Earthquake and tsunami forecasts: relation of slow slip events to subsequent earthquake rupture.

The 5 September 2012 M(w) 7.6 earthquake on the Costa Rica subduction plate boundary followed a 62-y interseismic period. High-precision GPS recorded numerous slow slip events (SSEs) in the decade leading up to the earthquake, both up-dip and down-dip of seismic rupture. Deeper SSEs were larger than shallower ones and, if characteristic of the interseismic period, release most locking down-dip of the earthquake, limiting down-dip rupture and earthquake magnitude. Shallower SSEs were smaller, accounting for some but not all interseismic locking. One SSE occurred several months before the earthquake, but changes in Mohr-Coulomb failure stress were probably too small to trigger the earthquake. Because many SSEs have occurred without subsequent rupture, their individual predictive value is limited, but taken together they released a significant amount of accumulated interseismic strain before the earthquake, effectively defining the area of subsequent seismic rupture (rupture did not occur where slow slip was common). Because earthquake magnitude depends on rupture area, this has important implications for earthquake hazard assessment. Specifically, if this behavior is representative of future earthquake cycles and other subduction zones, it implies that monitoring SSEs, including shallow up-dip events that lie offshore, could lead to accurate forecasts of earthquake magnitude and tsunami potential.

Haematopoietic stem cell transplantation as primary therapy of sporadic adult Burkitt lymphoma.

High dose chemoradiotherapy and haematopoietic stem cell transplantation (SCT) is used as primary therapy for patients diagnosed with Burkitt lymphoma (BL). Forty-three adults presented with sporadic BL in British Columbia between 1987 and 2003. Twenty patients had bone marrow involvement. Sixteen patients did not proceed to SCT because of chemorefractory disease (n = 9) or other reasons (n = 7). Twenty-seven patients proceeded to SCT and had a 3-year event-free survival of 51%. In conclusion, approximately 50% of patients with chemosensitive BL who undergo SCT can be cured; however, a significant number of patients will not proceed to SCT because of early resistance or recurrence.

Primary paranasal sinus lymphoma: natural history and improved outcome with central nervous system chemoprophylaxis.

Non-Hodgkin's lymphoma of the paranasal sinus is an uncommon presentation of extranodal lymphoma. Its natural history, treatment and prognosis have been infrequently characterized in the medical literature; however, a tendency to involve the central nervous system (CNS) has been noted. In British Columbia (population 4 million), a central database for lymphomas has allowed us to accurately track cases of paranasal sinus lymphoma diagnosed since 1980. A retrospective review was performed on the 44 patients who presented with primary paranasal sinus lymphoma (stage I or II) between 1980 and 1999. Histologic features were identified and immunophenotypic classification performed. Complete diagnostic and follow-up data including stage, treatment, response rates, sites of relapse and survival data were available for all patients. There were 26 men and 18 women. The types of lymphoma found were: diffuse large B cell (including immunoblastic), n = 37 (84%); T/NK nasal type, n = 3 (8%); peripheral T cell, not otherwise classified, n = 2 (4%); and others, n = 2 (4%). The median age at presentation was 66 years (range 27-97 years). The median follow-up for living patients was 114 months. For all 44 patients, the 5- and 10-year overall survivals were 48% and 41% and the disease-specific survivals 62% and 62%, respectively. Beginning in May 1985, intrathecal chemotherapy was added to our standard treatment plan of multi-agent chemotherapy and local irradiation. Before 1985, 2 of 5 patients developed leptomeningeal metastasis. Following the institution of intrathecal chemotherapy, only 8% (3 of 39) of patients have developed CNS disease. Introduction of intrathecal chemoprophylaxis was also associated with an improvement in overall survival from 20% to 51% and disease-specific survival from 40% to 65%. Primary paranasal sinus lymphoma is an uncommon presentation of lymphoma that carries the potential risk of spreading to the leptomeninges. Treatment with combined modality chemotherapy and irradiation can cure many patients and the addition of intrathecal chemotherapy may reduce the risk of CNS relapse.

Allogeneic haematopoietic stem-cell transplantation for relapsed and refractory aggressive histology non-Hodgkin lymphoma.

Forty-four patients with relapsed or refractory aggressive histology non-Hodgkin lymphoma (NHL) (diffuse large B cell, n = 23; peripheral T cell, n = 5; transformed B cell, n = 16) proceeded to allogeneic stem cell transplant (allo-SCT) between 1987 and 2003. Median age at transplant was 40 years (range 19-56 years). At the time of transplant, 35 were chemosensitive and nine were chemorefractory. Thirty-three patients had matched sibling donors and 11 had unrelated donors. Forty-two patients (95%) received radiation-based conditioning regimens. Event-free survival (EFS) and overall survival (OS) at 5 years was 43% [95% confidence interval (CI): 27-58%] and 48% (95% CI: 32-63%) respectively. Treatment-related mortality was 25% at 1 year. Grade III-IV acute graft-versus-host disease (GVHD) was the only significant variable affecting OS and EFS, and had a negative impact. Chronic GVHD did not influence survival. Lymphoma relapse <12 months after initial therapy predicted for increased risk of relapse post-transplant (P = 0.02). Patients with chemorefractory lymphoma were not at increased risk of relapse (P = 0.20) with four of nine patients remaining alive without disease 12-103 months post-transplant. In conclusion, allo-SCT for relapsed or refractory aggressive histology NHL results in long-term EFS and OS of 40-50%. Patients with chemorefractory disease can have a durable remission post-transplant.

