Probability Of Failure-free Survival Research Articles

High treatment failure rate in haematogenous compared to non-haematogenous periprosthetic joint infection.

A higher failure rate has been reported in haematogenous periprosthetic joint infection (PJI) compared to non-haematogenous PJI. The reason for this difference is unknown. We investigated the outcome of haematogenous and non-haematogenous PJI to analyze the risk factors for failure in both groups of patients. Episodes of knee or hip PJI (defined by the European Bone and Joint Infection Society criteria) treated at our institution between January 2015 and October 2020 were included in a retrospective PJI cohort. Episodes with a follow-up of > one year were stratified by route of infection into haematogenous and non-haematogenous PJI. Probability of failure-free survival was estimated using the Kaplan-Meier method, and compared between groups using log-rank test. Univariate and multivariate analysis was applied to assess risk factors for failure. A total of 305 PJI episodes (174 hips, 131 knees) were allocated to the haematogenous (n = 146) or the non-haematogenous group (n = 159). Among monomicrobial infections, Staphylococcus aureus was the dominant pathogen in haematogenous PJI (76/140, 54%) and coagulase-negative staphylococci in non-haematogenous PJI (57/133, 43%). In both groups, multi-stage exchange (n = 55 (38%) in haematogenous and n = 73 (46%) in non-haematogenous PJI) and prosthesis retention (n = 70 (48%) in haematogenous and n = 48 (30%) in non-haematogenous PJI) were the most common surgical strategies. Median duration of antimicrobial treatment was 13.5 weeks (range, 0.5 to 218 weeks) and similar in both groups. After six years of follow-up, the probability of failure-free survival was significantly lower in haematogenous compared to non-haematogenous PJI (55% vs 74%; p = 0.021). Infection-related mortality was significantly higher in haematogenous than non-haematogenous PJI (7% vs 0% episodes; p = 0.001). Pathogenesis of failure was similar in both groups. Retention of the prosthesis was the only independent risk factor for failure in multivariate analysis in both groups. Treatment failure was significantly higher in haematogenous compared to non-haematogenous PJI. Retention of the prosthesis was the only independent risk factor for failure in both groups.

Survival neural networks for time-to-event prediction in longitudinal study

Time-to-event prediction has been an important practical task for longitudinal studies in many fields such as manufacturing, medicine, and healthcare. While most of the conventional survival analysis approaches suffer from the presence of censored failures and statistically circumscribed assumptions, few attempts have been made to develop survival learning machines that explore the underlying relationship between repeated measures of covariates and failure-free survival probability. This requires a purely dynamic-data-driven prediction approach, free of survival models or statistical assumptions. To this end, we propose two real-time survival networks: a time-dependent survival neural network (TSNN) with a feed-forward architecture and a recurrent survival neural network (RSNN) incorporating long short-term memory units. The TSNN additively estimates a latent failure risk arising from the repeated measures and performs multiple binary classifications to generate prognostics of survival probability, while the RSNN with time-dependent input covariates implicitly estimates the relation between these covariates and the survival probability. We propose a novel survival learning criterion to train the neural networks by minimizing the censoring Kullback–Leibler divergence, which guarantees monotonicity of the resulting probability. Besides the failure-event AUC, C-index, and censoring Brier score, we redefine a survival time estimate to evaluate the performance of the competing models. Experiments on four datasets demonstrate the great promise of our approach in real applications.

BCR-ABL Fusion Transcripts In Patients With Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Experience With Ponatinib From MD Anderson Cancer Center

