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Background: Pain Science Education (PSE) seeks to increase patients understanding of their pain, to improve clinical outcomes. It has been primarily developed and tested within western cultures. There is a lack of research exploring its use with people from ethnically minoritised groups., Objective: To explore Healthcare Professionals (HCPs) experiences of delivering PSE to people with persistent pain from ethnically minoritised groups., Methods: In this qualitative study semi-structured interviews were carried out with a convenience sample of 14 HCPs who routinely deliver PSE to patients from ethnically minoritised groups. The interviews were analysed using reflexive thematic analysis., Results: Three themes were identified: 1) Biomedical model or disengagement, 2) Pain is a taboo topic, and 3) The importance of cultural competence. Participants believed that people from ethnically minoritised groups disengaged with PSE sooner in comparison to non-ethnically minoritised groups and this was rooted in a strong biomedical understanding of pain and preference for biomedical treatments. Addressing patients' beliefs was deemed difficult as participants felt that pain was considered a taboo amongst some ethnically minoritised groups and HCPs lacked sufficient training in cultural competency to confidently address their pain-related misconceptions., Conclusions: Overall, HCPs found that many people from ethnically minoritised groups held strongly biomedical views and/or a cultural reluctance to discuss pain. These factors made pain discussions challenging leading to disengagement from PSE and a preference for passive care. Cultural competency training and access to culturally competent PSE resources may facilitate engagement with PSE for people from ethnically minoritised background., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Health researchers and policy-makers increasingly urge both patient and clinician engagement in shared decision making (SDM) to promote patient-centered care. Although SDM has been examined in numerous clinical settings, it has received little attention in solid organ transplantation. This paper describes the application of SDM to the kidney transplantation context. Several distinctive features of kidney transplantation present challenges to SDM including fragmented patient-provider relationships, the time-sensitive and unpredictable nature of deceased organ offers, decision-making processes by transplant providers serving as both organ guardians (given the organ scarcity) versus advocates for specific patients seeking transplantation, variable clinical practices and policies among transplant centers, and patients' potentially compromised cognitive status and literacy levels. We describe potential barriers to and opportunities for SDM, and posit that SDM is feasible, warranting encouragement in kidney transplantation. We propose strategies to promote and overcome obstacles to SDM in kidney transplantation. We contend that engagement in SDM can be facilitated by re-organization of clinical care, communication and education of providers and patients., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The Organ Procurement and Transplantation Network (OPTN) mandates that organ recipients provide "specific informed consent" before accepting organs that the OPTN defines as "increased risk". However, the OPTN does not provide specific guidelines for what information should be disclosed to potential recipients. Such vagueness opens the door to inadequate informed consent. This paper examines the ethical dimensions of informed consent when the prospective living donor has self-reported behaviors associated with increased risk for infection transmission. Donor privacy is a primary ethical concern that conflicts with recipients' informed consent for use of increased risk organs. We propose that both the increased risk status and the specific behavior be disclosed to the recipient. Because the actual risk posed is linked to the type of risk behavior, disclosure is therefore needed to make an informed decision. The donor's risk behavior is material to recipients' decision making because it may impact the donor-recipient relationship. This relationship is the foundation of the donation and acceptance transaction, and thus comprises a critical feature of the recipient's informed consent. Optimizing a recipient's informed consent is essential to protecting patient safety and autonomy., (©Copyright 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Using a parametric carcinogenesis model, we disentangle the superimposing effects of primary and relapse therapies of Hodgkin's disease on secondary neoplasias., Patients and Methods: We analyze eight randomized trials of the German Hodgkin's lymphoma study group [5357 individuals, 67 secondary acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and 97 secondary non-Hodgkin's lymphoma (NHL)]. Primary therapies were divided into four groups: radiotherapy alone, moderately dosed COPP/ABVD-like chemotherapies for intermediate and advanced stages and BEACOPP escalated., Results: For secondary AML/MDS, the hazards after primary therapies are proportional (maximum at 3.4 years), while the hazard after relapse therapy is more peaked (maximum at 1.8 years). Intermediate and advanced stage chemotherapy resulted in a cumulative risk of 1.5%, while the risk after BEACOPP escalated is higher (4.4%, P = 0.004) and comparable with that after relapse therapy (4.5%). For secondary NHL, there are no differences in cumulative risk between the primary therapies (2.9%), while the risk after relapse therapy is increased (6.6%, P = 0.002)., Conclusions: BEACOPP escalated moderately increases the risk of secondary AML/MDS but not NHL. No differences were found between other chemotherapies of advanced stages and intermediate stages. Secondary AML/MDS occurs faster after relapse treatment than after primary treatment.

