RESUMO
In more than 30% of B-cell precursor acute lymphoblastic leukaemia (B-ALL), chromosome 21 sequence is overrepresented through aneuploidy or structural rearrangements, exemplified by intrachromosomal amplification of chromosome 21 (iAMP21). Although frequent, the mechanisms by which these abnormalities promote B-ALL remain obscure. Intriguingly, we found copy number neutral loss of heterozygosity (CN-LOH) of 12q was recurrent in iAMP21-ALL, but never observed in B-ALL without some form of chromosome 21 gain. As a consequence of CN-LOH 12q, mutations or deletions of the adaptor protein, SH2B3, were converted to homozygosity. In patients without CN-LOH 12q, bi-allelic abnormalities of SH2B3 occurred, but only in iAMP21-ALL, giving an overall incidence of 18% in this sub-type. Review of published data confirmed a tight association between overrepresentation of chromosome 21 and both CN-LOH 12q and SH2B3 abnormalities in B-ALL. Despite relatively small patient numbers, preliminary analysis linked 12q abnormalities to poor outcome in iAMP21-ALL (p = 0.03). Homology modelling of a leukaemia-associated SH2 domain mutation and in vitro analysis of patient-derived xenograft cells implicated the JAK/STAT pathway as one likely target for SH2B3 tumour suppressor activity in iAMP21-ALL.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 21 , Perda de Heterozigosidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas/genética , Proteínas Adaptadoras de Transdução de Sinal , Humanos , Interleucina-7/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular , Mutação , Fator de Transcrição STAT5/fisiologiaRESUMO
Outcomes for teenage and young adult (TYA) patients with acute lymphoblastic leukaemia (ALL) who relapse on contemporary risk-adapted paediatric protocols are largely unknown and there is no consensus on optimal salvage strategies. We assessed the treatment and outcome of TYA patients (aged 16-24 years) recruited to the UKALL2003 trial, who relapsed following attainment of complete morphological remission. Forty-two of 223 patients (18·8%) relapsed, the majority (n = 26, 62%) on treatment. Thirty-eight (90%) patients received salvage treatment, with 22 (58%) achieving second remission (CR2) and 21 patients receiving an allogeneic haematopoietic cell transplant (alloHSCT). Post-relapse outcomes were poor with a 5-year overall survival (OS) of 23% (95% confidence interval; 11-37%). Outcomes for patients relapsing on active treatment were inferior to those relapsing after completing treatment (5-year OS 9% vs. 52%, log-rank P = 0·001). No patient with B cell ALL relapsing on treatment was alive at the end of the study period. TYA patients with ALL who relapse on the UK paediatric protocol, UKALL2003, are largely unsalvageable with conventional approaches aimed at achieving CR2 followed by alloHSCT. Future efforts should be aimed at identifying those patients who are destined to relapse and exploring novel treatment approaches for this high-risk group and for those who do relapse.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Neoplasia Residual , Recidiva , Terapia de Salvação , Taxa de Sobrevida , Reino Unido/epidemiologia , Adulto JovemRESUMO
For pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared with other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GVHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (<18 years) with ALL in first complete remission (CR1; n = 257, 40%) or second complete remission (CR2; n = 383, 60%) who received myeloablative conditioning followed by a single-unit UCBT from 2000 to 2012. Most received antithymocyte globulin (88%) or total body irradiation (TBI; 69%), and cord blood grafts were primarily mismatched at 1 (50%) or 2+ (34%) HLA loci. Considering patients in CR1, the rates of 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 59%, 52%, and 23%, respectively. In multivariate analysis (MVA), acute GVHD (grades II to IV) and TBI protected against relapse. In patients in CR2, rates of 5-year OS, LFS, and the cumulative incidence of relapse were 46%, 44%, and 28%, respectively. In MVA, longer duration from diagnosis to UCBT (≥30 months) and TBI were associated with decreased relapse risk. Importantly, receiving a fully HLA matched graft was a strong risk factor for increased relapse in MVA. An exploratory analysis of all 640 patients supported the important association between the presence of acute GVHD and less relapse but also demonstrated an increased risk of nonrelapse mortality. In conclusion, the impact of GVHD as a graft-versus-leukemia marker is evident in pediatric ALL after UCBT. Strategies that promote graft-versus-leukemia while harnessing GVHD should be further investigated.