RESUMEN
Post-transplantation lymphoproliferative disorders (PTLD) are associated with poor patient and graft survival. The risk of rejection and subsequent graft loss are increased by the reduction of immunosuppression therapy, the cornerstone of PTLD treatment. This multicentre, retrospective, nonrandomized cohort study includes 104 adults who developed PTLD after renal or simultaneous renal/pancreatic transplantation between 1990 and 2007. It examines the effect of calcineurin inhibitor (CNI) withdrawal on long-term graft and patient survival. At 10 years postonset of PTLD, the Kaplan-Meier graft loss rate was 43.9% and graft loss or death with functioning graft was 64.4%. Cox multivariate analysis determined risk factors of graft loss as PTLD stage greater than I-II and CNI withdrawal, and for graft loss and mortality, these remained risk factors along with age over 60 years. Type and location of PTLD, year of diagnosis, and chemotherapy regime were not independent risk factors. Multivariate analysis determined CNI withdrawal as the most important risk factor for graft loss (HR = 3.07, CI 95%: 1.04-9.09; P = 0.04) and death (HR: 4.00, CI 95%: 1.77-9.04; P < 0.001). While long-term stable renal function after definitive CNI withdrawal for PTLD has been reported, this review determined that withdrawal is associated with reduced graft and patient survival.
Asunto(s)
Inhibidores de la Calcineurina/efectos adversos , Infecciones por Virus de Epstein-Barr/etiología , Inmunosupresores/efectos adversos , Trasplante de Riñón , Trastornos Linfoproliferativos/etiología , Complicaciones Posoperatorias/etiología , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/uso terapéutico , Inhibidores de la Calcineurina/administración & dosificación , Inhibidores de la Calcineurina/uso terapéutico , Creatina/sangre , Sustitución de Medicamentos , Infecciones por Virus de Epstein-Barr/mortalidad , Infecciones por Virus de Epstein-Barr/patología , Infecciones por Virus de Epstein-Barr/terapia , Femenino , Francia/epidemiología , Tasa de Filtración Glomerular , Rechazo de Injerto/epidemiología , Rechazo de Injerto/etiología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Humanos , Huésped Inmunocomprometido , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Riñón/fisiopatología , Trastornos Linfoproliferativos/mortalidad , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/terapia , Masculino , Persona de Mediana Edad , Trasplante de Páncreas , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/patología , Complicaciones Posoperatorias/terapia , Modelos de Riesgos Proporcionales , Radioterapia Adyuvante , Diálisis Renal , Insuficiencia Renal/etiología , Insuficiencia Renal/mortalidad , Insuficiencia Renal/terapia , Estudios Retrospectivos , Factores de Riesgo , Rituximab , Adulto JovenRESUMEN
AIMS: Ductal carcinoma (DC) of the prostate is an entity distinct from the common acinar cancer (AC), both on clinical and morphological aspects. We aimed to analyze the expression of molecules involved in either hormonal signalling or androgen independent pathways, in DC compared to high grade AC. METHODS AND RESULTS: A tissue microarray was constructed with samples from 24 cases of DC and 27 cases of high grade AC. Immunohistochemistry was performed using antibodies directed against: Ki67; androgen receptor (AR); PSA; 5alpha-reductase 1, 2, 3; oestrogen receptors alpha and beta (ERA and ERB); aromatase; Alpha keto reductase 1C3; Squalene epoxidase (SQLE); BCAR1; Src. Cell proliferation and ERB staining were significantly increased in DC compared to AC. In contrast, the expressions of enzymes SQLE, aromatase, and 5 alpha reductase 2, were higher in AC. Staining for BCAR1 and Src, markers associated with androgen-independent pathways, was increased in DC compared to AC. These differences remained significant after adjusting for pTNM stage. CONCLUSIONS: These results suggest that the hormone related molecular pathways that drive cancer progression might be different in AC and DC. The decrease in steroid synthesis related enzymes, together with up-regulation of the BCAR1-Src pathway, emphasizes the biological particularities of DC.
