Anita Gustavsson

Early and late invasive pneumococcal infection following stem cell transplantation: a European Bone Marrow Transplantation survey

Summary.  Streptococcus pneumoniae (S. pneumoniae) may cause severe and lethal infections months and years following stem cell transplantation (SCT). In a prospective survey over a 3·5‐year period, we assessed the incidence, risk factors and outcome for invasive pneumococcal infection (IPI) following SCT. Fifty‐one episodes of IPI were reported: 43 episodes after bone marrow transplantation (BMT) and 8 after peripheral blood stem cell transplantation (PBSCT); 35 after allogeneic SCT and 16 after autologous SCT. Seven IPI episodes, all bacteraemias, were defined as early, occurring 1–35 d (median 3 d) post transplantation. Forty‐four episodes were defined as late (≥ 100 d post SCT), occurring 4 months to 10 years (median 17 months) post transplantation. The incidences of early and late IPI were 2·03/1000 and 8·63/1000 transplantations respectively (P = 0·001). A higher incidence of late IPI was observed after BMT than after PBSCT (10·99 versus 3·23/1000; P < 0·01) and after allogeneic versus autologous SCT (12·20 versus 4·60/1000; P < 0·01). There was a higher estimated incidence of IPI in allogeneic patients with than in those without graft‐versus‐host disease (GVHD) (18·85 versus 8·25/1000; P = 0·015). The mortality rate was 20%, including 2/7 of early and 8/44 of late IPI. S. pneumoniae is a rare but important complication during the aplastic phase after SCT. In conclusion, S. pneumoniae is a significant cause of morbidity late post‐transplantation, especially in allogeneic patients, and particularly those with GVHD. The high IPI mortality rate, both early and late post‐transplantation, requires preventive approaches, mainly effective immunization.

Scalp hypothermia to prevent chemotherapy-induced alopecia is effective and safe: a pilot study of a new digitized scalp-cooling system used in 74 patients.

GoalsThe aim of this study was to examine the efficacy and safety of a new digitized, controlled, scalp-cooling system to prevent chemotherapy-induced alopecia.MethodSeventy-four female cancer patients who received 13 varying chemotherapy regimens were included in a nonrandomized pilot study. The Digni 2–3 with Dignicap system consists of a refrigerator unit and a control unit integrated into a mobile cabinet and connected to a tight-fitting cooling cap. This system maintains a constant scalp temperature of +5°C for many hours. In this study, 60 patients were treated for ovarian cancer with either taxane or epirubicin combination chemotherapy. Eight patients with Hodgkins lymphoma, three with breast cancer, two with endometrial cancer, and one with sarcoma were also included. Photo documentation and patient assessment of hair loss and discomfort were performed.ResultsIn anthracycline-treated patients, total prevention of hair loss was observed, whereas hair loss in paclitaxel/docetaxel-treated patients was minimal to none. The combination of anthracycline and taxane resulted in more hair loss, but only three of six patients used a wig. Scalp cooling was generally very well tolerated; only two of 74 patients discontinued use of the cold cap due to discomfort. No scalp metastases occurred over a median follow-up period of 15 months.ConclusionsThe digitized, controlled, scalp-cooling system represents an effective and safe device that should be clinically evaluated in a randomized trial and in studies using other chemotherapy regimens to determine optimal temperatures and durations of cooling for maximal efficacy.

Radiation-Associated Sarcomas are Characterized by Complex Karyotypes with Frequent Rearrangements of Chromosome Arm 3p