Nephrotoxicity induced by cisplatin involves tubular cell necrosis and apoptosis; the latter of which may be initiated by multiple mechanisms including activation of the intrinsic mitochondrial pathway. In cultured tubular epithelial cells, cisplatin can activate the proapoptotic protein Bax resulting in cytochrome c release, caspase activation, and apoptosis. Definitive evidence for the involvement of Bax in cisplatin nephrotoxicity in vivo, however, is lacking. We analyzed Bax regulation during cisplatin nephrotoxicity in wild-type mice and determined the pathological role of Bax using mice in which this gene was knocked out. In wild-type mice, cisplatin induced Bax in renal tubular cells which became active, accumulated in the mitochondria, and was accompanied by acute kidney injury. Compared with the wild-type mice renal function, as measured by blood urea nitrogen and serum creatinine, was partially but significantly preserved in Bax knockout mice. The number of apoptotic cells was decreased as was general tissue damage. Additionally, cisplatin-induced cytochrome c release was attenuated in the Bax-deficient mice. This significant decrease in apoptosis and in cytochrome c release was also mirrored in primary cultures of proximal tubular cells prepared from Bax knockout animals. Collectively, our results provide compelling evidence for a role of Bax and its related apoptotic pathway in cisplatin nephrotoxicity.

Background: Despite several investigations, second malignancy risks (SMR) following radiotherapy alone (RT), chemotherapy alone (CT) and combined chemoradiotherapy (CRT) for Hodgkin's lymphoma (HL) remain controversial., Patients and Methods: We sought individual patient data from randomised trials comparing RT versus CRT, CT versus CRT, RT versus CT or involved-field (IF) versus extended-field (EF) RT for untreated HL. Overall SMR (including effects of salvage treatment) were compared using Peto's method., Results: Data for between 53% and 69% of patients were obtained for the four comparisons. (i) RT versus CRT (15 trials, 3343 patients): SMR were lower with CRT than with RT as initial treatment (odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.62-0.98 and P = 0.03). (ii) CT versus CRT (16 trials, 2861 patients): SMR were marginally higher with CRT than with CT as initial treatment (OR = 1.38, CI 1.00-1.89 and P = 0.05). (iii) IF-RT versus EF-RT (19 trials, 3221 patients): no significant difference in SMR (P = 0.28) although more breast cancers occurred with EF-RT (P = 0.04 and OR = 3.25)., Conclusions: Administration of CT in addition to RT as initial therapy for HL decreases overall SMR by reducing relapse and need for salvage therapy. Administration of RT additional to CT marginally increases overall SMR in advanced stages. Breast cancer risk (but not SMR in general) was substantially higher after EF-RT. Caution is needed in applying these findings to current therapies.

