RESUMO
Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV- HIV- PCNSL and 2 EBV- HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV- PCNSL. As with prior studies, EBV- HIV- PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV- PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV- HIV- PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.
Assuntos
Neoplasias do Sistema Nervoso Central/etiologia , Neoplasias do Sistema Nervoso Central/imunologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Linfoma/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/virologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/isolamento & purificação , Humanos , Tolerância Imunológica , Linfoma/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Transcriptoma , Microambiente TumoralRESUMO
BACKGROUND: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial. PATIENTS AND METHODS: The R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged ≥18 years with bulky stage I-IV DLBCL (n = 1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated. RESULTS: 177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX) n = 163, intravenous (IV) MTX n = 2, prophylaxis type unknown n = 11 and IT MTX and cytarabine n = 1). At a median follow-up of 6.5 years, 21 cases of CNS relapse (isolated n = 11, with systemic relapse n = 10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI, >1 extranodal site of disease and presence of a 'high-risk' extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively. CONCLUSION: Despite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence. CLINICALTRIALS.GOV: ISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Sistema Nervoso Central/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Anticorpos Monoclonais Murinos/administração & dosagem , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prednisona/administração & dosagem , Estudos Prospectivos , Rituximab/administração & dosagem , Vincristina/administração & dosagemRESUMO
BACKGROUND: There is an on-going debate whether 2- or 3-weekly administration of R-CHOP is the preferred first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). The UK NCRI R-CHOP14v21 randomized phase 3 trial did not demonstrate a difference in outcomes between R-CHOP-14 and R-CHOP-21 in newly diagnosed DLBCL patients aged 19-88 years, but data on elderly patients have not been reported in detail so far. Here, we provide a subgroup analysis of patients ≥60 years treated on the R-CHOP14v21 trial with extended follow-up. PATIENTS AND METHODS: Six hundred and four R-CHOP14v21 patients ≥60 years were included in this subgroup analysis, with a median follow-up of 77.7 months. To assess the impact of MYC rearrangements (MYC-R) and double-hit-lymphoma (DHL) on outcome in elderly patients, we performed a joint analysis of cases with available molecular data from the R-CHOP14v21 (N = 217) and RICOVER-60 (N = 204) trials. RESULTS: Elderly DLBCL patients received high dose intensities with median total doses of ≥98% for all agents. Toxicities were similar in both arms with the exception of more grade ≥3 neutropenia (P < 0.0001) and fewer grade ≥3 thrombocytopenia (P = 0.05) in R-CHOP-21 versus R-CHOP-14. The elderly patient population had a favorable 5-year overall survival (OS) of 69% (95% CI: 65-73). We did not identify any subgroup of patients that showed differential response to either regimen. In multivariable analysis including individual factors of the IPI, gender, bulk, B2M and albumin levels, only age and B2M were of independent prognostic significance for OS. Molecular analyses demonstrated a significant impact of MYC-R (HR = 1.96; 95% CI: 1.22-3.16; P = 0.01) and DHL (HR = 2.21; 95% CI: 1.18-4.11; P = 0.01) on OS in the combined trial cohorts, independent of other prognostic factors. CONCLUSIONS: Our data support equivalence of both R-CHOP application forms in elderly DLBCL patients. Elderly MYC-R and DHL patients have inferior prognosis and should be considered for alternative treatment approaches. TRIAL NUMBERS: ISCRTN 16017947 (R-CHOP14v21); NCT00052936 (RICOVER-60).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Feminino , Rearranjo Gênico , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Seleção de Pacientes , Medicina de Precisão , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Fatores de Risco , Rituximab , Fatores de Tempo , Resultado do Tratamento , Reino Unido , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
WHAT IS KNOWN AND OBJECTIVE: Human herpesvirus-8 (HHV-8)-positive, HIV-negative multicentric Castleman's disease is a rare lymphoproliferative disorder with no standardized treatment. Concurrent Kaposi's sarcoma, another HHV-8-related disease, is uncommon in HIV-negative patients. The role of antiviral therapy and rituximab in HIV-negative patients is not well established. CASE DESCRIPTION: We report a case of a 5-year, durable remission of HHV-8-positive, HIV-negative comorbid multicentric Castleman's disease and Kaposi's sarcoma treated with long-term valganciclovir, following initial rituximab and liposomal doxorubicin. WHAT IS NEW AND CONCLUSION: Currently, there is no defined role for antiviral therapy in the treatment of HIV-negative HHV-8-positive multicentric Castleman's disease and Kaposi's sarcoma. Ganciclovir followed by indefinite, continuous valganciclovir is thought to have contributed significantly to the durable response in this case.