Ionizing radiation is a well-known risk factor for sarcoma development. To investigate whether radiation-associated sarcomas are characterized by chromosome aberrations that distinguish them from de novo sarcomas, we identified those patients in our series of more than 500 cytogenetically abnormal sarcomas that fulfilled the following criteria: (1) each patient should have been irradiated for another malignancy at least 3 years prior to the sarcoma diagnosis, and (2) the sarcoma should have developed within the field of radiation. Ten patients fulfilling these criteria could be retrieved (median age at sarcoma diagnosis was 55 years, range 17-79; median latency period between primary tumor and radiation-associated sarcoma was 9 years, range 4-30). The diagnoses were typical for radiation-associated sarcomas: 2 each of malignant fibrous histiocytoma, leiomyosarcoma, and pleomorphic sarcoma, and 1 each of osteosarcoma, fibrosarcoma, myxofibrosarcoma, and spindle cell sarcoma. All 10 cases had relatively complex karyotypes with multiple, mostly unbalanced, structural rearrangements, similar to what has been reported in de novo sarcomas of the corresponding histologic subtypes. The only cytogenetic features that were unusually frequent among the radiation-associated sarcomas were the finding of unrelated clones in 3 cases, and loss of material from chromosome arm 3p, in particular 3p21-3pter, in 8 cases. Loss of the same chromosome segment has been described in 4 of the 8 previously published cases of radiation-associated sarcomas that have been analyzed after short-term culturing, which makes this imbalance significantly (P < 0.001) more frequent among radiation-associated sarcomas (12 of 18 cases) than among unselected cases of the corresponding histologic subtypes (74 of 282 cases). In contrast to the cytogenetic results, no 3p deletions were detected among the 6 cases of the present series that could be analyzed by comparative genomic hybridization (CGH). The most frequent imbalance detected by CGH was gain of 15cen-q15 (3 cases), followed by loss of chromosome 13 and gain of 5p, and 7cen-q22, each detected in 2 cases.

Long-term risk of cardiovascular disease in Hodgkin lymphoma survivors-Retrospective cohort analyses and a concept for prospective intervention

Previous studies have shown increased cardiovascular mortality as late side effects in Hodgkin lymphoma (HL) patients. This study identifies stratifying risk factors for surveillance and defines concepts for a clinical feasible and noninvasive prospective protocol for intervention of cardiovascular side effects. HL patients diagnosed between 1965 and 1995 (n = 6.946) and their first‐degree relatives (FDR) were identified through the Swedish Cancer Registry and the Swedish Multigeneration Registry. For the HL and FDR cohort, in‐patient care for cardiovascular disease (CVD) was registered through the Hospital Discharge Registry, Sweden. Standard incidence ratios of developing CVD for the HL cohort were calculated. A markedly increased risk for in‐patient care of CVD was observed in HL patients with HL diagnosed at age 40 years or younger and with more than 10 years follow‐up. In the HL survivors, a family history of congestive heart failure (CHF) and coronary artery disease (CAD) increased the risk for these diseases. The Swedish Hodgkin Intervention and Prevention study started in 2007. In the pilot feasibility study for prospective intervention (47 patients), about 25% of the cases had side effects and laboratory abnormalities. These patients were referred to a cardiologist or general practitioner. In the prospective cohort, a positive family history for CHF or CAD could be a stratifying risk factor when setting up a surveillance model. The prospective on‐going study presents an intervention model that screens and treats for comorbidity factors. This article also presents an overview of the study concept.

Bulky disease is the most important prognostic factor in Hodgkin lymphoma stage IIB.

Abstract: The aim of this study was to evaluate treatment results for Hodgkin lymphoma (HL) patients younger than 60 yr in stage IIB, treated according to the Swedish National Care Programme. The intention was also to identify specific subgroups depending on the number of negative prognostic factors the patients have, in order to optimise and differentiate future treatment. In total, 99 patients with HL stage IIB, diagnosed between 1985 and 1994, have been analysed. There were 47 men and 52 women and the median age was 33 yr (range 17–59). Eighty‐six patients presented with supradiaphragmatic disease and 13 with infradiaphragmatic. The HL specific and overall 10‐yr survival was 73 and 65%, respectively. The HL‐specific survival for patients in pathological stage IIB tended to be better, although not statistically significant than for clinical stage IIB, despite less chemotherapy (P = 0.1). The patients in stage IIB who were selected for laparotomy were, however, younger and with fewer negative prognostic factors. The only significant negative prognostic factor was bulky disease (P = 0.001). The following factors also tended to have a negative influence on the prognosis although not statistically significant: the International Prognostic Score, the number of involved lymph node stations, extranodal involvement and leucocyte count >15 × 109/L. In conclusion, we suggest that bulky disease should be taken into account when treating patients with stage IIB HL.