IntroductionThe presence of the BCR-ABL fusion gene, resulting from the Philadelphia chromosome is the hallmark of CML. The most commonly observed transcripts in CML are b3a2 (e14a2) and b2a2 (e13a2). It is not known whether the transcript type may impact response to newer TKI. We report our experience of ponatinib in patients with CML-CP with different BCR-ABL transcripts. MethodsA total of 85 pts with CML-CP [47 relapsed refractory (RR) and 38 frontline] who were treated at our institution between 2008 and 2013 on clinical trials with ponatinib were included in this analysis. Conventional cytogenetic analysis was done in bone marrow (BM) cells using a G-banding technique, and the BCR-ABL fusion transcripts were identified by the use of quantitative real-time polymerase chain reaction assay. ResultsAmong the 47 RR patients, 14 (30%) had the b2a2 transcript (median age 47 years; range 21–82), 23 (49%) had a b3a2 transcript (median age 61; range 24–94 years), and 10 (21%) co-expressed both transcripts (median age 45; range 49–79). Two pts with e1a2 transcripts were not included in the analysis. RR patients received a median of 3 prior therapies including interferon, imatinib, nilotinib, dasatinib, bosutinib, omacetaxine and SCT. Ten (71 %) of those with b2a2 were previously treated with ≥3 different TKI (imatinib, dasatinib, nilotinib and bosutinib); of the pts with b3a2, 12 (52%) were treated with ≥3 different TKI (imatinib, dasatinib, nilotinib and bosutinib) and in the group of pts with both transcripts 5 (50%) received 3 different TKI (imatinib, dasatinib, nilotinib). T315I mutation was present in 9 (19%) pts of which 2 were b2a2, 5 were b3a2 and 2 were both. After a median follow-up of 22.4 months, the rates of overall complete cytogenetic (CCyR) and major molecular responses (MMR) were 55% and 40%. Among these RR patients, the response with b2a2, b3a2 and both transcripts, were CCyR: 50% vs. 61% vs. 50% and MMR 29% vs. 52% vs. 30%, respectively. The 3-year probability of failure free survival (FFS) was 54%, 87% and 68% for pts with b2a2, b3a2 and both groups (P=0.08). The 3-year probability of overall survival (OS) was 62%, 100% and 100% for pts with b2a2, b3a2 and both groups (P=0.03).Among the 38 pts in the frontline setting, 17 (44%) had the b2a2 transcript (median age 50.7 years; range 21–74), 14 (36%) had b3a2 transcript (median age 49.7; range 29–72 years), and 7 (18%) presented with both transcripts (median age 56; range 38–63). The Sokal risk group for those with the b2a2 transcript was high in 2/17 (12%), intermediate in 4/17 (23%), and low in 11/17 (65%). For pts with b3a2 all 14/14 (100%) were low risk, and the group with both transcripts had 0%, 1/7(14%) and 6/7 (85%), respectively. There were two pts who went off study due to toxicity. For the evaluable pts with b2a2, b3a2 and both transcripts, the median levels of transcripts at 3 months were 0.098, 0.091 and 0.042 respectively. Similarly the median levels of transcripts at 6 months were 0.00525, 0.0035 and 0.0035 respectively. The magnitude of early CCyR was very high in all groups thus not allowing to discriminate among the transcripts. The median OS was 6.6 months and none of the pts have died. ConclusionsAlthough all pts have a good overall survival those receiving ponatinib after prior TKI failure with b3a2 transcripts have a higher rate of CCyR and MMR vs. patients with b2a2 transcripts. This mirrors what we have reported with other TKI. With early results, no difference is seen in the frontline setting perhaps because of the overall excellent results. The mechanism of differential responsiveness of pts with b2a2 transcripts and b3a2 transcripts warrants further investigation. Disclosures:Kantarjian:ARIAD, Novartis, BMS, Phizer: Research Funding. Jabbour:Ariad, BMS, Novartis, and Pfizer: Consultancy. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.

Outcome of Very Late Relapse in Patients with Hodgkin's Lymphomas

Recurrences of Hodgkin's Lymphoma (HL) 5 years after the initial therapy are rare. The aim of this study is to report a single centre experience of the clinical characteristics, outcome, and toxicity of pts who experienced very late relapses, defined as relapses that occurred 5 or more years after the achievement of first complete remission. Of 532 consecutive pts with classical HL treated at our Institute from 1985 to 1999, 452 pts (85%) achieved a complete remission. Relapse occurred in 151 pts: 135 (29.8%) within 5 years and 16 over 5 years (3.5%, very late relapses). Very late relapses occurred after a median disease-free interval of 7 years (range: 5–18). Salvage treatment induced complete remission in 14 pts (87.5%). At a median of 4 years after therapy for very late relapse, 10 pts (63%) are still alive and free of disease and 6 (37%) died (1 from progressive HL, 1 from cardiac disease, 1 from thromboembolic disease, 1 from HCV reactivation, and 2 from bacterial infection). The probability of failure-free survival at 5 years was 75%. The majority of deaths are due to treatment-related complications. Therapy regimens for very late relapse HL are warranted to minimize complications.