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Condicionamento Pré-Transplante , Doadores não Relacionados , Adolescente , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Recidiva , Fatores de Risco , Taxa de Sobrevida , Fatores de TempoAssuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Trombose dos Seios Intracranianos/epidemiologia , Trombose dos Seios Intracranianos/etiologia , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Avaliação de Resultados da Assistência ao Paciente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos Retrospectivos , Fatores de Risco , Trombose dos Seios Intracranianos/diagnóstico , Trombose dos Seios Intracranianos/terapia , Reino Unido/epidemiologia , Adulto JovemRESUMO
AIMS: To assess the value of laboratory tests available for the investigation of iron status in a population of young British South Asian children. METHODS: Blood count, red cell distribution width (RDW), percentage hypochromic red cells (%hypo), concentrations of C-reactive protein (CRP), zinc protoporphyrin (ZPP), ferritin, soluble transferrin receptor, plasma iron measurements and incidence of deletional forms of α-thalassaemia were determined. RESULTS: Haemoglobin, mean cell haemoglobin (MCH), ferritin and CRP values classified iron status in 151/205 (73.6%) consecutive children aged 4-43â months. Fifty-four could not be classified: 12 were anaemic with findings, other than normal CRP values, indistinguishable from those with anaemia of inflammation and 42 were non-anaemic with reduced MCH values. All 42 had normal ferritin concentration and 8 of 36 successfully tested had deletional α-thalassaemia trait. Despite apparent iron sufficiency the RDW, %hypo and ZPP values of these 42 were not significantly different from the 32 children classified with iron-deficient erythropoiesis. The gene frequency of deletional α-thalassaemia trait in the entire group was 8.6%. CONCLUSIONS: Among 205 British South Asian children aged 4-43â months with high incidences of anaemia, iron deficiency, infection and α-thalassaemia, 151 (73.6%) were classified using haemoglobin, MCH, ferritin and CRP values. In 42 non-anaemic, iron-sufficient children with subnormal MCH values, that is with a phenotype of α-thalassaemia trait, RDW, %hypo and ZPP values did not differ significantly from those with iron-deficient erythropoiesis. Raised RDW, %hypo and ZPP values should be interpreted with caution in non-anaemic young British South Asian children with microcytosis.
Assuntos
Doenças Hematológicas/diagnóstico , Deficiências de Ferro , Talassemia alfa/classificação , Proteína C-Reativa/análise , Pré-Escolar , Contagem de Eritrócitos/métodos , Feminino , Ferritinas/sangue , Hemoglobinas/análise , Humanos , Lactente , Masculino , Talassemia alfa/diagnósticoRESUMO
We explored the feasibility of unrelated donor haematopoietic stem cell transplant (HSCT) upfront without prior immunosuppressive therapy (IST) in paediatric idiopathic severe aplastic anaemia (SAA). This cohort was then compared to matched historical controls who had undergone first-line therapy with a matched sibling/family donor (MSD) HSCT (n = 87) or IST with horse antithymocyte globulin and ciclosporin (n = 58) or second-line therapy with unrelated donor HSCT post-failed IST (n = 24). The 2-year overall survival in the upfront cohort was 96 ± 4% compared to 91 ± 3% in the MSD controls (P = 0·30) and 94 ± 3% in the IST controls (P = 0·68) and 74 ± 9% in the unrelated donor HSCT post-IST failure controls (P = 0·02).The 2-year event-free survival in the upfront cohort was 92 ± 5% compared to 87 ± 4% in MSD controls (P = 0·37), 40 ± 7% in IST controls (P = 0·0001) and 74 ± 9% in the unrelated donor HSCT post-IST failure controls (n = 24) (P = 0·02). Outcomes for upfront-unrelated donor HSCT in paediatric idiopathic SAA were similar to MSD HSCT and superior to IST and unrelated donor HSCT post-IST failure. Front-line therapy with matched unrelated donor HSCT is a novel treatment approach and could be considered as first-line therapy in selected paediatric patients who lack a MSD.