Assuntos
Antineoplásicos/uso terapêutico , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Doxorrubicina/análogos & derivados , Ganciclovir/análogos & derivados , Rituximab/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Antivirais/uso terapêutico , Hiperplasia do Linfonodo Gigante/virologia , Doxorrubicina/uso terapêutico , Ganciclovir/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por Herpesviridae/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Sarcoma de Kaposi/virologia , ValganciclovirRESUMO
BACKGROUND: Targeting platelet-derived growth factor receptor-ß (PDGFR-ß) is a potential strategy to reduce tumour-related interstitial fluid pressure, enhance cytotoxic drug uptake and reduce chemoresistance. This study aimed to define safe doses of gemcitabine plus oxaliplatin when combined with imatinib (potent PDGFR-ß inhibitor) in patients with advanced gemcitabine-refractory pancreatic cancer (PC). PATIENTS AND METHODS: Using a 3 + 3 dose escalation design, patients of performance status zero or one were entered into five sequential dose levels (DLs) of gemcitabine [day 1, from 400 (DL1) to 1000 mg/m(2) (DL4)] and oxaliplatin [day 2, 85 (DL1-4) and 100 mg/m(2) (DL5)] two weekly. Imatinib 400 mg od was given for 7 days (day minus 2-5) each cycle. RESULTS: Twenty-seven patients received 168 cycles in total. Median age was 61 years (44-74 years). Dose-limiting toxicities occurred in two of two patients at DL5 (G4 thrombocytopenia, G3 lethargy), defined as the maximum tolerated dose and one of six patients at DL4 (G3 lethargy). DL4 was expanded. There were 2 of 27 partial responses and 14 of 27 stable disease [disease control 52%, 95% confidence interval (CI) 32% to 71%]. Median progression-free survival and overall survival were 4.6 (95% CI 2.1-7.0) and 5.6 months (95% CI 2.5-8.7), respectively. CONCLUSION: In gemcitabine-refractory PC, gemcitabine (1000 mg/m(2)) and oxaliplatin (85 mg/m(2)) can be safely combined with imatinib given on a 7 days on and 7 days off intermittent schedule.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Mesilato de Imatinib , Estimativa de Kaplan-Meier , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Pancreáticas/mortalidade , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , GencitabinaRESUMO
Basal and triple-negative breast cancer phenotypes are characterised by unfavourable biological behaviour and outcome. Although certain studies have examined their pathological and molecular profile, the vascular characteristics of lymphatic and blood vessels have not been examined. Immunohistochemical staining with podoplanin, CD34 and CD31 was used to examine lymphatic and microvessel density, as well as vascular invasion in 197 basal-like and in 99 triple-negative breast tumours and compared against 200 non-basal and 334 non-triple-negative cases. All specimens were lymph node negative. Vascular invasion was identified as blood or lymphatic vascular invasion by the differential expression of markers. All measurements were correlated with clinicopathological features and prognosis. No significant difference was detected between the basal and triple-negative groups in terms of lymphatic or microvessel density or vascular invasion. However, both the basal and the triple-negative groups showed significantly higher microvessel density than did the non-basal and non-triple-negative groups (P=0.017 and P<0.001, respectively). Unlike microvessel density, no significant difference was detected in lymphatic density between the basal or triple-negative groups compared with their respective controls. Interestingly, vascular invasion, almost entirely lymphatic invasion, was detected in 27% of the basal and in 26% of the triple-negative groups with no significant difference in comparison with control groups. In both basal and triple negatives, vascular invasion was associated with poorer survival by univariate and multivariate analyses. The 20-year overall survival rate in basal-like tumours was 55% in vascular invasion-positive cases compared with 73% in vascular invasion-negative tumours (P=0.012), and 46% in triple-negative vascular invasion-positive compared with 79% in vascular invasion-negative tumours (P=0.001). Basal-like vs non-basal-like and triple-negative vs non-triple-negative tumours have similar vascular characteristics in terms of lymphatic vessel density and vascular invasion but higher microvessel density, suggesting that such groups may preferentially benefit from anti-angiogenic therapy. Vascular invasion was, in all phenotypes, almost entirely lymphatic vessel invasion and could stratify basal-like and triple-negative phenotypes into distinct prognostic groups.