A molecular risk score based on 4 functional pathways for advanced classical Hodgkin lymphoma

AbstractDespite improvement in the treatment of advanced classical Hodgkin lymphoma, approximately 30% of patients relapse or die as result of the disease. Current predictive systems, determined by clinical and analytical parameters, fail to identify these high-risk patients accurately. We took a multistep approach to design a quantitative reverse-transcription polymerase chain reaction assay to be applied to routine formalin-fixed paraffin-embedded samples, integrating genes expressed by the tumor cells and their microenvironment. The significance of 30 genes chosen on the basis of previously published data was evaluated in 282 samples (divided into estimation and validation sets) to build a molecular risk score to predict failure. Adequate reverse-transcription polymerase chain reaction profiles were obtained from 262 of 282 cases (92.9%). Best predictor genes were integrated into an 11-gene model, including 4 functional pathways (cell cycle, apoptosis, macrophage activation, and interferon regulatory factor 4) able to identify low- and high-risk patients with different rates of 5-year failure-free survival: 74% versus 44.1% in the estimation set (P < .001) and 67.5% versus 45.0% in the validation set (P = .022). This model can be combined with stage IV into a final predictive model able to identify a group of patients with very bad outcome (5-year failure-free survival probability, 25.2%).

Preceding immunosuppressive therapy with antithymocyte globulin and ciclosporin increases the incidence of graft rejection in children with aplastic anaemia who underwent allogeneic bone marrow transplantation from HLA‐identical siblings

The incidence of graft rejection was determined in 66 children with acquired aplastic anaemia (AA) following bone marrow transplantation (BMT) from a related donor. Eleven of 65 evaluable patients experienced either early or late rejection. Multivariate analysis identified previous immunosuppressive therapy with antithymocyte-globulin (ATG) and ciclosporin (CsA) as a risk factor for graft rejection (relative risk: 16.6, P = 0.001). Patients who received ATG and CsA had a significantly lower probability of failure-free survival than those who did not (69.7 +/- 6.2% vs. 87.9 +/- 8.0%, P = 0.044). These results suggest that BMT should be instituted immediately in children with severe AA who have human leucocyte antigen-identical siblings.

Prospective, Randomized, Multicenter Study Comparing Antithymocyte Globulin (ATG) Alone with ATG Plus Cyclosporine (CsA) for Treatment of Children with Nonsevere Aplastic Anemia (nSAA).