Assuntos
Anemia Aplástica/terapia , Transplante de Medula Óssea/estatística & dados numéricos , Transplante de Células-Tronco de Sangue Periférico/estatística & dados numéricos , Infecções por Adenoviridae/tratamento farmacológico , Infecções por Adenoviridae/epidemiologia , Adolescente , Adulto , Anemia Aplástica/mortalidade , Soro Antilinfocitário , Transfusão de Sangue/estatística & dados numéricos , Transplante de Medula Óssea/efeitos adversos , Estudos de Casos e Controles , Criança , Pré-Escolar , Ciclosporina/uso terapêutico , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Infecções por Herpesviridae/tratamento farmacológico , Infecções por Herpesviridae/epidemiologia , Histocompatibilidade , Humanos , Imunossupressores/uso terapêutico , Lactente , Estimativa de Kaplan-Meier , Tempo de Internação/estatística & dados numéricos , Doadores Vivos , Masculino , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/epidemiologia , Disfunção Primária do Enxerto/epidemiologia , Qualidade de Vida , Estudos Retrospectivos , Irmãos , Taxa de Sobrevida , Linfócitos T , Resultado do Tratamento , Ativação Viral , Adulto JovemRESUMO
AIMS: To assess the sensitivity of an adult-derived red cell distribution width (RDW) reference limit in the detection of iron deficiency in young children. METHODS: Haematological analysis performed on a cohort of 13-month-old healthy term infants of North European ancestry. RESULTS: 21/98 infants were iron-deficient (>2.5% hypochromic red cells). Of the remaining 77, 35 with RDW >13.9% also had evidence of incipient iron deficiency on the basis of significantly lower haemoglobin (11.5 vs 11.8 g/dl, p=0.046), mean cell volume (75.6 vs 77.8 fl, p=0.002) and mean cell haemoglobin (25.4 vs 26.2 pg, p=0.002) values and higher zinc protoporphyrin (55 vs 44 µmol/molhaem, p<0.001) values than those of the 42 with RDW ≤13.9%. CONCLUSIONS: An adult-derived RDW reference limit has utility in screening for iron deficiency at the age of 13 months. The incidence of non-anaemic iron deficiency in this group was 52.8%.
Assuntos
Anemia Ferropriva/sangue , Anemia Ferropriva/diagnóstico , Índices de Eritrócitos , Eritrócitos/química , Programas de Rastreamento/métodos , Anemia Ferropriva/epidemiologia , Humanos , Incidência , Lactente , Sensibilidade e EspecificidadeRESUMO
Deregulated expression of CRLF2 (CRLF2-d) arises via its juxtaposition to the IGH@ enhancer or P2RY8 promoter. Among 865 BCP-ALL children treated on MRC ALL97, 52 (6%) had CRLF2-d, but it was more prevalent among Down syndrome patients (54%). P2RY8-CRLF2 (n = 43) was more frequent than IGH@-CRLF2 (n = 9). CRLF2-d was not associated with age, sex, or white cell count, but IGH@-CRLF2 patients were older than P2RY8-CRLF2 patients (median 8 vs 4 years, P = .0017). Patients with CRLF2-d were more likely to present with enlarged livers and spleens (38% vs 18%, P < .001). CRLF2-d was not seen in conjunction with established chromosomal translocations but 6 (12%) cases had high hyperdiploidy, and 5 (10%) had iAMP21. Univariate analysis suggested that CRLF2-d was associated with an inferior outcome: (event-free survival [EFS] hazard ratio 2.27 [95% confidence interval 1.48-3.47], P < .001; OS 3.69 [2.34-5.84], P < .001). However, multivariate analysis indicated that its effect was mediated by other risk factors such as cytogenetics and DS status (EFS 1.45 [0.88-2.39], P = .140; OS 1.90 [1.08-3.36], P = .027). Although the outcome of IGH@-CRLF2 patients appeared inferior compared with P2RY8-CRLF2 patients, the result was not significant (EFS 2.69 [1.15-6.31], P = .023; OS 2.86 [1.15-6.79], P = .021). Therefore, we concluded that patients with CRLF2-d should be classified into the intermediate cytogenetic risk group.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Receptores de Citocinas/genética , Adolescente , Criança , Pré-Escolar , Aberrações Cromossômicas , Intervalo Livre de Doença , Síndrome de Down/complicações , Síndrome de Down/genética , Síndrome de Down/imunologia , Elementos Facilitadores Genéticos , Feminino , Expressão Gênica , Genes de Cadeia Pesada de Imunoglobulina , Humanos , Hibridização in Situ Fluorescente , Lactente , Estimativa de Kaplan-Meier , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prognóstico , Regiões Promotoras Genéticas , Receptores Purinérgicos P2/genética , Translocação GenéticaRESUMO
SUMMARY: We aimed to evaluate the role of flowcytometric immunophenotyping (FCI) as an adjunct to histologic examination in pediatric lymphoma. We conducted a retrospective review of 39 fresh tissue samples and 2 pleural fluids submitted to the histopathology department with a clinical suspicion of lymphoma during a 4-year period, where FCI was performed. The FCI results were correlated with the final histologic diagnosis. The study comprised 38 lymphoid lesions and 3 nonlymphoid tumors. The concordance of FCI for all lesions was 71% and that for non-Hodgkin lymphoma was 75%. When Hodgkin lymphoma was excluded, the correlation was 93.1%. In 3 cases of nonhematologic tumors, FCI was useful in excluding a lymphoma. In one of them, FCI supported the diagnosis of neuroblastoma when CD81, CD9, GD2, and CD56 were added to the FCI panel. FCI produced rapid same-day results with a high sensitivity for benign lymphoid lesions and non-Hodgkin lymphoma. It was not helpful for Hodgkin lymphoma. Although the main application of FCI was to assess lymphoid lesions, it was also useful in the identification of nonlymphoid tumors, especially neuroblastoma. As the prevalence of lymphomas in children differ from that in adults, we believe that the algorithm proposed by us to triage specimens using imprint cytology can optimize the use of FCI in routine pediatric pathology practice.
