Olav Jonas Bergmann

Oral mucosal lesions, microbial changes, and taste disturbances induced by adjuvant chemotherapy in breast cancer patients

OBJECTIVE The aim of the study was to examine oral mucosal lesions, microbial changes, and taste disturbances induced by adjuvant chemotherapy (CT) in breast cancer patients during and 1 year after treatment. STUDY DESIGN Forty-five consecutive breast cancer patients, eligible for adjuvant CT with cyclophosphamide, epirubicin or methotrexate, and 5-fluorouracil were followed before, during, 6 months and 1 year after CT and were compared to a control group of 31 breast cancer patients not receiving adjuvant CT. RESULTS During CT, oral mucosal lesions developed including erythema (n = 10, 22%) and ulceration (n = 7, 16%). Five patients (11%) were diagnosed with oral candidosis. Scores of dental bacterial plaque and gingival inflammation increased during CT and the oral microbial composition changed towards a more acidophilic flora. Taste disturbances were experienced by 84% (n = 38) of the patients in the CT group. CONCLUSION In breast cancer patients, moderate-intensive adjuvant CT caused oral mucosal lesions, oral candidosis, taste disturbances and a more acidophilic oral microflora. These adverse effects were temporary and the majority of the patients were mildly affected.

High Serum Concentration of YKL-40 Is Associated with Short Survival in Patients with Acute Myeloid Leukemia

Purpose: YKL-40 is secreted by cancer cells, macrophages, and neutrophils. It may be a growth or differentiation factor, play a role in angiogenesis, or protect against apoptosis. High serum YKL-40 is associated with poor prognosis in solid carcinomas. The aim was to examine serum YKL-40 in patients with acute myeloid leukemia (AML). Experimental Design: YKL-40 was measured by ELISA in serum from 77 patients recently diagnosed with AML before and during the first month of chemotherapy. Results: Forty (52%) of the AML patients had elevated serum YKL-40 (compared with age-matched healthy subjects) and their survival was shorter than in patients with normal serum YKL-40 (median, 128 days; interquartile range, 18-629 days versus 386 days; interquartile range, 180-901; P = 0.018 Mann-Whitney test). Univariate analysis of serum YKL-40 (logarithmically transformed and treated as a continuous covariate) showed significant association with survival within the first month after start of chemotherapy [hazard ratio (HR), 1.7; 95% confidence interval (CI), 1.2-2.4; P = 0.002], first 12 months (HR, 1.6; 95% CI, 1.2-2.0; P = 0.0002), and overall survival (HR, 1.3; 95% CI, 1.1-1.6; P = 0.003). Multivariate Cox analysis showed that serum YKL-40 was an independent prognostic variable for survival (first month: HR, 1.7; P = 0.011; 12 months: HR, 1.6; P = 0.0002; overall survival: HR, 1.4; P = 0.002). High serum YKL-40 at start of chemotherapy was a risk factor for pneumonia within the first month, and serum YKL-40 increased (P = 0.002) at time of pneumonia and was unchanged in patients without infections. Conclusions: Serum YKL-40 is a prognostic biomarker of survival in AML patients. Its role in AML and infections needs to be determined.

NPM1 mutation is a stable marker for minimal residual disease monitoring in acute myeloid leukaemia patients with increased sensitivity compared to WT1 expression.

Mutation in the NPM1 gene occurs in 60% of acute myeloid leukaemia (AML) patients with normal karyotype. NPM1 mutation is potentially a superior minimal residual disease (MRD) marker compared to WT1 gene overexpression by being specific to the malignant clone, although experimental evidence published so far includes very limited numbers of relapsed cases. Also, the stability of the NPM1 mutation has been questioned by reports of the mutation being lost at relapse. In the present study we compared NPM1 mutation and WT1 overexpression as MRD markers in 20 cases of relapsed AML. The 20 patients experienced a total of 28 morphological relapses. Karyotypic evolution was detected in 56% of relapses. All relapses were accompanied by high levels of NPM1 mutation, along with high WT1 mRNA levels, thus demonstrating complete stability of both markers during relapse. Detectable NPM1 mutation following a period of morphological remission was accompanied by a morphological relapse in all cases. In contrast, WT1 expression was detected in 33% of the NPM1 mutation negative samples. This background WT1 expression produced by non‐leukaemia cells was highly variable, both between and within patients, and limited the de facto sensitivity of the WT1 expression analysis. The present study therefore provides important experimental evidence demonstrating that NPM1 mutation is superior to WT1 overexpression as marker of MRD in NPM1‐mutated AML, even in the presence of extensive karyotypic evolution.