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Carcinoma de Células Acinares/patología , Carcinoma Ductal/patología , Próstata/patología , Neoplasias de la Próstata/patología , Carcinoma de Células Acinares/inmunología , Carcinoma de Células Acinares/metabolismo , Carcinoma Ductal/inmunología , Carcinoma Ductal/metabolismo , Proteína Sustrato Asociada a CrK/genética , Proteína Sustrato Asociada a CrK/metabolismo , Genes src , Humanos , Inmunohistoquímica , Inmunofenotipificación , Masculino , Próstata/metabolismo , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Transducción de Señal , Regulación hacia ArribaRESUMEN
Preservation of fertility has become a growing concern in young females with Hodgkin lymphoma (HL). However, the rate of pregnancy after the current most frequently prescribed ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and darcarbazine) chemotherapy for HL has rarely been studied. In this study, we aim to determine the impact of ABVD on the fertility of women treated for HL. We conducted a noninterventional, multicenter study of female patients of childbearing age who were treated for HL. Two healthy apparied women nonexposed to chemotherapy (our controls) were assigned for each patient. Fertility was assessed by the number of pregnancies and births after HL treatment. Sixty-seven patients were included. The median age at diagnosis was 24.4 years (range, 16-43). HL was a localized disease for 68.7%. Of all the patients, 53.7% started at least 1 pregnancy after treatment vs 54.5% of the controls (P = .92). Of all the patients who desired children, 81% had at least 1 pregnancy. Patients treated with ABVD did not have a longer median time to pregnancy (4.8 years in the group of patients and 6.8 years for controls). Across patients, there were 58 pregnancies and 48 births (ratio, 1:2) and 136 pregnancies and 104 births (ratio, 1:3) for the control cohort. No increase in obstetric or neonatal complications has been reported in HL in our study. The number of pregnancies, births, and the time to start a pregnancy in young women treated with ABVD for HL is not different from that of controls. Therefore, females with HL treated with ABVD should be reassured regarding fertility.
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Enfermedad de Hodgkin , Embarazo , Niño , Recién Nacido , Humanos , Femenino , Adolescente , Adulto Joven , Adulto , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/tratamiento farmacológico , Vinblastina/efectos adversos , Bleomicina/efectos adversos , Dacarbazina/efectos adversos , Doxorrubicina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , FertilidadRESUMEN
BACKGROUND: Trephine bone marrow biopsy (BMB) in internal medicine has only been studied in fever of unknown origin and inflammation of unknown origin. The aim was to assess BMB diagnostic yield according to main indications and patient characteristics in internal medicine. Quality of BMB and contribution of bone marrow aspiration (BMA) to BMB were also analyzed. METHODS: BMB performed in the internal medicine department of Poitiers university hospital between January 2000 and December 2015 were retrospectively analyzed. Patient characteristics, BMB indications, quality parameters, and results were collected from medical records. Contributive BMB was BMB allowing accurate final diagnosis. Diagnostic yield was the proportion of contributive BMB among total BMB performed. RESULTS: A total of 468 BMBs conducted for primary diagnostic purpose from 468 patients were analyzed. Cytopenia(s) and the indication 'adenopathy and/or splenomegaly and/or hepatomegaly' represented 70% of the indications. Overall BMB diagnostic yield was 32.7%, lymphoma being the main histologic finding (31%). Among indications, cytopenia(s) had the highest diagnostic yield (49.1%). Isolated fever of unknown origin had low diagnostic yield (5.6%). Factors independently associated with contributive BMB were: anemia, neutropenia, circulating immature granulocytes or blasts, monoclonal gammopathy, period of BMB processing, quality of BMB, and immunohistochemestry (IHC) analysis. Concomitant BMA improved diagnostic yield by 5.5%, mostly for myelodysplastic syndromes. CONCLUSION: Cytopenia(s), blood cythemias and monoclonal gammopathy are indications with the highest diagnostic yield. Concomitant BMA and IHC analysis should be systematically performed to increase BMB diagnostic yield in internal medicine.