Assuntos
Vasos Sanguíneos/patologia , Neoplasias da Mama/patologia , Vasos Linfáticos/patologia , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Biomarcadores Tumorais/metabolismo , Vasos Sanguíneos/metabolismo , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Feminino , Humanos , Linfangiogênese , Metástase Linfática , Vasos Linfáticos/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neovascularização Patológica , Prognóstico , Taxa de SobrevidaRESUMO
PURPOSE: There is no standard second-line therapy for patients with oesophagogastric cancer who progress following first-line chemotherapy for advanced disease or relapse following radical multi-modality therapy. The aim of this retrospective study was to evaluate survival following rechallenge with platinum plus fluoropyrimidine (PF) +/- epirubicin. METHODS: Patients treated with PF +/- epirubicin for oesophagogastric cancer at our institution were identified from the electronic prescribing database. Patients rechallenged with PF +/- epirubicin >3 months after completing initial chemotherapy were eligible. Primary endpoint was survival, calculated from day 1 of rechallenge treatment to date of death or last follow-up. Secondary endpoints were progression-free survival and response rate to PF-based re-challenge. RESULTS: Between 2000 and 2008, 950 patients treated with PF +/- epirubicin for oesophagogastric cancer were identified. 298 patients progressed or relapsed >3 months after completing chemotherapy, of whom 106 patients were rechallenged with PF-based chemotherapy. Median progression-free survival and overall survival were 5.1 and 10 months, respectively, from date of rechallenge for patients treated with initial radical intent and 3.9 and 6.6 months, respectively, in patients treated with palliative intent from diagnosis. In a survival analysis, no significant prognostic factors were identified. CONCLUSION: Selected patients with oesophagogastric cancer who relapse or progress >3 months after initial treatment with PF +/- epirubicin may benefit from re-introduction of PF-based chemotherapy.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Intervalo Livre de Doença , Esquema de Medicação , Epirubicina/administração & dosagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Cuidados Paliativos/métodos , Compostos de Platina/administração & dosagem , Pirimidinas/administração & dosagem , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: While potential risks of diagnostic medical radiation are acknowledged, actual exposure of patients in routine clinical practice is poorly documented. AIM: To quantify such exposure to vulnerable abdominal organs in patients with inflammatory bowel disease who are already at risk of intestinal cancer. METHODS: All incidences of exposure to diagnostic medical radiation were documented in a consecutive series of 100 patients with inflammatory bowel disease (62 Crohn's disease, 37 ulcerative colitis, 1 indeterminate colitis) attending a hospital-based clinic. Total effective dose (mSv) was calculated using published tables. Predictors of high or no irradiation were evaluated by multivariate logistic regression analysis. RESULTS: Thirteen patients had no documented diagnostic irradiation. Twenty-three patients received an effective dose greater than 25 mSv. An at-risk effective dose >50 mSv was received by 11 patients. Dosage was higher in patients with Crohn's disease than ulcerative colitis (P = 0.02) and in patients undergoing surgery (P = 0.004). However, no predictive factors for high radiation dosage or for no exposure were identified. CONCLUSIONS: At-risk irradiation from diagnostic medical radiation is common in patients with inflammatory bowel disease, and might potentially contribute to the elevated risk of intra-abdominal and other cancers. The level of irradiation should be considered in clinical decisions regarding abdominal imaging.
