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OBJECTIVE: The transforming growth factor beta superfamily member macrophage inhibitory cytokine 1 (MIC-1) is expressed upon macrophage activation, regulated by the p53 pathway, and linked to clinical events in atherosclerosis and cancer. Since rheumatoid arthritis (RA) shares similar etiopathologic mechanisms with the above diseases, we sought to determine the clinical utility of determining MIC-1 serum levels and MIC-1 genotype in the management of RA. METHODS: Ninety-one RA patients were recruited. Serum was collected from 83 of these patients and synovial biopsy samples were collected from the remaining 8 patients. Of the 83 patients from whom serum was collected, 61 were treated on an outpatient basis (defined as having nonsevere disease), and 22 patients went on to undergo hemopoietic stem cell transplantation (HSCT) (defined as having severe disease). RESULTS: Serum levels of MIC-1 were higher in RA patients and reflected disease severity independently of classic disease markers. MIC-1 was detected in rheumatoid synovial specimens, and allelic variation of MIC-1 was associated with earlier erosive disease and severe treatment-resistant chronic RA. Additionally, algorithms including serum and/or allelic variation in MIC-1 predicted response to HSCT, the presence of severe disease, and joint erosions. CONCLUSION: Determination of serum levels of MIC-1 and MIC-1 genotype may be clinically useful in the management of RA as well as in selection of patients for HSCT, since they predict disease course and response to therapy. The data indicate a potential role for MIC-1 in RA pathogenesis. These results warrant larger prospective studies to fully delineate and confirm a role for MIC-1 genotyping and serum estimation in patient selection for HSCT and in the management of RA. [ABSTRACT FROM AUTHOR]

Background: Epidemiologic evidence suggests an inverse association between sun exposure and follicular lymphoma risk., Methods: We conducted an Australian population-based family case-control study based on 666 cases and 459 controls (288 related, 171 unrelated). Participants completed a lifetime residence and work calendar and recalled outdoor hours on weekdays, weekends, and holidays in the warmer and cooler months at ages 10, 20, 30, and 40 years, and clothing types worn in the warmer months. We used a group-based trajectory modeling approach to identify outdoor hour trajectories over time and examined associations with follicular lymphoma risk using logistic regression., Results: We observed an inverse association between follicular lymphoma risk and several measures of high lifetime sun exposure, particularly intermittent exposure (weekends, holidays). Associations included reduced risk with increasing time outdoors on holidays in the warmer months [highest category OR = 0.56; 95% confidence interval (CI), 0.42-0.76; Ptrend < 0.01], high outdoor hours on weekends in the warmer months (highest category OR = 0.71; 95% CI, 0.52-0.96), and increasing time outdoors in the warmer and cooler months combined (highest category OR = 0.66; 95% CI, 0.50-0.91; Ptrend 0.01). Risk was reduced for high outdoor hour maintainers in the warmer months across the decade years (OR = 0.71; 95% CI, 0.53-0.96)., Conclusions: High total and intermittent sun exposure, particularly in the warmer months, may be protective against the development of follicular lymphoma., Impact: Although sun exposure is not recommended as a cancer control policy, confirming this association may provide insights regarding the future control of this intractable malignancy., (©2023 The Authors; Published by the American Association for Cancer Research.)