Treatment outcome in patients younger than 60 years with advanced stages (IIB-IV) of Hodgkin's disease : the Swedish National Health Care Programme experience.

Abstract: Background –Despite improved treatment results achieved in Hodgkins disease (HD), only about 70% of patients with advanced stages are cured. The primary aim of this study was to evaluate the outcome of advanced stages (IIB–IVB) of HD in younger patients in an unselected population‐based group of patients. The patients were recommended individualized treatment with respect to number of chemotherapy (CT) courses and post‐CT radiotherapy (RT) based on pretreatment characteristics and tumour response. Secondly, we investigated if variables of prognostic importance could be detected. Patients and methods –Between 1985–92, 307 patients between 17–59 yr of age (median 36) were diagnosed with HD in stages IIB–IVB in 5/6 health care regions in Sweden. Median follow‐up time was 7.8 yr (1.3–13). Retrospectively, laboratory parameters were collected. Results –In total, 267 (87%) patients had a complete response (CR). The overall and disease‐free 10‐yr survivals in the whole cohort were 76% and 67%, respectively. There was no difference in survival between the groups of patients who received 6 or 8 cycles of CT. Survival was not higher for patients in CR after CT when RT was added. For those in PR after CT, additional RT raised the frequencies of CR. A selected group of pathologically staged patients was successfully treated with a short course (2 cycles) of CT+RT. In univariate analyses survival was affected by age, stage IVB, bone‐marrow involvement, B‐symptoms, S‐LDH, S‐Alb and reaching CR or not after 2, 4 and 6 cycles of CT. In a multivariate analysis, age and reaching CR after 6 cycles of CT remained statistically significant. Conclusions –The lack of difference in survival between the groups of patients who received 6 versus 8 cycles of CT indicates a successful selection of patients for the shorter treatment. Reaching a rapid CR significantly affected outcome. Whether some patients need less CT than the generally recommended 8 courses can properly only be evaluated in a randomised study. Additional RT may play a role in successful outcome, particularly if residual tumours are present, but its precise role can also only be defined in prospectively randomised studies. Reaching CR after CT was the most important variable affecting survival besides age.

Methyl-GAG, ifosfamide, methotrexate and etoposide (MIME) as salvage therapy for Hodgkin's disease: a prospective study.

Abstract: This study presents the results of a prospective study of methylgag, ifosfamide, methotrexate and etoposide (MIME) as salvage regimen for Hodgkins disease (HD) in Sweden. Sixty‐four patients with recurrent or refractory HD were treated with MIME between July 1988 and December 1993. All patients except one had, earlier, been treated with and failed consecutive or alternating MOPP and ABVD. Median age was 37 yr (range 14–73). Twenty patients (31%) achieved a complete remission (CR) and 17 (27%) a partial remission (PR), giving an overall response rate of 58%. The 5‐yr survival for all patients was 43%. In a multivariate analysis, the most important factors predicting a poor survival were the presence of extranodal disease at relapse, male gender and high age. Twenty‐nine patients were treated with high‐dose chemotherapy with stem‐cell rescue after MIME. Those patients had a similar survival compared to the patients responding to MIME but not treated with high‐dose chemotherapy. We conclude that MIME induces remissions in a high proportion of patients with recurrent and refractory HD with acceptable toxicity. The remissions probably need consolidation, but the nature of this consolidation is still controversial.

A population-based study of the outcome for patients with first relapse of Hodgkin's lymphoma

