test, respectively. Most patients who received any lipid-lowering therapy were receiving moderate-/high-intensity statins (n = 133,029; 60.6%). Among the study cohort who had 2 LDL-C tests (n = 91,841; 32.6%), 48.5% of patients who received any lipid-lowering therapy did not achieve LDL-C levels < 2.0 at index date, whereas 36.6% did not achieve LDL-C levels < 2.0 or a 50% reduction at the follow-up test.
The current study revealed that only two-thirds of patients with ASCVD were receiving pharmacotherapy and of those, a significant proportion did not reach recommended LDL-C levels. A remarkable treatment gap was identified for at-risk ASCVD patients. Further implementation strategies are required to address this undermanagement.
Le cholestérol à lipoprotéines de faible densité (cholestérol LDL) est un indicateur important du développement et de la prise en charge de la maladie cardiovasculaire athérosclérotique (MCVAS). Par la présente, nous décrivons la prise en charge du cholestérol LDL à l’aide d’un traitement hypolipémiant chez les patients de l’Alberta, au Canada, qui ont reçu un diagnostic clinique de MCVAS.
Nous avons réalisé une étude rétrospective en procédant au couplage des multiples bases de données du système de santé pour examiner les caractéristiques cliniques, les traitements et les évaluations du cholestérol LDL. Nous avons repéré les patients ayant une MCVAS grâce à une définition particulière de cas selon la Classification internationale des maladies, 9e révision, modification clinique, et la Classification statistique internationale des maladies et des problèmes de santé connexes, 10e révision, adaptation canadienne, entre 2011 et 2015. Nous avons évalué les taux de cholestérol LDL à la première mesure (analyse de référence) et à la deuxième mesure (analyse de suivi) durant la période étudiée. Nous avons évalué les taux de cholestérol LDL en nous basant sur les recommandations des lignes directrices de la Société canadienne de cardiologie de 2016 en vue d’obtenir des concentrations < 2,0 mmol/l ou une réduction de 50 %. Nous avons regroupé les traitements par statines en catégories d’intensité, c’est-à-dire faible, modérée et élevée.
Parmi les 281 665 individus considérés atteints de la MCVAS durant la période étudiée, 219 488 (77,9 %) avaient une analyse de référence de cholestérol LDL, alors que 120 906 (55,1 %) et 144 607 (65,9 %) se faisaient prescrire respectivement avant et après leur analyse de référence un traitement hypolipémiant. La plupart des patients qui ne recevaient aucun traitement hypolipémiant recevaient des statines d’intensité modérée ou élevée (n = 133 029; 60,6 %). Parmi la cohorte étudiée qui subissait 2 analyses de cholestérol LDL (n = 91 841; 32,6 %), 48,5 % des patients qui ne recevaient aucun traitement hypolipémiant ne parvenaient pas à obtenir des concentrations de cholestérol LDL < 2,0 à la date de référence, alors que 36,6 % ne parvenaient pas à obtenir des concentrations de cholestérol LDL < 2,0 ou une réduction de 50 % à l’analyse de suivi.
La présente étude a révélé que seuls les deux tiers des patients atteints de MCVAS recevaient une pharmacothérapie et, parmi ces derniers, une proportion importante ne parvenait pas à obtenir les concentrations de cholestérol LDL recommandées. Nous avons noté des écarts de traitement considérables entre les patients exposés au risque de MCVAS. D’autres stratégies de mise en œuvre sont requises pour remédier à cette prise en charge inadéquate.
A number of reports have shown a propensity of nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) to transform into diffuse large B-cell lymphoma (DLBCL). Long-term data on the incidence and ...outcomes of transformed NLPHL are lacking. A comprehensive analysis of the actively maintained Mayo Clinic Lymphoma Database was performed. Between 1970 and 2011, 222 consecutive adult patients with new untreated NLPHL were identified. Median age at diagnosis was 40 years, and 146 (66%) were males. The median follow-up was 16 years. Seventeen patients (7.6%) developed a transformation to DLBCL. The median time to transformation was 35 months (range, 6-268 months). Based on the observed 17 transformations during 2304 patient-years of follow-up, the rate of transformation was 0.74 per 100 patient-years. In a multivariate analysis, use of any prior chemotherapy (P = .04) and splenic involvement (P = .03) were significantly associated with increased risk of transformation. The 5-year overall survival (OS) in those with transformed disease was 76.4%, and transformation did not adversely affect OS when compared with patients who did not experience transformation. In this large single-institution cohort with long-term follow-up, the risk of transformation was lower than that observed in other low-grade lymphomas.
•The risk of transformation of NLPHL to DLBCL is 0.74 per 100 patient-years of follow-up.•Risk factors for transformation include prior exposure to chemotherapy and splenic involvement at time of diagnosis.
Cellular cholesterol homeostasis is a fundamental and highly regulated process. Transcription factors known as sterol regulatory element binding proteins (SREBPs) coordinate the expression of many ...genes involved in the biosynthesis and uptake of cholesterol. Dysregulation of SREBP activation and cellular lipid accumulation has been associated with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). This review will provide an overview of ER stress and the UPR as well as cholesterol homeostasis and SREBP regulation, with an emphasis on their interaction and biological relevance.
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