New expert advice on cancer in pregnancy.

Cancer in pregnancy is rare, and most physicians lack knowledge in handling pregnant cancer patients. This review summarises the present knowledge on this condition. In the Netherlands, an Advisory Board on Cancer in Pregnancy was established in 2012. The board supports Dutch physicians' decisions in the management of pregnant patients with cancer. In 2021 the International Advisory Board on Cancer in Pregnancy was established, and in continuation, the Danish Advisory Board on Cancer in Pregnancy (DABCIP) has now been founded. DABCIP consists of 22 members from 13 different medical disciplines.

Pretreatment Hemoglobin Adds Prognostic Information To The NCCN-IPI In Patients With Diffuse Large B-Cell Lymphoma Treated With Anthracycline-Containing Chemotherapy.

BACKGROUND: Hemoglobin (Hgb) concentration at diagnosis is associated with outcome in cancer. In a recently reported simplified 3-factor prognostic score in Hodgkin lymphoma, Hgb, along with age and clinical stage, outperformed the classical International Prognostic Score with seven parameters. METHODS: In the present study, we investigated if pretherapeutic Hgb concentration added prognostic information to the NCCN-IPI in diffuse large B-cell lymphoma. We included patients from the Danish Lymphoma Registry (LYFO; N = 3499) and from the Molecular Epidemiology Resource (MER; N = 1225), Mayo Clinic and University of Iowa. Four sex-specific Hgb groups were defined: below transfusion threshold, from transfusion threshold to below lower limit of normal, from lower limit of normal to the population mean, and above the mean. We used multivariable Cox regression to estimate the hazard rate ratios (HR) and 95% CIs for overall survival (OS) and event-free survival (EFS), adjusting for sex, NCCN-IPI, comorbidity, and rituximab treatment. RESULTS: Approximately half of the patients had Hgb levels below the lower limit of normal. Compared to patients with Hgb levels above the mean, an inferior OS was directly correlated with lower pretreatment Hgb within the predefined groups (HR=1.23, HR=1.51, and HR=2.05, respectively). These findings were validated in the MER. CONCLUSION: Based on multivariable analysis, lower pretreatment Hgb, even within the normal range but below the mean, added prognostic information to established indices such as the NCCN-IPI and the Charlson comorbidity index.

Treatment intensity and survival in patients with relapsed or refractory diffuse large B-cell lymphoma in Denmark: a real-life population-based study.

PURPOSE: High-dose chemotherapy with autologous stem cell transplantation (ASCT) is considered to be the only curative treatment option for patients with refractory or relapsed diffuse large B-cell lymphoma (DLBCL). Due to toxicity, not all patients are eligible for this treatment leading to different treatment intensities. Here, we aim to analyze the impact of treatment intensity on survival in patients previously treated with rituximab and chemotherapy, and, furthermore, to analyze the association between socioeconomic position and treatment intensity, defined as palliation, non-salvage, and salvage regimens. MATERIALS AND METHODS: We identified patients with refractory or relapsed DLBCL diagnosed in 2000-2015 in the Danish National Lymphoma Registry (n=1,228). We analyzed the impact of treatment intensity on survival in patients previously treated with rituximab (n=277) using a Cox proportional hazards model. Multinomial regression analyses were performed to identify associations between socioeconomic factors and treatment intensity for the entire cohort. RESULTS: In the rituximab era, the 5-year overall survival (OS) was 31% for patients receiving salvage regimens (n=194), and 17% for patients receiving non-salvage regimens (n=83). In the adjusted analysis, HR was 1.88, 95% CI: 0.9-3.9 for patients receiving salvage regimens. Patients living alone were significantly less likely to receive salvage regimens, as were patients with two or more comorbidities. CONCLUSION: We observed a better OS in patients treated with salvage regimens compared with non-salvage regimens; however, the adjusted analysis contradicts this. Furthermore, our results indicate that there is a chance of remission for patients not eligible for ASCT.