Introduction: Flow cytometry (FCM) is widely used in the diagnosis of mature B-cell neoplasms (MBN), and FCM data are usually consistent with morphological findings. However, diffuse large B-cell lymphoma (DLBCL), a common MBN, is sometimes not detected by FCM. This study aimed to explore factors that increase the likelihood of failure to detect DLBCL by FCM., Methods: Cases with a final diagnosis of DLBCL that were analysed by eight-colour FCM were retrospectively collated. Clinical, FCM, histopathological and genetic data were compared between cases detected and cases not detected by FCM., Results: DLBCL cases from 135 different patients were analysed, of which 22 (16%) were not detected by FCM. In samples not detected by flow cytometry, lymphocytes were a lower percentage of total events (p = 0.02), and T cells were a higher percentage of total lymphocytes (p = 0.01). Cases with high MYC protein expression on immunohistochemistry were less likely to be missed by FCM (p = 0.011). Detection of DLBCL was not different between germinal centre B-cell (GCB) and non-GCB subtypes, not significantly affected by the presence of necrosis or fibrosis, and not significantly different between biopsy specimens compared to fine-needle aspirates, or between samples from nodal compared to extranodal tissue., Conclusion: The study identifies several factors which affect the likelihood of DLBCL being missed by FCM. Even with eight-colour analysis, FCM fails to detect numerous cases of DLBCL., (© 2023 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Objectives: We aimed to examine the relationship between occupational exposure to extremely low-frequency magnetic fields (ELF-MFs) and follicular lymphoma (FL) risk., Methods: We conducted a family case-control study between 2011 and 2016 in Australia and included 681 cases. Controls were either a family member of cases (related (n=294), unrelated (n=179)) or were unrelated recruited for a similarly designed Australian multiple myeloma study (n=711). We obtained detailed job histories using lifetime work calendars. We assigned exposure to ELF-MFs using an enhanced job exposure matrix, with a lag period of 10 years. We examined associations with FL risk using logistic regression accounting for relatedness between cases and controls. We performed sensitivity analyses including by control type, by sex, complete case analyses, ELF-MF exposure percentiles in addition to quartiles, ELF-MF exposure in the maximum exposed job, a shorter lag period (1 year) and the cumulative exposure in the most recent time period (1-9 years)., Results: We observed no association with the average intensity, duration or lifetime cumulative exposure to occupational ELF-MF exposure in the primary or sensitivity analyses., Conclusions: Our findings do not support an association between occupational ELF-MF exposure and FL risk. Although the inclusion of family members as part of the larger control group may have biased our risk estimates towards the null, findings were similar in sensitivity analyses restricted to cases and unrelated controls. Further research incorporating enhanced exposure assessment to ELF-MF is warranted to inform occupational safety regulations and any potential role in lymphomagenesis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The association between dietary intake of foods of animal origin and follicular lymphoma (FL) risk and survival is uncertain. In this study, we examined the relationship between dietary intake of dairy foods and fats, meat, fish and seafoods, and the likelihood of FL and survival., Methods: We conducted a population-based family case-control study in Australia between 2011 and 2016 and included 710 cases, 303 siblings and 186 spouse/partner controls. We assessed dietary intake of animal products prior to diagnosis (the year before last) using a structured food frequency questionnaire and followed-up cases over a median of 6.9 years using record linkage to national death data. We examined associations with the likelihood of FL using logistic regression and used Cox regression to assess association with all-cause and FL-specific mortality among cases., Results: We observed an increased likelihood of FL with increasing daily quantity of oily fish consumption in the year before last (highest category OR = 1.96, CI = 1.02-3.77; p -trend 0.06) among cases and sibling controls, but no associations with spouse/partner controls. We found no association between the likelihood of FL and the consumption of other types of fish or seafood, meats or dairy foods and fats. In FL cases, we found no association between meat or oily fish intake and all-cause or FL-specific mortality., Conclusion: Our study showed suggestive evidence of a positive association between oily fish intake and the likelihood of FL, but findings varied by control type. Further investigation of the potential role of environmental contaminants in oily fish on FL etiology is warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Odutola, van Leeuwen, Bassett, Bruinsma, Turner, Seymour, Prince, Milliken, Hertzberg, Roncolato, Opat, Lindeman, Tiley, Trotman, Verner, Harvey, Underhill, Benke, Giles and Vajdic.)