Abstract: Background : Our aims were to evaluate the response to salvage treatment in relation to initial treatment and to evaluate prognostic factors at the time of relapse in an unselected population of relapsing patients with Hodgkins lymphoma (HL). Patients and methods : In total, 124 patients younger than 60 yr of age with initial diagnosis of HL in Sweden relapsed between 1985 and 1995. Results : Fifty‐eight patients relapsed after initial treatment with radiotherapy (RT) only, 62 after combination chemotherapy (CT), of whom 30 had received additional involved‐field RT, and four after a short course of CT followed by extended‐field RT. For 37 patients among the 58 relapsers after initial RT treated according to the recommendations of the National guidelines, the 5‐yr Hodgkin‐specific survival (HLS) was 85%, overall survival (OS) 73% and event‐free survival (EFS) 62%, which is not inferior to survival in patients with primarily advanced stages. It was poorer in the 21 patients who initially had received RT only, even though they had been recommended for more extensive treatment. For patients initially treated with a full course (6–8 cycles) of CT the 5‐yr HLS was 60%, OS 58% and EFS 22%. Bulky disease and age at diagnosis strongly affected survival in a multivariate analysis. Conclusions : Patients initially treated with RT who relapse have a favourable outcome, provided they have been treated according to the recommendations of the guidelines at the time of diagnosis. Initially bulky disease and, as a consequence, additional RT as part of the initial treatment negatively affect survival at relapse in patients initially treated with a full course of CT.

Infradiaphragmatic Hodgkin's disease: the Swedish National Care Programme experience

Abstract: A Swedish national care programme has provided guidelines for staging, treatment and follow‐up of all patients with Hodgkins disease (HD) since 1985. Between January 1985 and December 1992, 920 patients were reported and followed prospectively. Of a total of 533 patients with stage I and II disease, 484 presented with supradiaphragmatic HD and 49 (9%) with infradiaphragmatic HD. The median follow‐up time was 4.3 yr (3.3–10 yr). Significant differences in average age (45±21 yr and 55±19 yr), male: female ratio (1.1 : 1 and 2.8 : 1) and B‐symptoms (25% and 47%) were observed in patients with supra‐ and infradiaphragmatic HD, respectively. Forty‐six patients with infradiaphragmatic HD were treated with a curative intention and 40 (87%) achieved a complete response. Eleven (28%) of the 40 patients have recurred and 8 patients have died of HD. Complete response rates and recurrence frequencies did not differ from those observed in patients with supradiaphragmatic HD. Mortality was, however, significantly higher (p=0.001) in the infradiaphragmatic group; this was due mainly to poorer effects of salvage treatment in an elderly population. In this population‐based study, patients with peripheral disease in stage IA respond well to inverted Y irradiation alone, whereas it appears to be important to give stage II patients chemotherapy or a combined modality treatment in order to avoid unacceptably high recurrence rates.

Early and intermediate stage Hodgkin's lymphoma - report from the Swedish National Care Programme

Abstract: In Sweden a National Care Programme provides treatment principles for Hodgkins lymphoma (HL) since 1985, for early and intermediate stages often less extensive than international recommendations. The purpose is to evaluate long‐term results of these principles. A total of 308 patients (167 men and 141 women), 17–59 yr old (median 31), diagnosed during 1985–92, pathological stage (PS) I‐III1A and I‐IIB and clinical stage (CS) I‐IIA, mean follow‐up 8.8 yr, were studied. Staging laparotomy was recommended in CS IIA. Recommended treatment was mantle or mini‐mantle radiotherapy (RT) alone in CS IA, and PS I‐IIA and subtotal nodal irradiation in PS III1A if the disease was not bulky. Patients in PS I‐IIA and III1A with bulky disease, and PS I‐IIB received one cycle of mechlorethamine, vincristine, prednisone, procarbazine/doxorubicin, bleomycin, vinblastine, lacarbazine (MOPP/ABVD) before irradiation. The remaining patients received three to four cycles of MOPP/ABVD with RT to bulky disease. Relapse‐free (RFS), Hodgkin specific (HLS), and overall survival (OS) at 10 yr were 74%, 92% and 85%. In the individual stages, RFS ranged from 53% (PSIII1A) to 90% (PS IA). RFS (P  = 0.006), HLS, and OS were significantly better in patients treated with chemotherapy compared with those treated with RT alone, especially in patients with bulky disease (P = 0.0005). The international prognostic score did not provide any prognostic information. The OS rates are in agreement with results from international centres during that time. The recommended treatment was sufficient to produce the desired results of <20–30% recurrences, except in PS III1A. Most relapses could be salvaged. Patients with risk factors treated with one MOPP/ABVD and RT had an excellent outcome, superior to those without risk factors treated with RT alone. These results favour the trend to treat early and intermediate stages with a short course of chemotherapy followed by limited RT.