Glucagon-Like Peptide-1 Is a Marker of Systemic Inflammation in Patients Treated with High-Dose Chemotherapy and Autologous Stem Cell Transplantation.

Autologous stem cell transplantation (ASCT) is challenged by side effects that may be propagated by chemotherapy-induced mucositis, resulting in bacterial translocation and systemic inflammation. Because gastrointestinal damage appears as an early event in this cascade of reactions, we hypothesized that markers reflecting damage to the intestinal barrier could serve as early predictive markers of toxicity. Glucagon-like peptide-1 (GLP-1), a well-known regulator of blood glucose, has been found to promote intestinal growth and repair in animal studies. We investigated fasting GLP-1 plasma levels in 66 adults undergoing ASCT for lymphoma and multiple myeloma. GLP-1 increased significantly after chemotherapy, reaching peak levels at day +7 post-transplant (median, 8 pmol/L [interquartile range, 4 to 12] before conditioning versus 10 pmol/L [interquartile range, 6 to 17] at day +7; P = .007). The magnitude of the GLP-1 increase was related to the intensity of conditioning. GLP-1 at the day of transplantation (day 0) was positively associated with peak C-reactive protein (CRP) levels (46 mg/L per GLP-1 doubling, P < .001) and increase in days with fever (32% per GLP-1 doubling, P = .0058). Patients with GLP-1 above the median at day 0 had higher CRP levels from days +3 to +10 post-transplant than patients with lower GLP-1 (P ≤ .041) with peak values of 238 versus 129 mg/L, respectively. This study, which represents the first clinical investigation of fasting GLP-1 in relation to high-dose chemotherapy, provides evidence that GLP-1 plays a role in regulation of mucosal defenses. Fasting GLP-1 levels may serve as an early predictor of systemic inflammation and fever in patients receiving high-dose chemotherapy.

Depth of neutrophil nadir after first cycle of R-CHOP predicts outcome in diffuse large B-cell lymphoma - a nationwide population-based cohort study.

We investigated if survival was predicted by nadir neutrophil counts after the first cycle of R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Neutrophil counts (109/L) were categorized in four grades in the nadir time frame. Prognostic indices and comorbidity levels were calculated and used to adjust the Cox regression model. Kaplan-Meier and Cox regression methods were used to estimate and compare survival. We identified 965 patients. Grade 4 neutropenia was present in 432 (45%). Grade 0 patients had a 5-year overall survival of 67%, grade 1-2: 78%, grade 3: 64%, and grade 4: 57%. Compared with grade 0 adjusted hazard ratios (HR) for death were: 0.77 (95% CI 0.49-1.21) for grade 1-2, 1.18 (95% CI 0.82-1.71) for grade 3, and 1.33 (95% CI 1.02-1.73) for grade 4. Grade 4 neutropenia after the 1st cycle of chemotherapy predicted inferior outcome compared with grade 0 and 1-2. Grade 1-2 neutropenia seemed to have superior outcome.

Pentaisomaltose, an Alternative to DMSO. Engraftment of Cryopreserved Human CD34+ Cells in Immunodeficient NSG Mice.