High-dose therapy and autologous hematopoietic stem-cell transplantation does not increase the risk of second neoplasms for patients with Hodgkin's lymphoma: a comparison of conventional therapy alone versus conventional therapy followed by autologous hematopoietic stem-cell transplantation.

PURPOSE: To determine the incidence of second malignancies among patients with Hodgkin's lymphoma (HL) treated with autologous hematopoietic stem cell transplantation (AHSCT) compared with patients receiving conventional therapy alone and to identify potential risk factors for their occurrence. PATIENTS AND METHODS: We analyzed data on 1,732 consecutive patients with HL treated at the British Columbia Cancer Agency from 1976 to 2001, including 202 patients undergoing AHSCT. The median follow-up duration was 9.8 years for the whole cohort, 9.7 years for those patients treated with conventional therapy, and 7.8 years from AHSCT. RESULTS: The cumulative incidence of developing any second malignancy 15 years after therapy for HL was 9% (risk ratio = 3.5; P < .001); however, the incidence did not differ between those patients receiving conventional therapy alone compared with those undergoing AHSCT (10% and 8%, respectively; P = .48). In multivariate analysis, the only factor significantly associated with an increased risk of developing any second neoplasm or solid tumor was age > or = 35 years (P < .0001). An increased risk of therapy-induced acute myeloid leukemia and therapy-induced myelodysplastic syndrome was seen for patients aged > or = 35 years (P = .03) and stage III/IV (P = .04). CONCLUSION: Patients with HL are at increased risk of developing a second neoplasm. However, those patients undergoing AHSCT do not seem to be at greater risk compared with those patients receiving conventional therapy alone, at least during the first decade after therapy.

High-dose chemotherapy and autologous stem cell transplantation for primary refractory or relapsed Hodgkin lymphoma: long-term outcome in the first 100 patients treated in Vancouver.

Beginning in 1985, patients in British Columbia with Hodgkin lymphoma (HL) that was not controlled by conventional chemotherapy routinely underwent high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT). Long-term complications of HD-ASCT have become apparent as more patients survive without recurrence of HL. Data were obtained retrospectively on the first 100 patients that underwent HD-ASCT for HL in Vancouver, focusing on relapse, treatment-related complications, and the occurrence of late events. Fifty-three patients remain alive (median follow-up, 11.4 years [range, 10.0-17.4 years]) with an overall survival (OAS) of 54% at 15 years. OAS was significantly better in patients in first relapse (67%) than in patients with primary refractory-induction failure (39%) and advanced disease (29%) (P = .002). The major cause of death was progression of HL (32% at 15 years). Treatment-related mortality, including death from second malignancy, was 17% at 15 years. Cumulative risk of a second malignancy was 9% at 15 years. Karnofsky performance status was at least 90% in 47 patients although hypogonadism (20 patients), hypothyroidism (12 patients), unusual infections (10 patients), anxiety or depression (7 patients), and cardiac disease (5 patients) were not uncommon in survivors. HD-ASCT can lead to durable remissions in relapsed or refractory HL with acceptable but definite late toxicity. The occurrence of late events necessitates lifelong medical surveillance.

The treatment of primary central nervous system lymphoma in 122 immunocompetent patients: a population-based study of successively treated cohorts from the British Colombia Cancer Agency.

BACKGROUND: The objective of this study was to evaluate the clinical outcome of a population-based cohort of immunocompetent patients with primary central nervous system lymphoma (PCNSL) treated with 3 different strategies over 13 years. METHODS: One hundred twenty-two consecutive patients (median age, 66 years) with PCNSL were identified. Three treatment strategies were employed: 1) whole-brain irradiation with (from January, 1990, to June, 1991) or without (from April, 1995, to December, 1999) cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-type chemotherapy (n=50 patients); 2) combined-modality therapy, including 1 g/m2 methotrexate plus whole-brain irradiation (from July, 1991, to March, 1995; n=34 patients); and 3) 8 g/m2 methotrexate alone (from January, 2000, to March, 2003) with whole-brain irradiation reserved for those with progressive disease (n=38 patients). Treatment failure was defined as progressive disease, disease recurrence, death from toxicity or lymphoma, or toxicity that necessitated a change in primary treatment. RESULTS: The median failure-free survival was 7 months, and the median overall survival (OS) was 17 months. The median OS was similar in all 3 eras. In this population-based analysis, one-third of patients did not receive the treatment strategy of the era. Therefore, the data also were analyzed by treatment received. On multivariate analysis (including era of treatment), 3 factors-age > 60 years, lactate dehydrogenase > normal, and omission of methotrexate-were associated significantly with poorer OS (hazard ratio: 2.3, 2.2, and 2.3, respectively). CONCLUSIONS: Outcomes for a general population with PCNSL remained constant despite different treatment strategies over three eras. For the two-thirds of patients who could receive potentially curative treatment, age, lactate dehydrogenase level, and receipt of > or = 1 g/m2 methotrexate appeared to be important determinants of OS.

