Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study.

BACKGROUND: Many patients with aggressive B-cell lymphomas and high clinical risk score still die of lymphoma after conventional R-CHOP chemoimmunotherapy. We hypothesized that intensified chemoimmunotherapy including systemic central nervous system (CNS) prophylaxis improves outcome and reduces the incidence of CNS-related events. PATIENTS AND METHODS: Inclusion criteria were age 18-65 years, primary diffuse large B-cell lymphoma or grade III follicular lymphoma without clinical signs of CNS disease and negative cerebrospinal fluid cytology, age-adjusted International Prognostic Index 2-3 and WHO performance score 0-3. Treatment consisted of six courses of R-CHOEP-14 followed by a course of high-dose cytarabine and a course of high-dose methotrexate. Primary end point was failure-free survival (FFS) at 3 years. RESULTS: A total of 156 eligible patients with a median age of 54 years (range 20-64) were included. Three toxic deaths were observed. Three-year overall survival (OS) and FFS rates (median observation time 52 months for survivors) were 81% and 65%, respectively. Seven patients experienced CNS relapse, all within 6 months. CONCLUSIONS: The results are promising with favorable 3-year OS and FFS rates, a low toxic death rate and a lower than expected number of CNS events. CNS progression might be further reduced by earlier CNS prophylaxis. CinicalTrials.gov. identifier NCT01502982.

Two escalated followed by six standard BEACOPP in advanced-stage high-risk classical Hodgkin lymphoma: high cure rates but increased risk of aseptic osteonecrosis.

BACKGROUND: From 1999, Norwegian guidelines recommend two escalated (esc) BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) followed by six standard (s) BEACOPP for patients with advanced-stage classical Hodgkin lymphoma (HL) with an international prognostic score (IPS) ≥ 4. We evaluated retrospectively the experience with this recommendation at the Norwegian Radium Hospital, also including all IPS 3 patients treated with the same regimen. PATIENTS AND METHODS: Forty-seven patients were treated between June 1999 and December 2008. IPS was 3 in 10 patients and ≥ 4 in 37. RESULTS: Thirty-five patients received eight cycles of BEACOPP, 12 patients received one to six cycles only, mainly due to toxicity. Sixty percent of patients had dose reductions. With median follow-up of survivors of 89 months, 5-year progression-free and overall survival are 84% [95% confidence interval (CI) 73% to 95%] and 91% (95% CI 82% to 100%), respectively. Toxicity was considerable with grade 3 or more infections/febrile neutropenia in 66% of patients, including one death and three cases of Pneumocystis jiroveci pneumonia. Of note, 10 patients (21%) experienced symptomatic aseptic osteonecrosis, of whom 3 have had hip replacement surgery after treatment. CONCLUSION: Two escBEACOPP plus six sBEACOPP is efficacious in advanced-stage high-risk HL. We document a high incidence of aseptic bone necrosis, possibly related to prednisolone.

Head Games: A Systematic Review and Meta-analysis Examining Concussion and Head Impact Incidence Rates, Modifiable Risk Factors, and Prevention Strategies in Youth Tackle Football.

OBJECTIVES: The aims were to (1) examine the rates and mechanisms of concussion and head impact in youth football (high school level or younger); (2) identify modifiable risk factors for concussion and head impact; and (3) evaluate the effectiveness of prevention strategies in tackle football at any level. METHODS: Nine databases (CINAHL Plus with Full Text; Cochrane Central Register of Controlled Trials; EMBASE; ERIC; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily; ProQuest Dissertations & Theses Global Database; PsycINFO; Scopus; and SPORTDiscus with Full Text) were searched using the search strategy focusing on four main concepts: concussion/head impact, tackle football, modifiable risk factors, and primary prevention. Two reviewers completed title, abstract, and full-text screening as well as risk of bias assessment (using the Downs and Black checklist), with a third author available to resolve any disagreements. MAIN RESULTS: After removing duplicates, 1911 articles were returned. Fifty-eight articles were included in the review and 20 in the meta-analysis. The overall combined rates of concussion (including game and practice-related concussion) based on the meta-analysis were 0.78 concussions/1000 athlete exposures [95% confidence interval (CI) 0.67-0.89] for high school football (ages 13-19) and 1.15 concussions/1000 athlete exposures (95% CI 0.89-1.41) for minor football players (ages 5-15). There is evidence that contact training and practice contact restrictions have reduced the rate of head impacts and concussion. Heads Up Football (an intervention focused on coach education and contact training) has been shown to reduce the rate of concussion by 32% and head impacts by 38% amongst high school football players. Limiting contact practices in high schools to 2 days per week reduced practice head impacts per player-season by 42%, and limiting full contact in practice to 75 min per week in the second week of the season and 60 min in week 3 and beyond resulted in a 54% decrease in the practice-related concussion rate (p = 0.003). CONCLUSIONS: This review identified a critical need for interventions to address the high rates of concussion and head impact in youth football. To date, contact training and contact restrictions have the strongest evidence supporting their effectiveness at reducing these rates. Future research should use consistent concussion definitions and validated injury surveillance systems, and ensure complete reporting of participant characteristics and sampling details. Prospero ID CRD42020193775.