Hematopoietic stem cell transplantation often involves the cryopreservation of stem cell products. Currently, the standard cryoprotective agent (CPA) is dimethyl sulfoxide (DMSO), which is known to cause concentration-related toxicity and side effects when administered to patients. Based on promising in vitro data from our previous study using pentaisomaltose (a 1 kDa subfraction of Dextran 1) as an alternative to DMSO for cryopreservation of hematopoietic progenitor cells (HPCs) from apheresis products, we proceeded to a preclinical model and compared the two CPAs with respect to engraftment of human hematopoietic stem and progenitor cells (HSPCs) in the immunodeficient NSG mouse model. Human HPCs from apheresis products were cryopreserved with either pentaisomaltose or DMSO, and the following outcomes were measured: (1) the post-thaw recovery of cryopreserved cells and clonogenic potential of CD34+ cells and (2) hematopoietic engraftment in NSG mice. We found that recovery and colony-forming cells data were comparable between pentaisomaltose and DMSO. The engraftment data revealed comparable human CD45+ levels in peripheral blood at 8 weeks and bone marrow at 16 weeks post transplantation. Additionally, the frequencies of CD34+CD38low/negative and myeloid/lymphoid cells in the bone marrow were comparable. We here demonstrated that long-term engrafting HSPCs were well preserved in pentaisomaltose and comparable to cells cryopreserved with DMSO. Although a clinical trial is necessary to translate these results into human use, the present data represent an important step toward the replacement of DMSO with a non-toxic alternative.

Styrene Exposure and Risk of Lymphohematopoietic Malignancies in 73,036 Reinforced Plastics Workers.

BACKGROUND: Styrene is an important industrial chemical that the general population is exposed to at low levels. Previous research has suggested increased occurrence of leukemia and lymphoma among reinforced plastics workers exposed at high levels of styrene. METHODS: We followed 73,036 workers of 456 small- and medium-sized Danish reinforced plastics companies from 1968 to 2011 and investigated the exposure-response relation between cumulative styrene exposure and incidence of lymphohematopoietic malignancies. We modeled styrene exposure from employment history, survey data, and historical styrene exposure measurements. We retrieved information on lymphohematopoietic malignancies from national cancer and patient registers. RESULTS: We identified 665 cases overall of 21 different lymphohematopoietic malignancies or combinations thereof, each with at least 20 cases, during 1,581,976 person-years of follow-up. Initial analyses suggested higher age, sex, and calendar year-adjusted incidence rate ratios (RRs) for acute myeloid leukemia, Hodgkin lymphoma, and T-cell lymphoma with higher estimates of cumulative styrene exposure. Accounting for time since exposure showed a trend by cumulative styrene exposure (P = 0.01) and a doubled risk (RR = 2.4; 95% CI, 1.2, 4.6) of acute myeloid leukemia following estimated high compared with estimated low cumulative exposure during the prior 15-29 years. We observed no increased risk following exposure during more recent years and less consistent risk patterns for Hodgkin lymphoma and T-cell lymphoma. CONCLUSIONS: This study, to our knowledge the largest epidemiologic study to date of occupational styrene exposure, suggests increased risk of acute myeloid leukemia following high styrene exposure with a latency period of about 15 years.

Prolonged hospitalization, primary refractory disease, performance status and age are prognostic factors for survival in patients with diffuse large B-cell lymphoma and transformed indolent lymphoma undergoing autologous stem cell transplantation.

In patients with relapsed diffuse large B-cell lymphoma (DLBCL), high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is standard treatment. Here, we aim to identify factors associated with survival in patients undergoing ASCT. A total of 369 patients with relapsed DLBCL undergoing ASCT from 2000 to 2012 were identified in the Danish National Lymphoma Registry. Information on clinical and socioeconomic factors was obtained from medical records and national registries. Factors associated with survival were assessed using a Cox's proportional hazards model. Median overall survival was 6.8 years, median progression-free survival was 2.6 years, and treatment-related mortality at Day 100 was 6%. Factors associated with a significant adverse impact on survival were age, primary refractory disease, prolonged hospitalization during salvage treatment, and performance status >0 prior to conditioning therapy. Reconsideration of ASCT for those patients may be required in order to select the right patients for this toxic procedure.

The Danish National Lymphoma Registry: Coverage and Data Quality.