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Biopsia/métodos , Médula Ósea/patología , Medicina Interna/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Primary or secondary immune deficiency (ID) is a risk factor, although rare, to develop Waldenström macroglobulinemia (WM). We aimed to better understand the incidence of this occurrence in the real-life and the outcome of either entity. We conducted a review of 194 WM in the Poitou-Charentes registry and identified 7 (3.6%) with a prior history of ID. Across the 7 WM with ID, 4 progressed to active WM disease and required treatment for WM with a median time between WM diagnosis and the first treatment of 1.5 years (range 0-3). The median time from ID to WM occurrence was 8 years (1-18). WM could develop from ID, although a rare event. Our first action was to systematically decrease immunosuppression with long-term control of ID. Half of indolent WM remained indolent despite ID and for remaining WM none appeared of poor risk WM.
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Síndromes de Inmunodeficiencia , Linfoma de Células B , Macroglobulinemia de Waldenström , Humanos , Incidencia , Macroglobulinemia de Waldenström/diagnóstico , Macroglobulinemia de Waldenström/epidemiologíaRESUMEN
BACKGROUND: The current pathological tumour-node-metastasis (pTNM) classification for upper tract urothelial carcinoma (UTUC) does not include any risk stratification of pT3 renal pelvicalyceal tumours. OBJECTIVE: To assess the prognostic impact of pT3 subclassification in a multicentre cohort of patients with UTUC of the renal pelvicalyceal system undergoing radical nephroureterectomy (RNU). DESIGN, SETTING, AND PARTICIPANTS: Data from all consecutive patients treated with RNU for pT3 renal pelvicalyceal UTUC at 14 French centres from 1995 to 2013 were reviewed retrospectively. INTERVENTION: A central pathology review (CPR) was used to stratify pT3 patients into those with infiltration of the renal parenchyma on a microscopic level (pT3a) versus those with infiltration of the renal parenchyma visible on gross inspection of the resection specimen and/or invasion of peripelvic fat (pT3b). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Inverse probability weighting (IPW)-adjusted Cox regression analyses were used to compare recurrence-free survival (RFS) and cancer-specific survival (CSS) between pT3a and pT3b patients. RESULTS AND LIMITATIONS: Overall, 202 patients were included and further stratified into pT3a (n = 98; 48.5%) and pT3b (n = 104; 51.5%) subgroups. Median time to follow-up in the weighted population was 68 (interquartile range, 50-95) mo. In IPW-adjusted Cox regression analyses, pT3b versus pT3a substage was associated with a significant adverse effect on RFS (hazard ratio [HR] = 2.02; 95% confidence interval [CI] = [1.36-3.01]; p < 0.001) and CSS (HR = 1.84; 95% CI = [1.20-2.82]; p = 0.005). The study is limited by its retrospective design. CONCLUSIONS: Using IPW-adjusted analyses after the CPR, we observed that RNU patients with pT3b renal pelvicalyceal UTUC had adverse prognosis as compared with those with pT3a disease. As such, this subclassification could help refine the current pTNM system for UTUC. PATIENT SUMMARY: In this report, we looked at the prognostic interest of stratifying patients with pT3 renal pelvicalyceal upper tract urothelial carcinoma based on the extent of local invasion. We found that those with extensive infiltration (pT3b) had adverse prognosis as compared with those with limited infiltration (pT3a). This information could be provided on pathology reports to further guide clinical decision making.
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Carcinoma de Células Transicionales , Neoplasias Renales , Neoplasias de la Vejiga Urinaria , Carcinoma de Células Transicionales/patología , Humanos , Neoplasias Renales/patología , Estadificación de Neoplasias , Nefroureterectomía , Pronóstico , Puntaje de Propensión , Estudios Retrospectivos , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Lymphoplasmocytic lymphona with monoclonal lgM, rare. Median age at diagnosis 70 years old, frail population. Heterogenous clinic presentation. Molecular diagnosis with MYD88. Treatment required for symptomatic WM patients only. 1st line therapy: DRC. Input of targeted therapies (ibrutinib) for frail patients, maintenance effect.