Background: The influence of early-life growth pattern and body size on follicular lymphoma (FL) risk and survival is unclear. In this study, we aimed to investigate the association between gestational age, growth during childhood, body size, changes in body shape over time, and FL risk and survival., Methods: We conducted a population-based family case-control study and included 706 cases and 490 controls. We ascertained gestational age, growth during childhood, body size and body shape using questionnaires and followed-up cases (median=83 months) using record linkage with national death records. We used a group-based trajectory modeling approach to identify body shape trajectories from ages 5-70. We examined associations with FL risk using unconditional logistic regression and used Cox regression to assess the association between body mass index (BMI) and all-cause and FL-specific mortality among cases., Results: We found no association between gestational age, childhood height and FL risk. We observed a modest increase in FL risk with being obese 5 years prior to enrolment (OR=1.43, 95 %CI=0.99-2.06; BMI ≥30 kg/m 2 ) and per 5-kg/m 2 increase in BMI 5 years prior to enrolment (OR=1.14, 95 %CI=0.99-1.31). The excess risk for obesity 5 years prior to enrolment was higher for ever-smokers (OR=2.00, 95 %CI=1.08-3.69) than never-smokers (OR=1.14, 95 %CI=0.71-1.84). We found no association between FL risk and BMI at enrolment, BMI for heaviest lifetime weight, the highest categories of adult weight or height, trouser size, body shape at different ages or body shape trajectory. We also observed no association between all-cause or FL-specific mortality and excess adiposity at or prior to enrolment., Conclusion: We observed a weak association between elevated BMI and FL risk, and no association with all-cause or FL-specific mortality, consistent with previous studies. Future studies incorporating biomarkers are needed to elucidate possible mechanisms underlying the role of body composition in FL etiology., Competing Interests: Conflict of interest statement All authors declare that they have no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The association between smoking and alcohol consumption and follicular lymphoma (FL) incidence and clinical outcome is uncertain. We conducted a population-based family case-control study (709 cases: 490 controls) in Australia. We assessed lifetime history of smoking and recent alcohol consumption and followed-up cases (median = 83 months). We examined associations with FL risk using unconditional logistic regression and with all-cause and FL-specific mortality of cases using Cox regression. FL risk was associated with ever smoking (OR = 1.38, 95%CI = 1.08−1.74), former smoking (OR = 1.36, 95%CI = 1.05−1.77), smoking initiation before age 17 (OR = 1.47, 95%CI = 1.06−2.05), the highest categories of cigarettes smoked per day (OR = 1.44, 95%CI = 1.04−2.01), smoking duration (OR = 1.53, 95%CI = 1.07−2.18) and pack-years (OR = 1.56, 95%CI = 1.10−2.22). For never smokers, FL risk increased for those exposed indoors to >2 smokers during childhood (OR = 1.84, 95%CI = 1.11−3.04). For cases, current smoking and the highest categories of smoking duration and lifetime cigarette exposure were associated with elevated all-cause mortality. The hazard ratio for current smoking and FL-specific mortality was 2.97 (95%CI = 0.91−9.72). We found no association between recent alcohol consumption and FL risk, all-cause or FL-specific mortality. Our study showed consistent evidence of an association between smoking and increased FL risk and possibly also FL-specific mortality. Strengthening anti-smoking policies and interventions may reduce the population burden of FL.

Background: Given the increasing numbers of multiple sclerosis (MS) patients undergoing autologous haematopoietic stem cell transplant (AHSCT) worldwide, and with women of childbearing age overrepresented in the target population, it is increasingly important to review fertility and pregnancy outcomes following AHSCT., Objective: To evaluate the rate of pregnancy and complications post-AHSCT for MS., Method: Retrospective evaluation of the rate of pregnancy and associated complications in a cohort of patients post-AHSCT with BEAM conditioning for MS since 2010 in a tertiary referral centre., Results: In our ongoing Phase 2 trial of AHSCT for MS, 55 patients have undergone AHSCT with 30 females being of childbearing age at time of transplantation. Four pregnancies occurred following AHSCT. Two pregnancies were carried to term. No maternal or neonatal complications were reported in either case. Two pregnancies were not carried to term due to elective terminations. Both of these patients became pregnant unexpectedly 2 years following AHSCT. Of the 21 male patients, one patient has fathered three children since his AHSCT. There were no newborn complications., Conclusions: This is the first report to our knowledge on fertility outcomes in both sexes post-AHSCT for MS. Patients of both sexes should be counselled prior to treatment on infertility and contraceptive use.