Clinical evidence of a graft-versus-lymphoma effect against relapsed diffuse large B-cell lymphoma after allogeneic hematopoietic stem-cell transplantation.

BACKGROUND: A graft-versus-lymphoma effect against diffuse large B-cell lymphoma (DLBCL) is inferred by sustained relapse-free survival after allogeneic stem-cell transplantation; however, there are limited data on a direct graft-versus-lymphoma effect against DLBCL following immunotherapeutic intervention by either withdrawal of immunosuppression or donor lymphocyte infusion (DLI). MATERIALS AND METHODS: An analysis was carried out to determine whether a direct graft-versus-lymphoma effect exists against DLBCL. The analysis was restricted to patients with DLBCL, who were either not in complete remission at day +100 after allogeneic stem-cell transplantation or subsequently relapsed beyond this time point. RESULTS: Fifteen patients were identified as either not in complete remission (n = 13) at their day +100 evaluation or subsequently relapsed (n = 2) and were assessed for subsequent responses after withdrawal of immunosuppression or DLI. Eleven patients were treated with either withdrawal of immunosuppression (n = 10) or a DLI (n = 1) alone; four patients received chemotherapy with DLI to reduce tumor bulk. Nine (60%) patients subsequently responded (complete = 8, partial = 1). Six responses occurred after withdrawal of immunosuppression alone. Six patients are alive (range 42-83+ months) in complete remission without further treatment. CONCLUSION: The demonstration of sustained complete remission following immunotherapeutic intervention provides direct evidence of a graft-versus-lymphoma effect against DLBCL.

Standard CHOP-21 as first line therapy for elderly patients with Hodgkin's lymphoma.

There is no consensus on the optimal chemotherapy regimen for Hodgkin's lymphoma patients > or = 60 years. We present our institution's results of 5 years, using CHOP-21 as standard for this patient group. Twenty-nine patients with a median age of 71 years (range, 60 - 91) were included in this cohort. Fifty-five percent had known co-morbidities. Stage I/IIA patients (38%) were treated with 2 - 4 cycles of CHOP followed by radiotherapy. Stage IIB - IV patients (62%) received 6 - 8 cycles of CHOP and for the majority (13/18 pts) no radiotherapy. Two treatment-related deaths occurred. Febrile neutropenia was the most common toxicity (31%). The complete response rate after CHOP +/- radiotherapy was 93%. With a median follow-up of 41 months, five patients have relapsed and four have died from Hodgkin's lymphoma. So far, no relapses have occurred after 2 years from the end of therapy. Overall survival and progression-free survival at 3 years were 79% and 76%, respectively. We conclude that CHOP-21 is a well-tolerated and effective treatment for elderly patients with Hodgkin's lymphoma.

Knowledge of and attitudes toward complementary and alternative therapies; a national multicentre study of oncology professionals in Norway.