Assuntos
Doenças Inflamatórias Intestinais/radioterapia , Neoplasias Induzidas por Radiação/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Relação Dose-Resposta à Radiação , Feminino , Humanos , Doenças Inflamatórias Intestinais/complicações , Masculino , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/prevenção & controle , Doses de Radiação , Medição de Risco/normasRESUMO
BACKGROUND: The advice on hair washing during brain irradiation is aimed at minimizing radiation induced skin toxicity. We performed a prospective randomized trial to assess the effect of advice on scalp care on the local skin reaction in patients undergoing cranial radiotherapy. METHODS: One hundred and nine patients undergoing cranial radiotherapy were randomized into two groups. Patients in group 1 were advised not to wash hair during treatment and patients in group 2 to maintain normal pattern of hair washing. They were assessed weekly over a period of 10 weeks from the start of treatment. Symptoms of pain and itching were recorded using a modified RTOG/EORTC acute skin reaction scoring system and skin reaction was assessed clinically using erythema/desquamation score. The frequency of hair washing and the distress of changing the practice of normal hygiene were recorded on a diary card. Skin reaction scores were compared as a summary measure using area under the curve per week (AUC/week) and median scores, and the differences between groups were assessed by means of the t-test. RESULTS: One hundred and nine patients commencing cranial radiotherapy according to standard protocol were randomized into the trial (group 1, 55 patients; group 2, 54 patients). Patients asked to restrict hair washing, washed at a lower average frequency. There were no significant differences between scores of skin reaction in the two groups for each of the variables measured. CONCLUSIONS: The practice of normal hair washing is not associated with increased severity of adverse skin reaction. As a request to change the pattern of normal hygiene may cause distress, the current advice should be to maintain normal hair washing during cranial radiotherapy.
Assuntos
Neoplasias Encefálicas/radioterapia , Doenças do Cabelo/prevenção & controle , Cabelo/efeitos da radiação , Radiodermite/prevenção & controle , Couro Cabeludo/efeitos da radiação , Higiene da Pele/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta à Radiação , Feminino , Doenças do Cabelo/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
PIP: A case history is reported of the traumatic experience of a woman hospitalized in order to remove her IUD. Sue, the 29-year-old patient who had 2 children (5-1/2 years and 1-1/2 years) had been referred to a gynecological clinic by her general practitioner for IUD removal. 6 weeks prior to her referral she had experienced 2 days of very severe pain and occasional pains since then--sharp, cramping pains that did not radiate and eased off following micturition. The pains were not related to bowels or intercourse. Attempts to remove the copper 7 IUD by the general practitioner and the family planning clinic failed. This was the case even though the strings were visible. Following routine preparation at the day surgery unit, Sue was given a general anesthetic. On examination the pelvic organs were all found to be normal and the strings of the copper 7 IUD were visible. Attempts to remove it with sponge-holding forceps and a curette were interrupted by a sudden vaginal blood loss. The laparoscope was introduced and a large hematoma of the right broad ligament was visible. Laparotomy through a lower midline incision was performed, and it was found that the IUD had perforated the right wall of the uterus. The right uterine vessels had been damaged when the removal was attempted. The hematoma was evacuated after ligation of the blood vessels and a right salpingo-oophorectomy was performed. The left tube and ovary had a normal appearance and were preserved. Hemostasis was secured and the abdomen was closed in layers as usual. A blood loss of about 2 liters was estimated. Sue was hospitalized for 3 weeks.^ieng