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Macroglobulinemia de Waldenström , Adenina/análogos & derivados , Edad de Inicio , Anciano , Análisis Mutacional de ADN/métodos , Anciano Frágil , Humanos , Técnicas de Diagnóstico Molecular/métodos , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/tendencias , Factor 88 de Diferenciación Mieloide/genética , Piperidinas , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Macroglobulinemia de Waldenström/diagnóstico , Macroglobulinemia de Waldenström/epidemiología , Macroglobulinemia de Waldenström/genética , Macroglobulinemia de Waldenström/terapiaRESUMEN
Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease treated with anti-CD20-based immuno-chemotherapy (R-CHOP). We identified that low levels of GAPDH predict a poor response to R-CHOP treatment. Importantly, we demonstrated that GAPDHlow lymphomas use OxPhos metabolism and rely on mTORC1 signaling and glutaminolysis. Consistently, disruptors of OxPhos metabolism (phenformin) or glutaminolysis (L-asparaginase) induce cytotoxic responses in GAPDHlow B cells and improve GAPDHlow B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDHhigh B cell lymphomas. Ultimately, we selected four GAPDHlow DLBCL patients, who were refractory to all anti-CD20-based therapies, and targeted DLBCL metabolism using L-asparaginase (K), mTOR inhibitor (T), and metformin (M) (called KTM therapy). Three out of the four patients presented a complete response upon one cycle of KTM. These findings establish that the GAPDH expression level predicts DLBCL patients' response to R-CHOP treatment and their sensitivity to specific metabolic inhibitors.
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Antimetabolitos Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Gliceraldehído-3-Fosfato Deshidrogenasas/genética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Células Cultivadas , Estudios de Cohortes , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Gliceraldehído-3-Fosfato Deshidrogenasas/metabolismo , Células HEK293 , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Prednisona/uso terapéutico , Pronóstico , Estudios Retrospectivos , Rituximab/uso terapéutico , Resultado del Tratamiento , Vincristina/uso terapéutico , Adulto JovenRESUMEN
PURPOSE: Predictive factors for biochemical recurrence (BCR) in localized prostate cancer (PCa) after brachytherapy are insufficient to date. Cellular radiosensitivity depends on DNA double-strand breaks, mainly repaired by the nonhomologous end-joining (NHEJ) system. We analyzed whether the expression of NHEJ proteins can predict BCR in patients treated by brachytherapy for localized PCa. METHODS AND MATERIALS: From 983 PCa cases treated by brachytherapy between March 2000 and March 2012, 167 patients with available biopsy material suitable for in situ analysis were included in the study. The median follow-up time was 47 months. Twenty-nine patients experienced BCR. All slides were reviewed to reassess the Gleason score. Expression of the key NHEJ proteins DNA-PKcs, Ku70, and Ku80, and the proliferation marker Ki67, was studied by immunohistochemistry performed on tissue microarrays. RESULTS: The Gleason scores after review (P=.06) tended to be associated with BCR when compared with the score initially reported (P=.74). Both the clinical stage (P=.02) and the pretreatment prostate-specific antigen level (P=.01) were associated with biochemical failure. Whereas the expression of Ku80 and Ki67 were not predictive of relapse, positive DNA-PKcs nuclear staining (P=.003) and higher Ku70 expression (P=.05) were associated with BCR. On multivariate analysis, among pretreatment variables, only DNA-PKcs (P=.03) and clinical stage (P=.02) remained predictive of recurrence. None of the patients without palpable PCa and negative DNA-PKcs expression experienced biochemical failure, compared with 32% of men with palpable and positive DNA-PKcs staining that recurred. CONCLUSIONS: Our results suggest that DNA-PKcs could be a predictive marker of BCR after brachytherapy, and this might be a useful tool for optimizing the choice of treatment in low-risk PCa patients.