Cytogenetic findings in adult secondary acute myeloid leukemia (AML): frequency of favorable and adverse chromosomal aberrations do not differ from adult de novo AML

During a 15-year period, 161 adult patients were diagnosed with secondary acute myeloid leukemia (s-AML) in the region of Southern Denmark. In 73 patients, the AML diagnosis was preceded by myelodysplastic syndrome (MDS-AML), in 31 patients by an antecedent hematologic disease, and in 57 patients by treatment with chemotherapy and/or irradiation (t-AML). Cytogenetic analysis was carried out in 93%, of which 61% had clonal chromosome aberrations. MDS-AML correlated to a normal karyotype (P < 0.001). t-AML correlated to abnormal clones with numerical and structural aberrations (P = 0.03), five or more unrelated aberrations (P = 0.03), marker chromosomes (P = 0.006), abnormal mitoses only (P = 0.01), female sex (P < 0.001), and -7 (P = 0.006). Centromeric breakage correlated to a complex karyotype (P = 0.01). The frequencies of aberrations in s-AML patients were compared with an age-matched group of de novo AML patients diagnosed in the same area and period. In this comparison, s-AML only correlated to -7 (P = 0.02). In 42 patients, we found that MDS patients with an abnormal karyotype were more likely to show cytogenetic evolution during progression to AML than MDS patients with a normal karyotype (P = 0.01). We conclude that population-based cytogenetic studies of adult s-AML and age- and sex-matched de novo AML show comparable distributions of chromosome abnormalities.

Prediction of haemorrhage in the early stage of acute myeloid leukaemia by flow cytometric analysis of platelet function

Haemorrhage is often responsible for the lethal course of acute myeloid leukaemia (AML). Previously, multiple platelet function defects were identified by flow cytometric analysis of platelet activation markers in AML. The role of flow cytometric analysis of platelet function in characterization of prognostic markers of haemorrhage in AML patients has not been well elucidated. The objective of this prospective study was to analyse platelet function in 50 AML patients at diagnosis and to compare results with clinical bleeding score, graded by common toxicity criteria. Platelet activation markers CD62P, CD42b, CD63 and PAC‐1 were analysed following in vitro activation by thrombin receptor activating peptide. The following plasma haemostasis parameters were measured: soluble P‐selectin, activated partial thromboplastin time, thrombin time, prothrombin time, d‐dimer, fibrinogen, and von Willebrand factor antigen. In a multivariate analysis, P‐selectin (CD62P) <36 molecules of equivalent soluble fluorochrome × 103 (P < 0·0015) and platelet count <40 × 109/l (P = 0·01) were significant predictors of haemorrhage at diagnosis. Haemorrhage at diagnosis predicted grade 3–4 haemorrhage in the first 28 d following diagnosis (P = 0·018). The presented results indicate that low P‐selectin is a prognostic marker of haemorrhage in AML.

Clinical Impact of Leukemic Blast Heterogeneity at Diagnosis in Cytogenetic Intermediate-Risk Acute Myeloid Leukemia

Individual cellular heterogeneity within the acute myeloid leukemia (AML) bone marrow samples can be observed by multi parametric flow cytometry analysis (MFC) indicating that immunophenotypic screening for leukemic blast subsets may have prognostic impact.

A population-based study of prognosis in advanced stage follicular lymphoma managed by watch and wait

Watch and wait (WAW) is a common approach for asymptomatic, advanced stage follicular lymphoma (FL), but single‐agent rituximab is an alternative for these patients. In this nationwide study we describe the outcome of patients selected for WAW. A cohort of 286 out of 849 (34%) stage III‐IVA FL patients seen between 2000 and 2011, were managed expectantly and included. The 5‐year progression‐free survival (PFS) was 35% [95% confidence interval (CI) 29–42]. The 10‐year overall survival (OS) was 65% (95%CI 54–78), and the cumulative risk of dying from lymphoma within 10 years of diagnosis was 13% (95%CI 7–20). Elevated lactate dehydrogenase and > four nodal regions involved were associated with a higher risk of lymphoma treatment and death from lymphoma. The WAW patients and a matched background population had similar OS during the first 50 months after diagnosis (P = 0·7), but WAW patients had increased risk of death after 50 months (P < 0·001). The estimated loss of residual life after 10 years was 6·8 months. The 10‐year cumulative risk of histological transformation was 22% (95%CI 15–29) and the 3‐year OS after transformation was 71% (95%CI 58–87%). In conclusion, advanced stage FL managed by WAW had a favourable outcome and abandoning this strategy could lead to overtreatment in some patients.