This study reports on oncology professionals' knowledge and attitude toward complementary and alternative medicines (CAM), classified according to their primary application as complementary or alternative methods. In June 2002, we conducted a national, multicentre survey of 828 Norwegian oncologists, nurses, clerks and therapeutic radiographers. A response rate of 61% was achieved. Only a few physicians (4%) described their reactions to alternative medicine as positive compared with nurses (33%), therapeutic radiographers (32%) and clerks (55%) (P<0.0001). Females showed a more positive view than males (33% versus 14%, P<0.0001). More participants expressed a positive attitude to complementary versus alternative medicines. Most respondents regarded healing by hand or prayer, homeopathy, and Iscador (mistletoe) as alternative therapies. In contrast, most respondents classified acupuncture, meditation, reflexology, music/art-therapy, aromatherapy and massage as complementary therapies. This survey demonstrates major differences, by gender as well as oncology health profession in views about and the classification of various CAM methods.

A supertypic HLA-DP specificity defined by two human-human hybridoma antibodies (TrB50; TrE11).

We here report two human-human hybridoma antibodies: TrB50 (IgG) and TrE11 (IgM), derived from the same donor. They displayed an identical reaction pattern with 76 Epstein-Barr virus-transformed cell lines. Of these, 29 lines were completely HLA-typed and both antibodies recognized all cells expressing DPwl (six lines), DPw3 (five lines), or DPw5 (three lines). In addition, they bound to one out of four DPw2+ cells and three out of four DPblank+ cells. This specificity correlated strikingly with a characteristic DP beta amino acid sequence (DEAV) at positions 84-87 that had been determined by others. Binding of 125I-labeled TrB50 to lymphoblastoid cells was inhibited by unlabeled IVA-12 (anti-DR + DP monomorphic) and by TrE11. Furthermore, antigens in lysates from TrB50+TrE11+ cells cross-linked TrB50 and TrE11 to the monomorphic anti-DP monoclonal antibody B7/21. Collectively the data provide strong evidence that the epitopes reside on DP molecules. TrE11 can be used to type for this DP beta supertypic specificity by microcytotoxicity using isolated blood B lymphocytes as targets or by a rosette assay directly on whole blood.

A human-human hybridoma antibody (TrB12) defining subgroups of HLA-DQw1 and -DQw3.

We have constructed an IgG, kappa human--human hybridoma Ab(TrB12), which precipitates a molecule consisting of two polypeptides of about 33 and 27 kD in size. TrB12 reacted with; (1) 7 out of 10 DQw1-positive cell lines in IIF, and all 10 in a rosette-assay; (2) 5 out of 12 DQw3-positive cells, both in IIF and the rosette-assay; (3) none of 4 DQw2 homozygous cells. Detergent cell lysate of DQw1 homozygous cell lines contained antigens that cross-linked the mouse monoclonal antibody Genox 353 G2a-5 (anti-DQw1) and TrB12. TrB12 competed with the mouse DQw3-specific monoclonal antibody IVD-12 for binding to DQw3 homozygous cells. The data imply that the TrB12 epitope is associated with molecules that carry DQw1 and DQw3 serological specificities. By radioimmunoassay, TrB12 and the mouse monoclonal antibody IIB3 divided both DQw1- and DQw3- bearing cell lines into three phenotypic groups: (1) TrB12+IIB3hi, (2) TrB12-IIB3lo, and (3) TrB12-IIB3-. For DQw1 the results suggest that the first two groups represent structural variants but the third group may reflect low expression of DQw1. For DQw3 the evidence suggests that all three phenotypes represent structural variants. DQw3 has previously been divided into two serologically defined alleles, TA10+IIB3- and TA10-IIB3+. The TrB12+IIB3hi and TrB12-IIB3lo variants of DQw3 described in this study probably represent novel subgroups of the TA10-IIB3+ allele.

Two HLA-DQ-specific human-human hybridoma antibodies (TrG6;TrC5) define epitopes also expressed by a transcomplementing hybrid DQ molecule (DQw7 alpha/DQw4 beta).