Assuntos
Doença de Hodgkin/diagnóstico , Linfoma não Hodgkin/diagnóstico , Neuroblastoma/diagnóstico , Adulto , Algoritmos , Biomarcadores Tumorais/metabolismo , Citometria de Fluxo , Doença de Hodgkin/imunologia , Doença de Hodgkin/metabolismo , Humanos , Técnicas Imunoenzimáticas , Imunofenotipagem , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/metabolismo , Neuroblastoma/imunologia , Neuroblastoma/metabolismo , Prognóstico , Estudos RetrospectivosRESUMO
Venous thrombosis is more frequent in patients treated for acute lymphoblastic leukaemia (ALL) than other malignancies and has distinctive causes, clinical features and remedies. The reported incidence varies from 1% to 36%, depending on the chemotherapy protocol and whether the reported cases are symptomatic or detected on screening radiography. The risk is thought to arise from increased thrombin generation at diagnosis combined with reduced thrombin inhibitory capacity due to depletion of circulating anti-thrombin (AT) by asparaginase. A number of patient and treatment variables have been reported to influence the risk of thrombosis including hereditary thrombophilia, early insertion of central venous catheters and exposure to a combination of steroids and asparaginase during induction. Erwinia asparaginase is associated with a lower risk of thrombosis compared with Escherichia coli asparaginase. The majority of symptomatic thromboses are related to central venous catheters and involve the upper venous system. Central nervous system thrombosis involving the cerebral venous sinuses is a unique feature of asparaginase-related thrombosis and is reported to occur in 1-3% of patients. Conclusive evidence to support the use of anti-coagulant treatment or AT concentrates for primary prevention is lacking, as is evidence for the efficacy of AT concentrates in the management of established thrombosis. Preventative strategies are hampered by conflicting data on factors that would enable identification of those at highest risk of thrombosis.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Trombose/complicações , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cateterismo Venoso Central/efeitos adversos , Criança , Humanos , Incidência , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Fatores de Risco , Trombofilia/complicações , Trombose/prevenção & controleRESUMO
Patients with acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21) comprise a novel and distinct biological subgroup. We prospectively screened 1630 (84%) patients treated on the UK MRC ALL97 protocol for iAMP21 and herein present demographic, clinical, and survival data on the 28 (2%) children found to harbor this abnormality. They had a common or pre-B ALL immunophenotype, were significantly older (median 9 years vs 5 years), and had a lower white cell count (median 3.9 vs 12.4) compared with children without this abnormality. Notably, patients with iAMP21 had a significantly inferior event-free and overall survival at 5 years compared with other patients: 29% (95% confidence interval [CI], 13%-48%) versus 78% (95% CI, 76%-80%) and 71% (95% CI, 51%-84%) versus 87% (95% CI, 85%-88%), respectively. As a result of this 3-fold increase in relapse risk, newly diagnosed patients with iAMP21 recruited to the current UK MRC ALL2003 trial are being treated on the high-risk arm and are considered for bone marrow transplantation in first remission.