Minimal Loss of Lifetime for Patients With Diffuse Large B-Cell Lymphoma in Remission and Event Free 24 Months After Treatment: A Danish Population-Based Study

Purpose The general outlook for patients with diffuse large B-cell lymphoma (DLBCL) in first remission is important information for patients and for planning post-treatment follow-up. The purpose of this study was to evaluate the survival of patients with DLBCL in remission compared with a matched general population. Methods A total of 1,621 patients from the Danish Lymphoma Registry who were newly diagnosed with DLBCL between 2003 and 2011 were included in this study. All patients were ≥ 16 years of age at diagnosis and had achieved complete remission or complete remission unconfirmed after first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP-like therapy. Results The 5-year post-treatment DLBCL survival was inferior to survival in the matched general population (78%; 95% CI, 76 to 80; v 87%; standardized mortality ratio, 1.75; P < .001). Excess mortality was present but reduced for patients achieving post-treatment event-free survival for 24 months (pEFS24; standardized mortality ratio, 1.27; P < .001). In age-stratified analyses, the survival of patients < 50 years of age was normalized to the general population after achieving pEFS24 ( P = .99). During the first 8 years after pEFS24, the average loss of lifetime was 0.31 mo/y (95% CI, 0.11 to 0.50 mo/y). Excess mortality diminished when analyzing death from lymphoma as competing event to death from other causes, suggesting that early and late relapse is responsible for increased mortality in patients with DLBCL. Conclusion Although this population-based study does not support complete normalization of survival for patients with DLBCL achieving pEFS24, the estimated loss of residual lifetime was low for patients in continuous remission 2 years after ending treatment. Therefore, pEFS24 is an appealing and relevant milestone for patient counseling and could be a surrogate end point in clinical trials.

The Danish National Chronic Lymphocytic Leukemia Registry

Aim In 2008, the Danish National Chronic Lymphocytic Leukemia Registry was founded within the Danish National Hematology Database. The primary aim of the registry is to assure quality of diagnosis and care of patients with chronic lymphocytic leukemia (CLL) in Denmark. Secondarily, to evaluate adherence to national guidelines and to provide source data for research purposes. Study population All patients diagnosed with CLL in Denmark from 2008 onward are included in the registry. Patients are followed in one of nine hematology centers. All centers participate in the registry and are all obliged to collect data. Main variables Predefined data are collected at the time of diagnosis, and follow-up at the time of significant events: treatment, progression, transplantation, and death. Parameters included in the International Workshop on Chronic Lymphocytic Leukaemia criteria for diagnosis, and for decision on treatment initiation as well as characteristics included in the CLL International Prognostic Index are collected. Descriptive data To ensure full coverage of Danish CLL patients in the registry, both continuous queries in case of missing data, and cross-referencing with the Danish National Patient Registry are performed. Data from the registry are published in an annual report summarizing the collected data, the overall survival for yearly cohorts, and the degree of data coverage. Per year approximately 450 new patients with CLL are registered in the registry, cumulative as of July 1, 2015, 3,082 patients have been registered. Conclusion The Danish National CLL Registry is based within the Danish National Hematology Database. The registry covers a cohort of all patients diagnosed with CLL in Denmark since 2008. It forms the basis for quality assessment of CLL treatment in Denmark and offers a unique opportunity for population-based research.

Double versus single high-dose melphalan 200 mg/m2 and autologous stem cell transplantation for multiple myeloma: a region-based study in 484 patients from the Nordic area

Autologous stem cell transplantation is still considered the standard of care in young patients with multiple myeloma (MM). This disease is the most common indication for high-dose therapy (HDT) supported by hematopoietic stem cell transplantation and much data support the benefit of this procedure. Results of randomized studies are in favor of tandem autologous transplantation although the effect on overall survival is unclear. Based on sequential registration trials in the Nordic area, we aimed to evaluate the outcome of conventional single or double HDT. During 1994–2000 we registered a total of 484 previously untreated patients under the age of 60 years at diagnosis who on a regional basis initially were treated with single [Trial NMSG #5/94 and #7/98 (N=383)] or double [Trial Huddinge Karolinska Turku Herlev (N=101)] high-dose melphalan (200 mg/m2) therapy supported by autologous stem cell transplantation. A complete or very good partial response was achieved by 40% of patients in the single transplant group and 60% of patients in the double transplant group (p=0.0006). The probability of surviving progression free for five years after the diagnosis was 25% (95% CL 18–32%) in the singletransplant group and 46% (95% CL 33–55%) in the double transplant group (p=0.0014). The estimated overall five-year survival rate was 60% in the single transplant group and 64% in the doubletransplant (p=0.9). In a multivariate analysis of variables, including single versus double transplantation, β2 microglobulin level, age, sex and disease stage, only β2 microglobulin level was predictive for overall survival (p>0.0001) and progression free survival (p=0.001). In accordance with these results, a 1:1 case-control matched comparison between double and single transplantation did not identify significant differences in overall and progression free survival. In this retrospective analysis up front double transplantation with melphalan (200 mg/m2) as compared to single transplantation did not seem to improve the final outcome among patients in the Nordic area. These data are in accordance with recent publications from the Bologna 96 trial indicating that a second transplant should not be recommended up front as standard care.