In contrast to treatment for childhood severe aplastic anemia (SAA), there is no consensus on the treatment of childhood nSAA. Two thirds of patients progress to SAA, suggesting the need to consider early immunosuppressive therapy (IST). ATG+CsA was superior to ATG alone in a German randomized trial that enrolled both patients with SAA and nSAA. However, subgroup analysis revealed no advantage of adding CsA for patients with nSAA. These findings formed the basis for this prospective, randomized study comparing ATG alone with ATG+CsA for treatment of childhood nSAA. From 1997 to 2004, 62 children with newly diagnosed nSAA were enrolled. Interim analysis was done in April 2005. Patients were randomized to receive either horse ATG (Lymphoglobuline, 1.5vial/10kg/day for 5 days; n=31) or ATG+CsA (6mg/kg/day; n=31). CsA was added for non-responders at day+90 in ATG group. The endpoints were hematologic response at 6 months and failure-free survival (FFS). Complete response (CR) was defined as a neutrophil count > 1.5x 109/L, a platelet count > 100x109/L, and a hemoglobin level > 11.0g/dl. Partial response (PR) was defined as a neutrophil count > 1.0x 109/L, a platelet count > 30x109/L, and a hemoglobin level > 8.0g/dl. FFS was defined as survival with a response. Clinical profiles of two treatment groups were comparable. Median age was 11 years and 10 years in ATG+CsA group and ATG group, respectively. Median time from diagnosis to treatment was 20 days and 23 days in ATG+CsA group, and ATG group, respectively. After 6 months, CR was observed in ATG+CsA group in 5 patients (16%) and PR in 12 patients (39%). In ATG groups, 2 patients (6%) achieved CR and 13 patients (42%) achieved PR. However, 19 patients in the ATG group received additional CsA. There were 22 failures in ATG group and 14 failures in ATG+CsA group. A total of 10 patients who failed initial therapy (7 in ATG group and 3 in ATG+CsA group) received a second IST. Bone marrow transplant (BMT) was attempted in 4 non-responders in ATG group and 6 non-responders in ATG+CsA group. Requiring CsA was a cause of failure in 8 patients of ATG group. The probability of FFS was 54.8% in ATG+CsA group compared with 26.7% in the ATG group (p=0.001). There was 1 death in each group: 1 from BMT-related toxicity in ATG+CsA group and 1 from bacterimia in ATG group. The 5-year survival rate was 94.8% in ATG+CsA group and 96.7% in ATG group. Conclusion; the hematologic response rate at 6 months and overall survival rate are comparable between the two groups, however the combination of ATG and CsA is superior to ATG alone in term of FFS for children with nSAA.

Radical Radiotherapy For Bladder Cancer: Retrospective Analysis of a Series of 459 Patients Treated in an Italian Institution

To contribute to the available evidence about the efficacy of exclusive radiotherapy for bladder cancer through a retrospective analysis of a large series of patients consecutively treated in a single institution. A total of 459 patients with UICC categories T1-T4, N0-Nx and M0 bladder cancer consecutively treated with radiotherapy alone with radical intent formed the clinical basis for this study. Many of them (and particularly the T1 cases) had poor medical conditions or were unfit for surgery. About half of the cases (54%) had a T2 tumour, and about 18% had T3-T4 disease. Eighty per cent of the cases received minimal doses in the target volume in the range 60-70 Gy; pelvic lymph nodes were treated in 34%. Simple radiotherapy techniques were used in most cases. Average follow-up for living patients was 4.4 years. Results were analysed according to number and type of relapses: overall survival, disease-specific survival, failure-free survival probability, acute and late toxicity (RTOG scale). Actuarial 5-year overall survival, disease-specific survival and failure-free survival rates at 5 years for the entire series were 36%, 56%, 33%, respectively. Age, T category (for all the end points) and tumour dose (only for failure-free survival) were significantly related to prognosis at multivariate survival analysis. Late enteric toxicity (6.1% of the cases) was significantly linked with the treated volumes (univariate analysis). Urinary late toxicity (23% of cases) was linked with age and T category (multivariate analysis). In both cases, toxicity was mostly Grade 1 or 2. The results of radiotherapy in this negatively selected series, accrued over a long period of time in patients treated with unsophisticated techniques, are reasonably good; they add to the evidence available to support the use of modern bladder-sparing programmes, including the association of chemo- and radiotherapy.

Impact of Latent Epstein-Barr Virus Infection on Outcome in Children and Adolescents With Hodgkin's Lymphoma