Background: Persons living with human immunodeficiency virus (HIV) are at elevated risk of developing the malignant diseases that require allogeneic stem cell transplantation (ASCT). Recent data suggest that these individuals are also at an elevated risk of certain complications post-ASCT. This risk may result from preexisting HIV-related factors affecting dynamics of immune reconstitution post-ASCT. However, to date, there has been little work describing the dynamics of immune reconstitution post-ASCT in persons with HIV and none comparing these data to controls without HIV., Methods: We assessed T-cell reconstitution in 6 ASCT with HIV recipients (HIV+ASCT) compared to a control population of 21 ASCT without HIV recipients. In a subset of HIV+ASCT recipients we performed additional flow cytometry profiling of CD8+ T-cell subsets and antigen specificity of reconstituting CD4+ and CD8+ T cells., Results: We observe no difference in post-ASCT CD4+ T cells between HIV+ASCT and HIV-negative ASCT recipients, despite much lower pre-ASCT CD4+ T-cell counts in the HIV+ASCT group. In contrast, we observed significantly higher CD8+ T-cell numbers in the HIV+ASCT group post-ASCT. The reconstituting CD8+ T-cells were predominantly CD45RO+, whereas homing markers and antigen specificity of these cells varied between participants., Conclusion: This study represents the most extensive characterization of immune-reconstitution post-ASCT in persons with HIV, and the first to our knowledge to compare these data to ASCT controls without HIV. The results indicate that immune reconstitution in this group can be affected by preexisting HIV infection and post-ASCT antigen exposure., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Herpes zoster (HZ) can have a substantial impact on quality of life (QoL). The vaccine efficacy (VE) of a recombinant zoster vaccine (RZV) was 68.2% (95% confidence interval [CI], 55.6% to 77.5%) in a phase 3 study in adult autologous hematopoietic stem cell transplant (HSCT) recipients (NCT01610414). Herein, we report the impact of RZV on patients' QoL. Autologous HSCT recipients were randomized 1:1 to receive 2 doses of RZV or placebo, given 1 to 2 months apart. QoL was measured by the Short Form Survey-36 and Euro-QoL-5 Dimension at baseline, 1 month, and 1 year postdose 2 and during suspected HZ episodes with the Zoster Brief Pain Inventory (ZBPI). The RZV impact on ZBPI burden of illness and burden of interference scores was estimated. The 2 scores were calculated from the area under the curve (days 0 to 182) of the ZBPI worst pain and ZBPI activities of daily living scores, respectively, assuming a score of 0 for patients not having a confirmed HZ episode. The ZBPI maximum worst pain score was significantly lower in the RZV than placebo group (mean: 5.8 versus 7.1, P = .011). Consequently, the VE estimates for HZ burden of illness (82.5%; 95% CI, 73.6 to 91.4) and burden of interference (82.8%; 95% CI, 73.3 to 92.3) were higher than the HZ VE estimate (ie, 68.2%). RZV showed significantly better QoL scores than placebo 1 week following rash onset among patients with confirmed HZ. In addition to reducing the risk of HZ and its complications, RZV significantly reduced the impact of HZ on patients' QoL in those who developed breakthrough disease., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Autologous haematopoietic stem cell transplantation (AHSCT) has been explored as a therapeutic intervention in multiple sclerosis (MS) over the last two decades; however, prospective clinical trials of the most common myeloablative conditioning regimen, BEAM, are limited. Furthermore, patient selection, optimal chemotherapeutic regimen and immunological changes associated with disease response require ongoing exploration. We present the outcomes, safety and immune reconstitution (IR) of patients with active, treatment refractory MS., Methods: This study was a single-centre, phase II clinical trial of AHSCT for patients with active relapsing remitting (RRMS) and secondary progressive MS (SPMS). Patients underwent AHSCT using BEAM (carmustine, etoposide, cytarabine, melphalan)+antithymocyte globulin chemotherapeutic regimen., Outcomes: The primary outcome was event-free survival (EFS); defined as no clinical or radiological relapses and no disability progression. Multiparameter flow cytometry was performed for evaluation of post-transplant IR in both MS and lymphoma patients receiving the same chemotherapy regimen., Results: Thirty-five patients (20 RRMS, 15 SPMS) completed AHSCT, with a median follow-up of 36 months (range 12-66). The median Expanded Disability Status Scores (EDSS) was 6 (2-7) and patients had failed a median of 4 (2-7) disease modifying therapies. 