BACKGROUND: The Danish National Lymphoma Register (LYFO) prospectively includes information on all lymphoma patients newly diagnosed at hematology departments in Denmark. The validity of the clinical information in the LYFO has never been systematically assessed. AIM: To test the coverage and data quality of the LYFO. METHODS: The coverage was tested by merging data of the LYFO with the Danish Cancer Register and the Danish National Patient Register, respectively. The validity of the LYFO was assessed by crosschecking with information from medical records in subgroups of patients. A random sample of 3% (N = 364) was made from all patients in the LYFO. In addition, four subtypes of lymphomas were validated: CNS lymphomas, diffuse large B-cell lymphomas, peripheral T-cell lymphomas, and Hodgkin lymphomas. A total of 1,706 patients from the period 2000-2012 were included. The positive predictive values (PPVs) and completeness of selected variables were calculated for each subgroup and for the entire cohort of patients. RESULTS: The comparison of data from the LYFO with the Danish Cancer Register and the Danish National Patient Register revealed a high coverage. In addition, the data quality was good with high PPVs (87% to 100%), and high completeness (92% to 100%). CONCLUSION: The LYFO is a unique, nationwide clinical database characterized by high validity, good coverage and prospective data entry. It represents a valuable resource for future lymphoma research.

Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial.

BACKGROUND: Standard treatment for patients with primary CNS lymphoma remains to be defined. Active therapies are often associated with increased risk of haematological or neurological toxicity. In this trial, we addressed the tolerability and efficacy of adding rituximab with or without thiotepa to methotrexate-cytarabine combination therapy (the MATRix regimen), followed by a second randomisation comparing consolidation with whole-brain radiotherapy or autologous stem cell transplantation in patients with primary CNS lymphoma. We report the results of the first randomisation in this Article. METHODS: For the international randomised phase 2 International Extranodal Lymphoma Study Group-32 (IELSG32) trial, HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and measurable disease were enrolled from 53 cancer centres in five European countries (Denmark, Germany, Italy, Switzerland, and the UK) and randomly assigned (1:1:1) to receive four courses of methotrexate 3·5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m(2) on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m(2) on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after the first stage were then randomly allocated between whole-brain radiotherapy and autologous stem cell transplantation. A permuted blocks randomised design (block size four) was used for both randomisations, and a computer-generated randomisation list was used within each stratum to preserve allocation concealment. Randomisation was stratified by IELSG risk score (low vs intermediate vs high). No masking after assignment to intervention was used. The primary endpoint of the first randomisation was the complete remission rate, analysed by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01011920. FINDINGS: Between Feb 19, 2010, and Aug 27, 2014, 227 eligible patients were recruited. 219 of these 227 enrolled patients were assessable. At median follow-up of 30 months (IQR 22-38), patients treated with rituximab and thiotepa had a complete remission rate of 49% (95% CI 38-60), compared with 23% (14-31) of those treated with methotrexate-cytarabine alone (hazard ratio 0·46, 95% CI 0·28-0·74) and 30% (21-42) of those treated with methotrexate-cytarabine plus rituximab (0·61, 0·40-0·94). Grade 4 haematological toxicity was more frequent in patients treated with methotrexate-cytarabine plus rituximab and thiotepa, but infective complications were similar in the three groups. The most common grade 3-4 adverse events in all three groups were neutropenia, thrombocytopenia, anaemia, and febrile neutropenia or infections. 13 (6%) patients died of toxicity. INTERPRETATION: With the limitations of a randomised phase 2 study design, the IELSG32 trial provides a high level of evidence supporting the use of MATRix combination as the new standard chemoimmunotherapy for patients aged up to 70 years with newly diagnosed primary CNS lymphoma and as the control group for future randomised trials. FUNDING: Associazione Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Foundation.

Low-molecular-weight carbohydrate Pentaisomaltose may replace dimethyl sulfoxide as a safer cryoprotectant for cryopreservation of peripheral blood stem cells.