The prognostic significance of latent Epstein-Barr virus (EBV) infection in Hodgkin's lymphoma (HL) is debated controversially. Especially in the pediatric age group, no conclusive data are available. Eight hundred forty-two children and adolescents (median age, 13.7 years) from pediatric multicenter treatment studies HD-90 and HD-95 were studied for latent EBV infection in Hodgkin's and Reed-Sternberg cells by immunostaining against latent membrane protein 1 (LMP-1). Results were compared with established risk factors. Two hundred sixty-three patients (31%) were LMP positive. EBV infection correlated with sex (39% male v 23% female; P < .001), histologic subtype (69% mixed cellularity v 22% nodular sclerosis v 6% lymphocyte predominance; P < .001) and young age. With a median follow-up of 4.9 years, 820 patients (97%) are alive. Probability of overall survival at 10 years (+/- standard deviation) for EBV-negative and -positive patients was 98.1% +/- 0.6% and 95.1% +/- 1.4%, respectively (P = .017 by log-rank test). A negative effect of EBV infection became evident for patients with nodular sclerosis subtype Bennett II (P = .02), and those treated for advanced stages (P = .003). In multivariate analysis, LMP positivity was an independent factor for adverse outcome (RR = 3.08). Probability of failure-free survival (FFS) in LMP positive and negative patients was 89.1% +/- 2.3% and 84.1% +/- 3.9%, respectively (P = .86). With effective combined treatment modalities in pediatric HL, latent EBV infection has no influence on FFS but is associated with an inferior overall survival in crucial subgroups.

The Impact of Disease Status at Transplant and Time to First Relapse on Outcome in Children and Adolescents with Hodgkin's Lymphoma Undergoing Autologous Stem Cell Transplantation.

The prognosis of Hodgkin's lymphoma (HL) in pediatric patients (pts) with current combined chemoradiotherapy regimens in general is excellent. Even those pts suffering from recurrent disease have a realistic chance for cure with salvage therapy regimens. 74 patients (<18 years at diagnosis; 69% male; 76% nodular sclerosis) mainly treated according to pediatric DAL or GPOH protocols received an autologous stem cell transplantation (ASCT) for recurrent or refractory disease between 1987 and 2003. 28 pts had progressive disease (PD, <3 months following the end of therapy), 34 had an early relapse (3–12 months following cessation of therapy) and 12 had a late relapse (>12 months after therapy). Prior to ASCT, pts had a median of 3 (range, 2–4) lines of therapy and a median of 2 (range, 1–4) relapses/PD. At transplant, 63 pts had chemosensitive disease, defined as complete (CR) or partial remission (PR) and 11 had chemoresistant disease, defined as no change (NC) or primary refractory disease (PRD). Conditioning regimens were BEAM or variants in 47, CVB in 19 and others in 6 pts. Peripheral blood stem cells were used for most patients (76%). All pts engrafted. Additional post transplant radiotherapy was given to 24 pts. At a median follow up of 2.7 years (range, 0.1–12.8) 45 pts (61%) are alive and 29 are dead, which was attributed to the original disease in 21 pts. 42 of 63 pts (68%) with chemosensitive are alive compared to 2 of 11 (18%) with resistant disease (p=.002). Time to first relapse significantly attributed to survival after ASCT (12 of 28 pts with PD, 24 of 34 pts with early and 9 of 12 with late relapses are alive; p=.02). 30 pts (42%) relapsed and only 9 of these (30%) are alive compared to 36 pts (86%) with no relapse after ASCT. One pt received a second ASCT without success and 7 were allografted (2 alive). Probability of overall survival (OS), failure-free survival (FFS), relapse rate (RR) and treatment related mortality (TRM) at 5 years were 59%, 50%, 44%, and 12%, respectively. The following factors were adversely related to OS: early recurrence (p=.046), chemoresistance (p=.003), relapse after SCT (p<.001). Probability of FFS in chemosensitive pts at 5 years was 59% while it was 0% in chemoresistant pts (p<.001). FFS was superior for pts receiving BEAM compared to CVB (p=.057). Number of treatment lines were associated with TRM (p=.02). Factors predicting treatment failure in multifactorial analysis were chemoresistant disease at transplant and primary PD. In conclusion, ASCT can be performed safely with BEAM conditioning in children and adolescents. From these results, ASCT should be offered to pediatric pts with early recurrence of HL. For those pts with refractory disease, however, allogeneic transplantation with reduced intensity conditioning should be considered timely to provide an immunotherapeutic approach and to minimize treatment related mortality.