Long-term disease-free survival of patients with advanced follicular lymphoma after allogeneic bone marrow transplantation.

Myeloablative allogeneic bone marrow transplantation (BMT) may be curative in patients with follicular non-Hodgkin's lymphoma, however, the impact of this therapy on long-term survival, disease progression and functional status is less clear. Twenty-nine patients (median age 42 years, range: 20-53) with advanced stage follicular lymphoma proceeded to allogeneic BMT a median of 25 (range: 8-154) months postdiagnosis, between 1985 and 2001, and have been followed for a minimum of 2 years. Eleven of 29 (38%) had refractory disease (n = 5 induction failure, n = 6 resistant relapse). Most (27 of 29, 93%) received total body irradiation-based conditioning; stem cell source was marrow from a related donor (n = 20) or unrelated donor (n = 9). Seventeen of 29 patients (59%) were alive a median of 5 years (range: 2-11) post-BMT with a median Karnofsky Performance Score of 100%. Death occurred because of transplant complications in seven patients (cumulative incidence of non-relapse mortality 24%), and progressive lymphoma in five patients (cumulative incidence of refractory/recurrent lymphoma 23%). The 5-year probability of overall and event-free survival was 58% and 53% respectively. Allogeneic BMT has resulted in long-term disease-free survival for approximately 50% of this cohort of patients with advanced follicular lymphoma and most of them now enjoy robust health.

Treatment of elderly Hodgkin's lymphoma patients with a novel 5-drug regimen (ODBEP): a phase II study.

Elderly patients with Hodgkin's lymphoma (HL) have a worse outcome than young patients. In an effort to improve the outcome in elderly HL patients, we used a 5-drug chemotherapy regimen called ODBEP (vincristine, doxorubicin, bleomycin, etoposide, prednisone) from 1986-1995. We hoped that by increasing dose intensity through delivery of treatment without delays, and increasing the number of non-cross-resistant chemotherapeutic drugs that were selected for minimal cumulative myelotoxicity, we might improve the cure rate in elderly patients with Hodgkin's lymphoma. Comparison was made with a similar group of patients treated from 1981-1986 with MOPP/ABV-variant chemotherapy. Ninety-nine patients who were 65 years or older, were diagnosed with HL from 1981-1995. Seventy-one patients had advanced disease and 55 of this group were treated with curative intent using multi-agent chemotherapy (ODBEP = 38; MOPP/ABV-variant = 17). ODBEP and MOPP/ABV-type treatment gave a median survival of 43 and 39 months, with 5-year overall survival (OS) of 42 and 32%, respectively. There was no statistically significant difference in OS or disease specific survival between the treatments. Both treatments were well tolerated, but ODBEP was less myelotoxic. ODBEP patients had a relative risk of 0.47 of developing febrile neutropenia compared to the MOPP/ABV-variant patients. In conclusion, treatment of elderly Hodgkin's lymphoma patients with ODBEP resulted in a similar OS and disease-specific survival compared to those treated with MOPP/ABV type chemotherapy, but appeared to be less toxic.

Brief chemotherapy and involved-region irradiation for limited-stage diffuse large-cell lymphoma: an 18-year experience from the British Columbia Cancer Agency.

PURPOSE: To evaluate clinical outcome of patients with limited-stage diffuse large-cell lymphoma (DLCL) treated with three cycles of chemotherapy followed by involved-region irradiation (IRRT). PATIENTS AND METHODS: Adults with limited-stage DLCL were treated with brief doxorubicin-containing chemotherapy regimens between 1980 and 1998. IRRT was administered 3 to 4 weeks after the third chemotherapy treatment in a dose equivalent to 30 Gy in 10 fractions. RESULTS: Three hundred and eight patients (median age, 64 years) were included, and 299 experienced complete remission. After a median follow-up of 86 months, 64 patients developed progressive disease, and 104 patients died (43 from lymphoma, three from toxicity, and 58 from other causes). Actuarial overall and progression-free survival (PFS) rates were, respectively, 80% and 81% at 5 years and 63% and 74% at 10 years. For subgroups identified using the Miller modification of the International Prognostic Index (IPI), the overall survival rates at 5 and 10 years were, respectively, 97% and 89% (no factors), 77% and 56% (one or two factors), and 58% and 48% (three or four factors), and the 5-year and 10-year PFS rates were, respectively, 94% and 89% (no factors), 79% and 73% (one or two factors), and 60% and 50% (three or four factors). Men with testicular presentation, had a definitely inferior outcome. CONCLUSION: Long-term outcome with three cycles of doxorubicin-based chemotherapy and IRRT confirms that this is a successful approach for the majority of patients with limited-stage DLCL. Subgroups with worse prognoses can be identified, and these patients should be offered alternative treatment approaches.