Background: Early adjustment of treatment may benefit the patient. In order to guide treatment adjustment, use of early response (ER) or early complete response (ECR), judged after the few initial cycles of chemotherapy, is common in pediatric and also adult Hodgkin's and non-Hodgkin's studies. Paradoxically, almost no data support this strategy., Patients and Methods: The influence of ECR on outcome was evaluated in three series of advanced Hodgkin's disease (HD), leading to a series of questions., Results: The 1982 EORTC study assessed prospectively the time frame needed to reach an apparent complete response (CR) through repeated tumor measurements. In patients assessed at mid-treatment before the fifth cycle, both 15 year freedom from progression (FFP) and overall survival (OS) were superior in ECR patients compared with other patients continued on the same treatment (61% versus 37%; P < 0.001). A series of questions arise from these observations. Question 1: is the shortening of treatment detrimental? In a randomized Swedish trial, in one arm treatment was shortened in patients evaluated from the fifth cycle as ECR as compared with the standard eight cycles arm, 10 year cause-specific-survival (CSS) was 53 versus 69% [not significant (ns)]; 10 year OS 49% versus 58% (ns). Conversely, in the EORTC 20884 study, ECR patients given only six cycles did as well as patients entering CR later and, for this reason, given eight cycles (identical 6 year event-free survival 75%). Question 2: is early treatment adaptation in patients who failed to reach ER beneficial? In the French MDH 90 trial, 15% of children failed to reach ECR after four cycles; in these children only, anthracyclines plus alkylating agents were given and the dose of radiotherapy increased, improving the results observed in the previous trial. In the EORTC 20884 study, patients who failed to reach an ECR were switched earlier to involved field RT: their results matched those of ECR patients, at the difference of the previous trial. Question 3: is ER a predicting factor that can be used with any type of treatment? Probably not, based on the German Hodgkin's Lymphoma Study Group trial HD 9: ECR is highly dependent on specific interval from treatment start and on treatment intensity., Discussion: More general questions stem from these results. Question 4: is the definition of ER secured? With conventional imaging, the different methods for response assessment at end treatment also lead to different response rates; the assessment in the middle of treatment itself and the use of newer imaging techniques may further increase the variation. Indeed, question 5 is: is ER a concept based on any biology? Correlation to markers, 99mTc uptake, PET and hematological tolerance might help to pinpoint how and why ER represents a surrogate for final outcome., Conclusion: ER is a surrogate for final outcome, reflecting both tumor burden and activity. This predictability may, and possibly should, impact on treatment.

Background: The bleomycin-etoposide-doxorubicin-cyclophosphamide-vincristine-procarbazine-prednisone (BEACOPP) regimen was developed to investigate the potential of moderate dose escalation of conventional polychemotherapy to improve the unsatisfactory treatment results in advanced-stage Hodgkin's lymphoma (HL). Following pilot studies, the randomised trial HD 9 demonstrated that BEACOPP (baseline dose) attained superior failure-free survival to COPP/ABVD, and that dose escalation made a further marked improvement. Toxicity was severe but manageable., Patients and Methods: The current GHSG multicentre randomised trial HD 12 has a 2 x 2 factorial design in order to make two comparisons: (i) eight cycles of escalated BEACOPP (as in HD9) are compared with four escalated cycles followed by four at baseline dose; (ii) the use of additional local radiotherapy to initial bulky disease and residual disease after chemotherapy is compared with chemotherapy alone, except where radiotherapy was prescribed by a central diagnostic panel. Eligible are patients aged 16-65 years with newly diagnosed HL of stage IIB with risk factors or stage III/IV. The EORTC multicentre trial 20012 randomises patients with HL stage III/IV to either eight cycles of ABVD or eight cycles of BEACOPP (four escalated + four baseline)., Results: The first interim analysis (January 2001) of HD 12 with 221 evaluable patients indicated continuation of recruitment. Recruitment will end in 2002 and the final data analysis will appear in 2006., Conclusions: The BEACOPP regimen is highly effective, and moderate dose escalation makes a further worthwhile improvement in tumour control. Current trials will measure BEACOPP against the international standard and show whether the amount of chemotherapy and/or radiotherapy can be reduced.

Successful autologous hematopoietic stem cell (HSC) transplantation in childhood acute lymphoblastic leukemia (ALL) requires the ability to either selectively kill the leukemia cells or separate normal from leukemic HSC. Based on previous studies showing that more than 95% of childhood B-lineage ALL express CD38, this study evaluated whether normal CD34(+)CD38(-) progenitors from children with B-lineage ALL could be isolated by flow cytometry. CD34(+) cells from bone marrow samples from 10 children with B-lineage ALL were isolated at day 28 of treatment, when clinical remission had been attained. The CD34(+) progenitor cells were flow cytometrically sorted into CD34(+)CD38(+) and CD34(+)CD38(-) populations. The absolute numbers of CD34(+)CD38(-) cells that could be isolated ranged from 401 to 6245. The cells were then analyzed for the presence of clonotypic rearrangements of the T-cell receptor (TCR) Vdelta2-Ddelta3 locus. Only patients whose diagnostic marrow had an informative TCR Vdelta2-Ddelta3 rearrangement were included in this study. Detection thresholds were typically 10(-4) to 10(-5) leukemic cells in normal marrow. In 6 of 10 samples analyzed, the sorted CD34(+)CD38(-) cells had no detectable Vdelta2-Ddelta3 rearrangements. In 4 cases, the clonotypic leukemic Vdelta2-Ddelta3 rearrangement was detected in the CD34(+)CD38(-) population, indicating that the putative normal HSC population also contained leukemic cells. The data indicate that although most childhood ALL cells express CD34 and CD38, leukemic cells are also frequently present in the CD34(+)CD38(-) population. Therefore, strategies to isolate and transplant normal HSC from children with ALL will require a more stringent definition of the normal HSC than the CD34(+)CD38(-) phenotype. (Blood. 2001;97:3925-3930)