BACKGROUND: Cryopreserved hematopoietic stem cell products are widely used for certain hematologic malignancies. Dimethyl sulfoxide (DMSO) is the most widely used cryoprotective agent (CPA) today, but due to indications of cellular toxicity, changes of the cellular epigenetic state, and patient-related side effects, there is an increasing demand for DMSO-free alternatives. We therefore investigated whether Pentaisomaltose (PIM), a low-molecular-weight carbohydrate (1 kDa), can be used for cryopreservation of peripheral blood stem cells, more specifically hematopoietic progenitor cell apheresis (HPC(A)) product. STUDY DESIGN AND METHODS: We cryopreserved patient or donor HPC(A) products using 10% DMSO or 16% PIM and quantified the recovery of CD34+ cells and CD34+ subpopulations by multicolor flow cytometry. In addition, we compared the frequency of HPCs after DMSO and PIM cryopreservation using the colony-forming cells (CFCs) assay. RESULTS: The mean CD34+ cell recovery was 56.3 ± 23.7% (11.4%-97.3%) and 58.2 ± 10.0% (45.7%-76.9%) for 10% DMSO and 16% PIM, respectively. The distribution of CD34+ cell subpopulations was similar when comparing DMSO or PIM as CPA. CFC assay showed mean colony numbers of 70.7 ± 25.4 (range, 37.8-115.5) and 67.7 ± 15.7 (range, 48-86) for 10% DMSO and 16% PIM, respectively. CONCLUSION: Our findings demonstrate that PIM cryopreservation of HPC(A) products provides recovery of CD34+ cells, CD34+ subpopulations, and CFCs similar to that of DMSO cryopreservation and therefore may have the potential to be used for cryopreservation of peripheral blood stem cells.

[Chemotherapy in the second and third trimester of pregnancy is compatible with the delivery of a healthy infant]. / Kemoterapi i andet og tredje trimester er foreneligt medforløsning af et raskt barn

This case report describes the delay in diagnosis and treatment of a diffuse large B-cell lymphoma in pregnancy of a 27-year-old woman. Chemotherapy was initiated in week 21 of pregnancy - the tumour regressed and the foetus had linear growth. The patient had caesarean section in week 34, and after delivery she received high doses of methotrexate and obtained complete remission. The two-year-old infant had a normal development.

Optimized patient-trajectory for patients undergoing treatment with high-dose chemotherapy and autologous stem cell transplantation.

PURPOSE: Before, during and after autologous hematopoietic stem cell transplantation (HD-ASCT) patients suffer from significant loss of physical function, and experience multiple complications during and after hospitalization. Studies regarding safety and feasibility of physical exercise interventions for patients undergoing treatment with HD-ASCT are missing. METHODS: Forty patients referred to HD-ASCT treatment, suffering from multiple myeloma, lymphoma or amyloidosis aged 23-70 years were enrolled in a prospective longitudinal study. The study consisted of a home-based exercise program for use in the ambulatory setting and supervised exercise sessions Monday to Friday for 30-40 minutes during admission. Safety of the exercise program and physical tests were assessed by using a weekly questionnaire and report of inadvertent incidences. Adherence to the home-based exercise program was reported by using a patient diary, weekly questionnaire and count of daily attendance in supervised sessions during hospital stay. Data collection was scheduled shortly after diagnosis, admission, discharge and eight weeks after discharge. Success criteria were: no severe adverse events in relation to exercise program and assessments; performance of three days of physical exercises during ambulatory period and hospital stay and 150 minutes of weekly physical activity. RESULTS: Of the 25 patients who completed the exercise program during the ambulatory period prior to HD-ASCT a mean weekly attendance to home exercises of 5.3 (± 2.8) days and a median weekly physical activity of 240 (± 153.8) minutes was found. During hospital stay the median attendance was 9 (± 3.9) days of 10 (± 6.9) possible. Two months after discharge the patients reported a median weekly physical activity of 360 (2745.5) minutes. No severe adverse events in relation to the exercise program or assessments were reported. CONCLUSION: Based on the enrolled number of patients the physical exercise intervention for patients undergoing HD-ASCT seems promising regarding feasibility and safety.