The Impact of Latent Epstein-Barr Virus Infection on Outcome in Children and Adolescents with Hodgkin's Lymphoma.

The prognostic significance of latent Epstein-Barr virus (EBV) infection in Hodgkin's lymphoma (HL) is debated controversially. Especially in the pediatric age group, no conclusive data are available due to small series.842 children and adolescents (55% male) with a median age of 13.7 years (range, 2–20) from consecutive pediatric DAL/GPOH multicenter treatment studies HD-90 and HD-95 were studied for the presence of latent EBV infection in Hodgkin and Reed-Sternberg cells by immunostaining against latent membrane protein 1 (LMP-1). Histology subtypes were as follows: nodular sclerosis (NSHL) 549, mixed cellularity (MCHL) 190, lymphocyte predominance (NLPHL) 90, lymphocyte depletion (LDHL) 6, lymphocyte-rich classical HL (LRCHL) 5, not specified 2. 88 patients had stage I, 470 had stage II, 172 had stage III and 112 had stage IV. B symptoms were present in 274 patients (33%). LMP status was compared with clinical parameters and established risk factors.A total of 263 patients (32%) were LMP positive. EBV infection correlated with gender (male 39% vs. female 23%; p<.001), histological subtype (MCHL 69% vs. NSHL 22% vs. NLPHL 6%; p<.001) and age (<10 years 67% vs ≥10 years 28%, p<.001. With a median follow-up of 4.9 years (0.3–12) 820 patients (97%) are alive. Probability of overall survival at 10 years (±SD) for EBV negative and positive patients was 98±1% and 95±1%, respectively (p=.017 by log-rank test). Probability of failure-free survival (FFS) in LMP positive and negative patients was 89±2% and 84±4%, respectively (p=.86). With respect to LMP status, a negative effect of latent EBV infection on overall survival became evident only for patients treated for advanced stages (p=.003), those with nodular sclerosis subtype Bennett II (p=.02) and B symptoms (p=.05). In a multivariate regression analysis, allocation to treatment group (RR=3.7) and LMP positivity (RR=3.01) were independent factors for overall survival and presence of B symptoms (RR=2.4) for FFS.Under current highly effective polychemotherapy with or without involved field radiotherapy in pediatric HL, latent EBV infection has no influence on FFS in univariate and multivariate analysis. LMP positivity, however, seems to be associated with an inferior overall survival in some subgroups.

Nodal marginal zone lymphoma: a heterogeneous tumor: a comprehensive analysis of a series of 27 cases.

We have reviewed the clinical, morphologic, immunophenotypical, and molecular features of a series of 27 cases of nodal marginal zone lymphoma with the aim of defining this entity more precisely. The series was characterized by a relatively favorable clinical course, with a low clinical stage at diagnosis (59% patients with clinical stage I-II) and a 5-year overall survival probability of 79%. However, the disease persisted in a relatively large fraction of the patients, thus yielding a 5-year failure-free survival probability of 22%. Molecular and immunohistochemical analyses of the series revealed heterogeneity in the frequency of IgV(H) somatic mutation and in the expression of IgD, CD43, MUM1, and CD38. Apart from the absence of nuclear Bcl10, no clear distinction could be made from the expression profiling of other B-cell lymphomas claimed to be derived from marginal zone B cells. Additionally, the immunophenotype of the tumoral cells in all cases but one differed from that described in monocytoid B cells. It was characterized by a Bcl2-, p21+, cyclin E+ profile. The analysis of apoptosis-regulator proteins disclosed abnormalities in the expression of survivin and active caspase 3, which could partially explain the abnormal regulation of apoptosis observed in these tumors. Molecular and immunohistochemical data obtained in this study strongly imply that there is significant heterogeneity among the cases included in the category termed nodal marginal zone lymphoma.