Background: The magnitude of chemotherapy dose escalation made possible by the use of recombinant haematopoietic growth factors has not been quantified in a randomized trial., Patients and Methods: Patients with refractory or relapsing Hodgkin's disease were randomized to receive the Dexa-BEAM regimen with escalating etoposide doses supported by placebo or granulocyte-macrophage colony-stimulating factor (GM-CSF). Using an adaptive sampling method independently in both arms, the etoposide dose was escalated until the maximal tolerated dose for the first cycle was reached., Results: Thirty patients were randomized to GM-CSF and thirty to placebo. The etoposide dose could be escalated considerably in both treatment arms. Maximal etoposide dose for the first cycle was 1920 mg/m2 for patients receiving GM-CSF and 1160 mg/m2 for patients receiving placebo (P = 0.045 one-sided), corresponding to a 65% higher etoposide dose and a 13% higher dose intensity with GM-CSF. Dose-limiting events were similar in both arms, consisting mainly of prolonged neutropenia and consecutive infections. Treatment efficacy was not different in the two treatment groups., Conclusions: While GM-CSF permits a somewhat higher dose escalation than placebo, the increase in dose intensity provided by GM-CSF is small. The use of CSF for interval reduction rather than dose escalation is the more effective strategy for dose intensification.

Paraffin blocks and clinical data from 521 patients with lymphocyte predominance Hodgkin disease (LPHD) diagnosed between 1970 and 1994 were collected from 16 European and United States oncological centers to establish the pathologic and clinical characteristics of a large patient cohort, to determine how frequent T-cell-rich large B-cell lymphoma (TCRLBCL) is among LPHD, and to find differential diagnostic criteria distinguishing between the 2 lymphoma categories. For this purpose, conventionally and immunohistologically stained sections were reviewed by a panel of hematopathologists. The diagnosis of LPHD was confirmed in only 219 of the 388 assessable cases (56.5%). This low confirmation rate was due mainly to the presence of a new variant of classical Hodgkin disease (CHD), which resembled, in terms of nodular growth and lymphocyte-richness, nodular LPHD and, in terms of the immunophenotype of the tumor cells, CHD and was designated nodular lymphocyte-rich CHD (NLRCHD). The nodules of LRCHD consisted-as in nodular LPHD-predominantly of B cells but differed from those present in LPHD in that they represented expanded mantle zones with atrophic germinal centers. Clinically, patients with LPHD and NLRCHD showed similar disease characteristics at presentation but differed in the frequency of multiple relapses and prognosis after relapse. Patients with LPHD and NLRCHD clearly differed from patients with CHD with nodular sclerosis or mixed cellularity, as they presented with an earlier disease stage and infrequent mediastinal involvement. As 97% of the LPHD cases showed a complete or partial nodular growth pattern, their differentiation from TCRLBCL was a rare problem in the present series. (Blood. 2000;96:1889-1899)

To determine prognostic factors and treatment outcome, patients with primary progressive Hodgkin lymphoma (HD) registered in the database of the German Hodgkin Lymphoma Study Group (GHSG) were analyzed retrospectively. Detailed records from randomized prospective multicenter trials performed between 1988 and 1998 of 3807 patients recruited in these trials were reviewed. The median age of the 206 patients available was 34 years (range, 16-71). Fifty-seven patients (28%) in intermediate stage and 149 patients (72%) in advanced stage developed progressive disease (PD). One hundred and fifty-three patients (74%) were treated with salvage chemotherapy, 47 patients (23%) with salvage radiotherapy, and 6 patients (3%) did not receive any therapy due to rapid PD. Seventy patients (34%) were treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation. The 5-year freedom from second failure (FF2F) and overall survival (OS) for all patients were 17% and 26%, respectively. The 5-year FF2F and OS for patients treated with HDCT were 31% and 43%, respectively. In multivariate analysis low Karnofsky performance score at the time of progression (P <.0001), age above 50 years (P =.019), and failure to attain a temporary remission on first-line treatment (P =.0003) were significant adverse prognostic factors for OS. Patients with none of these risk factors had a 5-year OS of 55% compared with 0% for patients with all 3 of these unfavorable prognostic factors. Although HDCT is a reasonable option for selected patients with primary progressive HD, the majority did not receive HDCT. Interestingly, salvage radiotherapy gave promising results in patients with localized PD. (Blood. 2000;96:1280-1286)