We have generated two IgG human-human hybridoma Abs, TrG6 and TrC5, that define subsets of HLA-DQ. TrG6 combined selectively with lymphoblastoid cell lines that expressed DQw1 or DQw4. By sequential immunoprecipitation, competition with other mAbs of defined specificity for binding to antigen, and experiments where HLA antigens from cell lysates crosslinked pairs of mAbs, it was established that TrG6 bound a DQ-molecule. mAb TrC5 specifically recognized DQw2+DR3+ and DQw7+DR5+ cells. The reaction pattern of TrC5 with HLA-loss mutants indicated that TrC5 bound to DQw2 of the DQw2+DR3+ haplotype. Antigens in lysate from DQw7+DR5+ cells crosslinked TrC5 to the murine mAbs Tü22 (anti-DQ monomorphic) and IVD-12 (anti-DQw7 + DQw8 + DQw9), demonstrating that on these cells the TrC5 epitope is located on DQw7 molecules. Lysates from DQw7+DR5+/DQw4+DRw8+ heterozygous cells crosslinked TrG6 and TrC5, and available evidence indicated that the epitopes defined by these two mAbs were expressed by the transcomplementing DQ-molecule DQw7 alpha/DQw4 beta, where the DQw7 alpha chain specifies epitope TrC5 and the DQw4 beta chain specifies epitope TrG6. Taken together with published nucleotide sequences of DQ alpha and beta genes, our data are consistent with the conclusion that the amino acids at positions 69 and/or 75 of the DQ alpha chain of DQw2+DR3+ and DQw7+DR5+ haplotypes are critical for epitope TrC5. The previously reported human-human hybridoma Ab TrB12 reacts with DQw6, DQw8, and DQw9. The specificity of the murine mAb IIB3 is similar to that of TrB12, but, unlike TrB12, IIB3 also binds DQw4+ cells.

A human-human hybridoma (Tr7E2) producing cytotoxic antibody to HLA-DQw1.

A human-human IgM (lambda) hybridoma antibody (called Tr7E2) was constructed by fusing Epstein-Barr virus-transformed cells from a multiparous woman with the human fusion partner KR12. By eosin exclusion microcytotoxicity the monoclonal antibody killed 12 of 13 human leukocyte antigen DQw1-bearing lymphoblastoid cells. No reaction was seen with any of 19 DQw1-negative cells. The single DQw1+ cell line that was not killed by Tr7E2 was the homozygous cell called 9WS 806 TAB (DR8,8; DQw1,1) of Japanese origin. The radioimmunoassay indicated that this result was probably not because of a decreased expression by this cell of DQ antigens, and these cells were killed by the mouse monoclonal antibody Genox3.53G2a5, reported to be specific for DQw1. Thus, the Tr7E2- cell line TAB probably expresses a novel structural DQw1 variant. Of 213 Norwegians, 107 were Tr7E2+ Genox+; none expressed only one of these epitopes. The putative split is, therefore, probably very rare in this population. Monodisperse magnetic polymer beads coated with Tr7E2 formed rosettes selectively with peripheral blood mononuclear cells from DQw1-positive individuals, suggesting a new approach to typing for class II antigens.

Mapping of an epitope defined by a human hybridoma antibody (TrD3): a new HLA-B supertype associated with a subset of HLA-Bw6.

The new human-human hybridoma TrD3 secretes a cytotoxic IgM mAb, which reacted with 28 of a panel of 56 HLA-typed lymphoblastoid cells. All 28 TrD3+ cells expressed the HLA-B supertype Bw6, whereas 10 Bw6+ cells were not recognized by the mAb. None of the 17 Bw4 homozygous cells were positive with TrD3. Thus, TrD3 divided the Bw6+ HLA-B specificities of the cell lines into two subgroups, namely, Bw6+TrD3+ and Bw6+TrD3-, and therefore defines a new HLA-B supertype. TrD3 reacted strongly with some B8+ cell lines and weakly or not at all with others, suggesting a new split of HLA-B8. Compared with cell lines, TrD3 reacted more weakly with freshly isolated T cells from blood. The Bw6-specific rat mAb SFR8-B6 partially blocked the binding of 125I-labeled TrD3 to a Bw6+ cell line. By using cell lines transfected with hybrid genes between HLA-B7 (Bw6+) and HLA-B27 (Bw6-) as targets in flow cytometry, critical residues for the TrD3 epitope could be mapped to the amino acid region 24-62 of the HLA class-I alpha 1 domain. Comparison of deduced amino acid sequences of TrD3-positive and -negative cells indicated that a tryptophane residue at position 95 destroyed the TrD3 epitope, and that one or more of the residues in positions 24, 45, and 46 may be critical, suggesting that it is a discontinuous epitope. It is notable that none of these residues are located on alpha-helixes.(ABSTRACT TRUNCATED AT 250 WORDS)

Persistent changes in the immune system 4-10 years after ABMT.