Clinical features of peripheral T-cell lymphomas in 78 patients diagnosed according to the Revised European-American lymphoma (REAL) classification

The aim of this study was to analyse the clinical characteristics and prognostic factors of peripheral T-cell lymphomas (PTCLs) according to the Revised European-American Lymphoma (REAL) classification. From 1994 to 1999, 78 patients were diagnosed with PTCLs, excluding cutaneous T-cell lymphomas and T-cell chronic lymphocytic leukaemia. The distribution of the histological subgroups were: PTCL unspecified (PTCL-U), 40%; angiocentric lymphoma, 32%; anaplastic large cell lymphoma (ALCL), 17%; angioimmunoblastic T-cell lymphoma (AILD), 6%; intestinal T-cell lymphoma, 3%; and panniculitic T-cell lymphoma, 3%. Patients with angiocentric lymphoma presented with favourable prognostic factors, whereas those with AILD presented with unfavourable prognostic factors. Most patients were treated with doxorubicin-containing combination chemotherapy (with or without radiation therapy). The overall complete remission rate was 61.2% (95% Confidence Interval (CI): 48.5–72.8%) and the 5-year probability of failure-free survival was 33.5%. Median survival of all patients was 45 months (range 0–64+ months) and the 5-year probability of survival was 36.2%. In the multivariate analysis, only the International Prognosis Index (IPI) was an independent prognostic factor for overall survival (P<0.01). Taken together, the proportion of angiocentric lymphoma in this study was higher than that in the studies of Western countries. PTCL responds poorly to treatment with low survival rates and the IPI is a useful prognostic factor for PTCL.

Long‐term outcome of acquired aplastic anaemia in children: comparison between immunosuppressive therapy and bone marrow transplantation

A total of 100 children under the age of 17 years with acquired aplastic anaemia (AA) were initially treated with immunosuppressive therapy (IST) (n = 63) or bone marrow transplantation (BMT) (n = 37) from an HLA‐matched family donor. The projected 10‐year survival rates were 55 ± 8% and 97 ± 3% respectively (P = 0·004). Because the IST group included 11 non‐responders who were salvaged by BMT from an HLA‐matched unrelated donor, we compared failure‐free survival (FFS) between the groups. The probability of FFS at 10 years was 97 ± 3% for the BMT group, compared with 40 ± 8% for the IST group (P = 0·0001). Seven patients evolved to myelodysplastic syndrome (MDS) with monosomy 7 and the estimated cumulative incidence of MDS 10 years after diagnosis was 20 ± 7% in the IST group. We compared the outcome of children treated with IST during the two consecutive periods of 1983–91 (group A, n = 40) and 1991–8 (group B, n = 23) to assess the impact of combined therapy with anti‐thymocyte globulin and cyclosporin. The probability of FFS at 7 years follow‐up was the same in the two groups (50 ± 8% vs. 40 ± 15%, P = 0·40). We recommend BMT as first‐line therapy in paediatric severe AA patients with an HLA‐matched family donor. Alternative donor BMT is recommended as salvage therapy in patients who relapse or do not respond to initial IST.

Primary Chemotherapy for Stage II Nonseminomatous Germ Cell Tumors of the Testis

Between 1979 and 1989, 122 patients with clinical stage II testicular nonseminoma were treated with primary platinum-based combination chemotherapy following orchiectomy. Of the patients 58 had Royal Marsden Hospital stage IIA (nodes less than 2cm. in diameter) and the other 64 had stage IIB (nodes 2 to 5cm. diameter) disease. With a median followup after chemotherapy of 5.5 years, 118 patients (97%) were disease-free. Two patients died of progressive germ cell tumors, 1 of bleomycin toxicity and 1 of coincidental disease. The 5-year actuarial survival probability was 95% (95% confidence intervals 91 to 99%) and the 5-year failure-free survival probability was 92% (95% confidence intervals 88 to 97%). Tumor substage was not predictive of relapse but did indicate the probability of lymphadenectomy for a post-chemotherapy residual mass since this was performed in 17% of the patients with stage IIA disease and 39% with stage IIB disease (p <0.05). Resected specimens contained mature teratoma (29), necrosis alone (5) or embryonal carcinoma (1). We conclude that for these clinical stages primary chemotherapy was as effective as primary lymph node dissection and a major operation was avoided in 68% of the cases.