Background: The seven-factor International Prognostic Score (IPS) has been developed and verified for patients with advanced stage Hodgkin's disease (HD). This report aims to assess the predictive power of the IPS for early stage HD patients., Patients and Methods: Data on patient characteristics, therapy and follow-up were available for 1424 adult patients in clinical stages I-IIIA treated for primary HD in two German Hodgkin's Lymphoma Study Group (GHSG) trials (1988-1994). Patients with risk factors or in stage IIIA received chemo radiotherapy (CMT; trial HD5); others received extended field radiotherapy (RT) alone (HD4). The IPS could be calculated for 712 HD5 and 249 HD4 patients (70%). The prognostic value of the IPS and its component factors was assessed using Cox proportional hazards regression. A search was made for additional factors which could add predictive power to the IPS., Results: The IPS identified 40% of the unfavourable early stage patients with an 8% lower disease-free survival at six years (hazard ratio 1.66, P = 0.0018). The factor 'low albumin' was the only score component giving a significant individual contribution. Allowing for the IPS, extranodal involvement, particularly in stages IIB-IIIA, was associated with worse prognosis, but no further significantly prognostic factors were revealed. The IPS identified a similar hazard ratio in HD4, although here the effect was not significant., Conclusions: The IPS for advanced HD has modest predictive ability in unfavourable early stage patients. Modification of the IPS for use with early stages may improve its prognostic power.

Although eosinophilic granulocytes are frequently observed in lymphatic tissue of Hodgkin's patients, no substantial data reveal the prognostic role, if any, of tissue eosinophilia. Thus, eosinophilia was analyzed histologically in 1511 diagnostic biopsy specimens of patients treated under protocol therapy of the German Hodgkin's Lymphoma Study Group between 1988 and 1994. Prominent eosinophilia was seen in 38% of cases, which differed among the histologic types of Hodgkin's disease (HD): none in lymphocyte predominant, 14% in lymphocyte rich classical, 40% in nodular sclerosis grade 1 (NS-1), 55% in nodular sclerosis grade 2, 43% in mixed cellularity (MC), and 54% in lymphocyte depleted. In a multivariate analysis, tissue eosinophilia proved to be the strongest prognostic factor for freedom from treatment failure (P <. 001) and overall survival (P <.001) in a stage-stratified model. Among NS-1 patients, the effect was highly significant. In MC, no significant effect of eosinophilia on survival could be demonstrated. Eosinophils secrete CD30 ligand that is capable of binding to CD30 positive HD cells. The activation of TRAF2, followed by NF-kappaB, which occurs on CD30L/CD30 binding, may explain the neoplastic proliferation and apoptosis protection of HD cells. TRAF2 is also activated by EBV-LMP expression, which is detectable in the majority of MC but not NS cases. In addition to the possibility that eosinophils are only passive indicators for other unknown prognostic determinants, it may be concluded that the positive clinical outcome of eosinophilia-negative NS cases could be due to lower NF-kappaB activity. (Blood. 2000;95:1207-1213)

Objective: We sought to compare our 5-year program of fragile X screening of high-risk gravid women with our program of fragile X testing of affected individuals (probands)., Study Design: All women referred to the prenatal genetics clinic from 1994 to 1998 who had a family history of unspecified mental retardation or learning or behavioral disorders (known fragile X families excluded) were offered fragile X screening. Results were compared with those of probands with the same diagnoses who underwent fragile X testing during the same time period., Results: We counseled 12,349 prenatal patients from 1994-1998, of whom 263 (2.1%) had a positive family history and underwent fragile X screening. No mutations or premutations were identified. In contrast, 31 (1.9%) of 1637 affected probands who underwent fragile X testing during the same time period had positive results, which was a significant difference (0/263 vs 31/1637; P <.05)., Conclusions: Testing the affected proband is superior to screening the pregnant relative of the proband for identification of families at risk for fragile X syndrome.

The BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen, a rearranged and accelerated version of the standard COPP/adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy, has been shown to be effective and safe in a previous pilot study for advanced stage Hodgkin's disease (HD). The present study aimed to determine a maximum practicable dose of three drugs, ie, etoposide, adriamycin, and cyclophosphamide, for which acute toxicities were acceptable and to assess the feasibility of the escalated scheme. Sixty untreated patients with advanced stage HD were enrolled in this study. Radiotherapy was given in 44 patients (73%) after chemotherapy to initial bulk lesions and residual disease. Granulocyte-colony stimulating factor (G-CSF) was given from day 8 to prevent prolonged neutrocytopenia and severe infections. The intended doses of adriamycin, etoposide, and cyclophosphamide in the BEACOPP schedule could be substantially escalated: adriamycin from 25 to 35, cyclophosphamide from 650 to 1,200, and etoposide from 100 to 200 mg/m2. The major toxicities were leukocytopenia and thrombocytopenia with considerable heterogeneity between individual patients. Of 60 patients, 56 (93%) achieved a complete remission (CR). At a median observation of 32 months, the rates of survival and freedom from treatment failure (FFTF) were estimated to be 91% (95% confidence interval 83% to 99%) and 90% (82% to 98%). These results show that a moderate dose escalation of adriamycin, cyclophosphamide, and etoposide of the baseline BEACOPP regimen is feasible. The escalated BEACOPP regimen shows very encouraging results in advanced stage HD and is now being compared in a randomized phase III study with BEACOPP at baseline dose level.

Epidemiological data suggest long-term oxygen therapy (LTOT) delivered by oxygen concentrators in patients with severe hypoxic chronic obstructive pulmonary disease (COPD) is under-prescribed by General Practitioners (GPs) in England and Wales. One reason for this may be the unavailability to GPs of a measure of arterial oxygenation needed to fulfil the defined prescription criteria. Provision of a non-invasive measure of oxygenation may improve detection of hypoxic subjects and increase appropriate prescribing. This study aimed to evaluate pulse oximetry in a general practice setting and to screen for severe undetected hypoxaemia fulfilling the LTOT prescription criteria in patients with COPD. All COPD patients attending surgery in two practices were screened with oximeters for hypoxaemia. Those with an oxygen saturation of < or = 92% were referred to hospital for formal arterial blood gas analysis and an oxygen concentrator assessment. GPs were asked to evaluate their experience in the ease of use and application of oximetry. The number of patients receiving oxygen by concentrator before the study was compared with the national rate and the number after the study with the estimated need suggested by epidemiological studies. Over a 12-month period a total of 114 patients were screened in the two practices with a combined list size of 15,742. Thirteen patients had saturations of < or = 92%. Two refused and 11 underwent formal arterial gas analysis. Three had PaO2 < 7.3 kPa and new prescriptions for oxygen concentrators were made in these previously unsuspected severely hypoxaemic subjects as a result. One other hypoxaemic subject was referred and found to have another treatable medical condition. The initial prevalence of concentrator prescription (0.013% CI 0.003, 0.047) was similar to the national rate (0.024%) and the prevalence observed after screening (0.031%, CI 0.013, 0.073) fell within the lower suggested prescription need of previous epidemiological data (0.02-0.10%). All practitioners found the oximeters simple to use and helpful in assisting with assessment of the severity of their patient's condition. Oximetry provides a readily usable non-invasive method of screening and when applied to all COPD patients seen in general practice can reveal those fulfilling the criteria for long term oxygen who would otherwise not be identified as needing this treatment.