Assuntos
Cromossomos Humanos Par 21/genética , Amplificação de Genes/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Criança , Pré-Escolar , Citogenética , Feminino , Humanos , Lactente , Masculino , Prognóstico , Taxa de SobrevidaRESUMO
We conducted a multicenter study of the safety, tolerability, and plasma pharmacokinetics of the parenteral formulation of voriconazole in immunocompromised pediatric patients (2 to 11 years old). Single doses of 3 or 4 mg/kg of body weight were administered to six and five children, respectively. In the multiple-dose study, 28 patients received loading doses of 6 mg/kg every 12 h on day 1, followed by 3 mg/kg every 12 h on day 2 to day 4 and 4 mg/kg every 12 h on day 4 to day 8. Standard population pharmacokinetic approaches and generalized additive modeling were used to construct the structural pharmacokinetic and covariate models used in this analysis. In contrast to that in adult healthy volunteers, elimination of voriconazole was linear in children following doses of 3 and 4 mg/kg every 12 h. Body weight was more influential than age in accounting for the observed variability in voriconazole pharmacokinetics. Elimination capacity correlated with the CYP2C19 genotype. Exposures were similar at 4 mg/kg every 12 h in children (median area under the concentration-time curve (AUC), 14,227 ng. h/ml) and 3 mg/kg in adults (median AUC, 13,855 ng. h/ml). Visual disturbances occurred in 5 (12.8%) of the 39 patients and were the only drug-related adverse events that occurred more than once. No withdrawals from the study were related to voriconazole. We conclude that pediatric patients have a higher capacity for elimination of voriconazole per kilogram of body weight than do adult healthy volunteers and that dosages of 4 mg/kg may be required in children to achieve exposures consistent with those in adults following dosages of 3 mg/kg.
Assuntos
Antifúngicos/efeitos adversos , Antifúngicos/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Triazóis/efeitos adversos , Triazóis/farmacocinética , Envelhecimento/metabolismo , Alelos , Antifúngicos/administração & dosagem , Peso Corporal/fisiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genótipo , Humanos , Hospedeiro Imunocomprometido , Injeções Intravenosas , Testes de Função Hepática , Masculino , Modelos Biológicos , Pirimidinas/administração & dosagem , Triazóis/administração & dosagem , VoriconazolRESUMO
Pulmonary hemorrhage is a rare cause of death in patients with acute leukemia. Within a 2-month period the authors observed two fatal pediatric cases, which were associated with opportunistic organisms of the genus Micrococcus. Both patients were receiving consolidation treatment for acute lymphoblastic leukemia. The authors discuss the causes of pulmonary hemorrhage in patients with leukemia and review the relevant literature. Micrococci have previously been considered as non-pathogenic, but there is considerable evidence for morbidity and mortality occurring, particularly in immunocompromised patients. The authors propose that micrococcal infection may have been a major predisposing factor for pulmonary hemorrhage in these thrombocytopenic patients.
Assuntos
Infecções por Bactérias Gram-Positivas/complicações , Hemorragia/etiologia , Pneumopatias , Pneumopatias/patologia , Micrococcus , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Pré-Escolar , Evolução Fatal , Feminino , Infecções por Bactérias Gram-Positivas/induzido quimicamente , Hemorragia/microbiologia , Humanos , Pneumopatias/microbiologia , Masculino , Infecções Oportunistas/complicações , Infecções Oportunistas/microbiologiaRESUMO
Relapse of childhood acute lymphoblastic leukaemia (ALL) involving the eye is a rare but challenging problem. Twenty cases occurred in patients treated on the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia XI and ALL97 trials between 1991 and 2001, representing 2.2% of ALL relapses. Seventeen occurred as a first relapse, either in isolation or combined with relapse at another site, and three occurred as a second relapse. All patients with intraocular disease at first relapse were treated with both chemotherapy and radiotherapy, but the doses and protocols used varied. Eleven of these 17 patients are alive and in complete remission with a median follow up of 4 years 2 months from relapse. All 11 children that were treated with a full chemotherapy relapse protocol, together with local radiotherapy have survived. Patients treated with chemotherapy of shorter duration and intensity, despite radiotherapy and/or bone marrow transplantation, did poorly with only one survivor, currently in chronic relapse. Consequently, we suggest that children with eye relapse of ALL be treated with an intensive relapse chemotherapy protocol with local ocular radiotherapy, whether the relapse occurs in isolation or in combination with relapse at another site.