The aim of the present study was to investigate whether the early changes in the immune system observed after ABMT would persist over years. Eighty-five patients with malignant lymphoma were treated with ABMT in Norway from 1987 until 1993. Of the 46 patients in CR by 1997, 36 were enrolled in our study. Median time from ABMT was 5 years (4-10 years). Immunophenotyping showed an increase in the median number of B cells (0.35 x 109/l in patients vs 0.28 x 109/l in controls), and a decrease in T cells (1.08 vs 1.35 x 109/l). Furthermore, a lower median count of CD4+ T cells (0.54 x 109/l in patients vs0.87 x 109/l in controls) resulted in reduced CD4/CD8 ratios (0.8 in patients vs 1.6 in controls). The subgroup of CD4+ T cells expressing the 'naive' phenotype CD45RA was 19.5% in patients vs 38% in controls. In contrast, the fraction expressing the 'memory' phenotype CD45RO was higher in the ABMT group (76% vs 54%). When stimulated, larger fractions of CD3+CD4+ cells in patients produced IFN-gamma (32% vs 16%) or IL-4 (7% vs 1%) compared to controls; thus a differentiation into the functionally separate subgroups Th1 and Th2, with a dominant Th2 response. Our data further suggest that the decrease in CD4+ T cell counts and the imbalance between CD45RA+ and CD45RO+ subsets persists 4-10 years after ABMT.

Humoral immunity to viral and bacterial antigens in lymphoma patients 4-10 years after high-dose therapy with ABMT. Serological responses to revaccinations according to EBMT guidelines.

The aim of this study was to investigate the late effects of ABMT on the immune system with regard to protective humoral immunity against common antigens and responses to recall antigens (vaccines). The vaccines were given according to EBMT guidelines from 1995. The protocol included 35 patients with malignant lymphoma in CR 4-10 years after ABMT, and 35 controls. The results show that prior to ABMT the proportion of patients with protective immunity against poliomyelitis, tetanus and diphtheria was similar to that of controls. At study entry 4-10 years after ABMT, the proportion of patients with protective immunity against poliomyelitis and diphtheria was reduced, while all patients maintained protection against tetanus. A significant decrease in geometric mean antibody concentrations or titres was observed against all three antigens during this period. Serum levels of antibodies against different pneumococcal serotypes were lower in the patients than in the controls prior to vaccination. The responses to pneumococcal vaccination, which is considered to be a T cell-independent vaccine, were studied. Unlike controls, a minority of patients achieved protective levels of antibodies after a single vaccination. Despite persistent levels of protective antibodies in many patients post ABMT, secondary booster responses after one vaccination with T cell-dependent vaccines (tetanus, diphtheria and polio) were absent. In conclusion, this study shows that post ABMT, a full re-vaccination program was necessary to mount responses comparable to those observed after a single vaccination in controls.

High level of fatigue in lymphoma patients treated with high dose therapy.

With the success of high dose therapy supported by autologous bone marrow transplantation (ABMT) for malignant lymphomas, medical late-effects and secondary effects on subjective health, like fatigue, are of concern. Fatigue is poorly understood and correlates have been barely addressed. Health-related quality of life (HRQL), fatigue, and correlates to fatigue, including endocrinological status and serum levels of interleukin-6, tumor necrosis factor, and soluble tumor necrosis factor receptors, were investigated in a cross-sectional study of 33 lymphoma patients (median age 39 years) 4-10 years after ABMT. The survivors were compared to general population norms. Fatigue was highly prevalent, and females reported significantly more fatigue and impaired HRQL compared to males and the normal population. Gonadal dysfunction was found in the majority of the patients, but no statistically significant endocrinological or immunological associations with fatigue could be demonstrated. The high level of fatigue among female long-term survivors after ABMT may be related to the gonadal dysfunction, but further studies of possible mechanisms behind fatigue are necessary.

Opinions on and use of alternative medicine among physicians, nurses and clerks in northern Norway.