Juvenile myelomonocytic leukemia (JMML) is a pediatric myelodysplastic syndrome that is associated with neurofibromatosis, type 1 (NF1). The NF1 tumor suppressor gene encodes neurofibromin, which regulates the growth of immature myeloid cells by accelerating guanosine triphosphate hydrolysis on Ras proteins. The purpose of this study was to determine if the NF1 gene was involved in the pathogenesis of JMML in children without a clinical diagnosis of NF1. An in vitro transcription and translation system was used to screen JMML marrows from 20 children for NF1 mutations that resulted in a truncated protein. Single-stranded conformational polymorphism analysis was used to detect RAS point mutations in these samples. We confirmed mutations of NF1 in three leukemias, one of which also showed loss of the normal NF1 allele. An NF1 mutation was detected in normal tissue from the only patient tested and this suggests that JMML may be the presenting feature of NF1 in some children. Activating RAS mutations were found in four patients; as expected, none of these samples harbored NF1 mutations. Because 10% to 14% of children with JMML have a clinical diagnosis of NF1, these data are consistent with the existence of NF1 mutations in approximately 30% of JMML cases.

The special nature and course of lymphocyte rich variants of Hodgkin's disease (HD) has been the subject of pathological and clinical studies since the 1930s. Patients with lymphocyte predominant (LP) HD, predominantly male and 25-45 years old, usually present with early clinical stage, cervical or inguinal involvement and few if any adverse prognostic factors. The disease progresses slowly, with fairly frequent relapses which are rarely fatal. Nonetheless, cases with advanced stage and deaths from Hodgkin's disease have been observed in LPHD. Recently, immunological studies have lead to a clear distinction between LPHD and classical HD including a lymphocyte rich classical version (LRCHD). Secondary low-grade NHLs occur more frequently after LPHD than after classical HD. They seem to be disease-related rather than treatment-induced. LPHD patients in earlier studies have tended to have a better prognosis than classical HD patients. When cohorts of the same clinical stage are compared, under modern protocol treatment this advantage seems to be minimal or absent. LPHD patients tend to relapse frequently but they survive these relapses better than classical HD patients. The resemblance to non-neoplastic disorders, capability for ongoing mutation, favorable clinical presentation and good survival rates after relapse all suggest that the optimal primary treatment strategy might be less intensive for LPHD than for classical HD. Late toxicities, which contribute considerably to the death rate, could thus be reduced. The long survival of several early stage LPHD patients without any treatment beyond lymph node excision could favour a 'watch-and-wait' strategy, albeit only after rigorous staging. New experimental therapy techniques such as immunotherapy might also be suitable. These possibilities must first be tested in a large-scale prospective study.

The BEACOPP chemotherapy regimen for advanced Hodgkin's disease employs a rearranged schedule permitting a shortened three-week cycle. With haematological growth factor support, the dosages of cyclophosphamide, etoposide and adriamycin could be moderately escalated. The 3-armed multicentre HD9 trial (recruitment 1993-1998; 1300 patients randomised) aimed to compare BEACOPP with the standard COPP/ABVD chemotherapy and to detect and measure the gain in efficacy, if any, due to moderate dose escalation of BEACOPP. Eight cycles were given, followed by local irradiation. The most recent interim analysis, with 689 evaluable patients, circa 40% of all expected events and a median observation time of 27 months, showed significant differences in progression rate (P) and in two-year freedom from treatment failure (F) between the treatment arms, with escalated BEACOPP (P = 2%, F = 89%) better than baseline BEACOPP (P = 9%, F = 81%) better than COPP/ABVD (P = 13%, F = 72%). Survival was not significantly different. Acute toxicity was more severe due to dose escalation, but remained manageable. These preliminary results suggest that BEACOPP improves efficacy. Moderate dose escalation is feasible with G-CSF support and appears likely to make a worthwhile improvement in the cure rate. The results must await confirmation (or otherwise) by the final analysis including all randomised patients and sufficiently mature data.

Antibodies against CD15, -30, and -20 are often used to support morphological diagnosis of Hodgkin's Disease (HD). The classical HD, i.e., the non-lymphocyte-predominance types, are CD15+, CD30+, and CD20- in general. However, the results for CD15 are less clear-cut in many studies, showing up to 40% of classical HD that lack positivity for this maker. Little is currently known about the relevance of antigen expression in relation to clinical outcome in HD. Therefore, the three markers were analyzed in 1751 cases from the German Hodgkin Study Group, using micro-wave epitope retrieval to optimize staining sensitivity. Eighty-three percent of the cases showed a classical immunophenotype (CD15+, CD30+, CD20-), twelve percent lacked CD15 positivity (CD15-, CD30+, CD20-), and five percent showed other combinations. For 1286 cases, clinical follow-up was available, which revealed significant differences for freedom from treatment failure (P = 0.0022) and overall survival (P = 0.0001) between cases with classical immunophenotype and CD15 negativity (CD30+, CD20-). Multivariate Cox regression using the three markers, age, sex, histology, stage, B-symptoms (fever, sweats, weight loss > 10% of body weight), hemoglobin, and erythrocyte sedimentation rate as factors showed that lack of CD15 expression in classical HD is an independent negative prognostic factor for relapses (P = 0.022) and survival (P = 0.0035). In conclusion, immunohistochemistry is able to identify classical HD cases with unfavorable clinical outcome.