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Biomarcadores de Tumor/metabolismo , Braquiterapia/estadística & datos numéricos , Proteína Quinasa Activada por ADN/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/radioterapia , Anciano , Francia/epidemiología , Humanos , Radioisótopos de Yodo/uso terapéutico , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/prevención & control , Prevalencia , Pronóstico , Neoplasias de la Próstata/epidemiología , Radiofármacos/uso terapéutico , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
PURPOSE: Double-strand breaks, the most lethal DNA lesions induced by ionizing radiation, are mainly repaired by the nonhomologous end-joining system. The expression of the nonhomologous end-joining pathway has never been studied in prostate cancer, and its prognostic value for patients undergoing radiotherapy remains unknown. METHODS: Pretreatment biopsies from 238 patients treated with exclusive external beam radiotherapy for localized prostate cancer with ≥ 2 years of follow-up were reviewed to reassess the Gleason score. Of these 238 cases, 179 were suitable for in situ analysis and were included in the tissue microarrays. Expression of the nonhomologous end-joining proteins Ku70, Ku80, DNA-dependent protein kinase, catalytic subunits (DNA-PKcs), and X-ray repair cross complementing 4-like factor was studied by immunohistochemistry, together with the proliferation marker Ki67. RESULTS: The predictive value of the Gleason score for biochemical relapse (using the Phoenix criteria) was markedly improved after review (P<.0001) compared with the initial score (P=.003). The clinical stage, pretreatment prostate-specific antigen level, and perineural invasion status were also associated with progression-free survival (P=.005, P<.0001, and P=.03, respectively). High proliferation (>4%) tends to be associated with biochemical recurrence; however, the difference did not reach statistical significance (P=.06). Although the expression of Ku70, Ku80, and X-ray repair cross complementing 4-like factor was not predictive of relapse, positive DNA-PKcs nuclear staining was closely associated with biochemical recurrence (P=.0002). On multivariate analysis, only the Gleason score, prostate-specific antigen level, and DNA-PKcs status remained predictive of recurrence (P=.003, P=.002, and P=.01, respectively). CONCLUSIONS: The results of the present study highly suggest that DNA-PKcs could be a predictive marker of recurrence after radiotherapy, independently of the classic prognostic markers, including the Gleason score modified after review.
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Proteína Quinasa Activada por ADN/metabolismo , Proteínas de Neoplasias/metabolismo , Recurrencia Local de Neoplasia , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/radioterapia , Anciano , Anciano de 80 o más Años , Antígenos Nucleares/metabolismo , Núcleo Celular/metabolismo , Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades/genética , Enzimas Reparadoras del ADN/metabolismo , Proteínas de Unión al ADN/metabolismo , Supervivencia sin Enfermedad , Humanos , Antígeno Ki-67/metabolismo , Autoantígeno Ku , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Valor Predictivo de las Pruebas , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Análisis de Matrices Tisulares/métodosRESUMEN
Renal failure, mostly related to myeloma cast nephropathy (MCN), is a frequent complication of multiple myeloma (MM), which occurs in up to 50% of patients during the course of the disease. Persistent renal failure in MM is associated with poor survival. Treatment of MCN relies on urgent symptomatic measures (alkalinisation, rehydration, correction of hypercalcemia, and withdrawal of nephrotoxic drugs), with rapid introduction of chemotherapy to efficiently reduce the production of monoclonal light chains (LC). Recent studies suggest that, in patients with MM and severe renal failure due to MCN, rapid removal of circulating LC, through intensive hemodialysis sessions using a new generation high cut-off dialysis membrane, might result in dialysis withdrawal in most patients. If the development of intensive therapy and new efficient chemotherapy agents (thalidomide, bortezomib, lenalidomide) has transformed the care and prognosis of MM, the modalities and safety of these therapeutic regimens in patients with renal failure remain to be defined. The association of bortezomib with dexamethasone should be considered currently as first-line treatment in patients with MM and impaired renal function.