In February 1997 a questionnaire on alternative medicine was distributed to 172 physicians, 374 nurses and 96 clerks, all employed in hospitals in the northern part of Norway. A response rate of 57% was achieved. The aim of the study was to compare different health professions regarding views on and use of alternative medicine. Among all respondents 56% described themselves as having a positive attitude towards alternative medicine (16% of the physicians, 71% of the nurses and 72% of the clerks). Twelve percent of physicians, 32% of nurses and 46% of clerks had been using alternative medicine. Female physicians and female nurses showed a more positive attitude and were more frequent users of alternative medicine than their male counterparts. Physicians had confidence in acupuncture, herbs and diets, mainly as treatment of muscle-skeletal disorders, and migraine. Nurses and clerks on the other hand tended to believe in various alternative methods against a broad range of disorders. Female physicians and nurses emphasised the importance of more information, knowledge and openness towards alternative treatments more than their male counterparts. They also believed that traditional medicine could benefit from adopting principles from alternative medicine.

Evaluation of medical equipment on the basis of users' experiences and hazard registration.

Assessment of medical technologies is an important topic in health services research. The article describes a special aspect of user-related evaluation of devices in Norway. The Norwegian hospitals have high technical capacity and standards but the equipment is not assessed before being purchased by the hospitals. The idealistic rules for technology assessment are of no use in practical situations. The health authorities in Norway have established a national database for users' experiences and hazard registration. When assessing equipment, it is necessary to take into consideration the situation and the people handling the devices. A system-analytic perspective is proposed for better understanding. The database for experiences with devices stores information concerning maintenance, repair and service, i.e. the whole life history of the medical technology. All this information will be accessible for the hospitals through electronic mail or electronic meetings.

Radon exhalation from the ground; method of measurements and preliminary results.

The paper will present a method for measurements of radon exhalation from the ground. The method is based on a combination of activated charcoal and TLD. This method is superior to the traditional charcoal method, because it yields a mean value for the exhalation rate during the whole in-growth time. Furthermore, by using the activated charcoal/TLD method, the decay time is not critical, because the TLD is irradiated from absorbed radon during the decay time. In this way, the method is usable for remote measurements by mail. The method has been tested in areas with "normal" ground and in areas where high indoor radon concentrations previously have been measured. Exhalation measurements were performed near to houses where the indoor radon concentrations were known, and in most cases there was a strong correlation between exhalation rate and indoor radon concentrations. The method thus seems to be usable for classification of building ground.

Risk perception related to depletion of the ozone layer and UV-B radiation in the arctic.

Increase in UV-B radiation, due to stratospheric ozone depletion, is an environmental threat to arctic ecosystems and the health of their inhabitants. The aims of this longitudinal study are to provide basic population risk perception data related to UV-B and ozone depletion, and to compare the UV-B risk perception over time and with risk perception related to other objects and occurrences. A survey questionnaire, calling for a total of 118 judgments, measures risk perception, worries, and anticipated consequences. In the 1996 study, 143 persons completed the questionnaire, 34 of whom belong to the indigenous Sami population. Risk perception and the possibility of protecting oneself against 13 risks were measured on 7-point scales. The mean risk rating for depletion of the ozone layer and UV-B radiation was moderate to high. The possibility of protection was rated relatively low. Women, the youngest, and respondents in the North were most worried and perceived the highest risks. The Sami respondents are less worried and perceive a lower risk, a realistic short-term evaluation due to their protection by pigment in the skin and their clothing habits.

Ultra-short course sirolimus contributes to effective GVHD prophylaxis after reduced-intensity allogeneic hematopoietic cell transplantation.

Reduced-intensity conditioning (RIC) allo-SCT is a potentially curative treatment approach for patients with relapsed Hodgkin's or non-Hodgkin's lymphoma. In the present study, 37 patients underwent RIC allo-SCT after induction treatment with EPOCH-F(R) using a novel form of dual-agent immunosuppression for GVHD prophylaxis with CsA and sirolimus. With a median follow-up of 28 months among survivors, the probability for OS at 3 and 5 years was 56%. Treatment-related mortality was 16% at day +100 and 30% after 1 year of transplant. Acute GVHD grades II-IV developed in 38% of patients, suggesting that the regimen consisting of CsA and an ultra-short course of sirolimus is effective in the prevention of acute GVHD.