There is wide consensus that lymphocyte predominance Hodgkin's disease (LPHD) represents a distinct clinicopathological entity of B-cell origin. However, inconsistent results of immunophenotyping studies and low confirmation rates among multi-center trials pose the question of whether LPHD really expresses heterogeneous marker profiles or whether it represents a mixture of morphologically similar entities. Among 2,836 cases reviewed by the German Hodgkin Study Group, immunophenotyping was performed on 1) cases classified or confirmed as LPHD by the reference panel (n = 104) or 2) cases not confirmed as LPHD but classified as classical HD (cHD) within the reference study trial (n = 104). In most cases, immunohistochemistry revealed a phenotype either LPHD-like (CD20+, CD15-, CD30-, CD45+) or cHD-like (CD15+, CD30+, CD20-, CD45-). In 27 cases, the immunophenotype was not fully conclusive. Additional markers for Epstein-Barr virus and CD57 and in situ hybridization for mRNA light chains allowed for a more clear-cut distinction between LPHD and cHD. However, in 25 of 104 cases, immunohistochemistry disproved the morphological diagnosis of LPHD of the panel experts, whereas 13 cases originally not confirmed as LPHD showed a LPHD-like immunopattern. Immunohistochemically confirmed LPHD cases showed a significantly better freedom from treatment failure (P = 0.033) than cHD; this was not observed in the original study classification based only on morphology (P > 0.05). Significantly better survival for LPHD cases improved from P = 0.047 (original study classification) to P = 0.0071 when classified by immunohistochemistry. Our results show that LPHD is a more immunohistochemical rather than a purely morphological diagnosis. Immunophenotyping of HD biopsies suspected of being LPHD is mandatory when a modified therapy protocol, that is, one different from those used in cHD, is discussed.

Since lymphocyte predominant Hodgkin's disease (LPHD) may comprise more than one entity, diagnostic criteria, clinical features, and treatment strategies are still being controversially discussed. Thus, in December 1994 a multinational project on lymphocyte predominant Hodgkin's disease was initiated by the European Task Force on Lymphoma. This project is aimed at clarifying the clinical and histopathological spectrum of LPHD, as well as its relation to T-cell- rich B-cell lymphoma and classical types of HD. 525 paraffin blocks and clinical data of 478 patients from 16 international centres were submitted. At the Third International Symposium on Hodgkin's Lymphoma in Cologne, 232 of these cases were discussed by an expert panel. The preliminary results are presented here. Most cases of LPHD were reclassified into nodular paragranuloma (NP) and lymphocyte rich classical HD. In both groups, a considerable number of cases with atypical features was observed. Few cases of NHL were found among the cohort. LPHD was generally treated according to common standards for HD. The whole group of LPHD did not have a better prognosis than NS; whereas early stage NP did perform better than early stage NS (data from the German Hodgkin's Lymphoma Study Group). There is however a striking discrepancy between good survival and the frequent relapses observed in NP which needs to be elucidated.

In this report we demonstrate evidence which strongly suggests that a receptor for platelet-activating factor (PAF) exists on a lymphoblastoid B cell line, LA350. PAF ranging in concentration from 10(-6)-10(-9)M initiated the incorporation of 32P into phosphatidic acid (PA) and phosphatidylinositol (PI) with no change in phosphatidylethanolamine (PE) and phosphatidylcholine (PC) over baseline. Lyso-PAF, the inactive precursor, at 10(-7)M had no effect on membrane phospholipid metabolism. In addition, PAF from 10(-6)-10(-8)M when added to Fura-2 containing B cells induced a rapid and significant rise of calcium within the cell, with lyso-PAF having no effect. These data suggest that PAF binds to a receptor on B cells and induces the hydrolysis of PI and a subsequent increase of intracellular calcium.