66% failed treatment with natalizumab. EFS at 3 years was 60%, (70% RRMS). Sustained improvement in EDSS was seen in 15 (44%) of patients. There was no treatment-related mortality. A sustained rise in CD39 + T regulatory cells, immunosuppressive CD56 hi natural killer cells and ablation of proinflammatory mucosal-associated invariant T cells was seen for 12 months following AHSCT in patients with MS. These changes did not occur in patients with lymphoma receiving the same chemotherapy for AHSCT., Conclusions: The EFS in our MS cohort is significantly greater than other high-efficacy immunosuppressive therapies and similar to other AHSCT studies despite a more heavily pretreated cohort., Trial Registration Number: ACTRN12613000339752., Competing Interests: Competing interests: IJS reports personal fees from Biogen, Merck, Sanofi Genzyme and Teva, outside the submitted work. JCM reports personal fees from Biogen, Merck, Sanofi Genzyme and Teva, outside the submitted work. YB reports grants and other from Genzyme-Sanofi, grants and other from Novartis, grants from Biogen, other from Teva, grants and other from Merck outside the submitted work and YB is a cofounder of Medical Safety Systems, which provides automated pathology monitoring for patients prescribed immunotherapies (including alemtuzumab) in Australia and (under the trading name RxMx) the USA. RZ has received speaker honoraria and consultant fees from Genzyme-Sanofi, Novartis, Claret Medical, Celgene and EMD Serono. He has received research support from EMD Serono, Genzyme-Sanofi, Claret Medical, Protembis, QuintilesIMS and Novartis. outside the submitted work. DDFM has received a research grant from Phebra outside the submitted work., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Empirical antifungal therapy is frequently used in hematology patients at high risk of invasive aspergillosis (IA), with substantial cost and toxicity. Biomarkers for IA aim for earlier and more accurate diagnosis and targeted treatment. However, data on the cost-effectiveness of a biomarker-based diagnostic strategy (BDS) are limited. We evaluated the cost effectiveness of BDS using results from a randomized controlled trial (RCT) and individual patient costing data. Data inputs derived from a published RCT were used to construct a decision-analytic model to compare BDS (Aspergillus galactomannan and PCR on blood) with standard diagnostic strategy (SDS) of culture and histology in terms of total costs, length of stay, IA incidence, mortality, and years of life saved. Costs were estimated for each patient using hospital costing data to day 180 and follow-up for survival was modeled to five years using a Gompertz survival model. Treatment costs were determined for 137 adults undergoing allogeneic hematopoietic stem cell transplant or receiving chemotherapy for acute leukemia in four Australian centers (2005-2009). Median total costs at 180 days were similar between groups (US$78,774 for SDS [IQR US$50,808-123,476] and US$81,279 for BDS [IQR US$59,221-123,242], P = .49). All-cause mortality was 14.7% (10/68) for SDS and 10.1% (7/69) for BDS, (P = .573). The costs per life-year saved were US$325,448, US$81,966, and US$3,670 at 180 days, one year and five years, respectively. BDS is not cost-sparing but is cost-effective if a survival benefit is maintained over several years. An individualized institutional approach to diagnostic strategies may maximize utility and cost-effectiveness., (© The Author 2017. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) can lead to significant changes to the HIV reservoir and HIV immune responses, indicating that further characterization of HIV-infected patients undergoing HSCT is warranted., Methods: We studied 3 patients who underwent HSCT after either reduced intensity conditioning or myeloablative conditioning regimen. We measured HIV antigens and antibodies (Ag/Ab), HIV-specific CD4 T-cell responses, HIV RNA, and DNA in plasma, peripheral blood mononuclear cells, isolated CD4 T cells from peripheral blood, and lymph node cells. The patients remained on antiretroviral therapy throughout the follow-up period., Results: All patients have been in continued remission for 4-6 years post-HSCT. Analyses of HIV RNA and DNA levels showed substantial reductions in HIV reservoir-related measurements in all 3 patients, changes in immune response varied with pronounced reductions in 2 patients and a less dramatic reduction in 1 patient. One patient experienced unexpected viral rebound 4 years after HSCT., Conclusions: These 3 cases highlight the substantial changes to the HIV reservoir and the HIV immune response in patients undergoing allogeneic HSCT. The viral rebound observed in 1 patient indicates that replication competent HIV can re-emerge several years after HSCT despite these marked changes.

There is a strong argument for the use of antifungal prophylaxis in high-risk patients given the significant mortality associated with invasive fungal disease, the late identification of these infections, and the availability of safe and well-tolerated prophylactic medications. Clinical decisions about which patients should receive prophylaxis and choice of antifungal agent should be guided by risk stratification, knowledge of local fungal epidemiology, the efficacy and tolerability profile of available agents, and estimates such as number needed to treat and number needed to harm. There have been substantial changes in practice since the 2008 guidelines were published. These include the availability of new medications and/or formulations, and a focus on refining and simplifying patient risk stratification. Used in context, these guidelines aim to assist clinicians in providing optimal preventive care to this vulnerable patient demographic., (© 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.)

Objectives: To identify risk factors for non-Hodgkin's lymphoma (NHL) in people with HIV infection., Design and Setting: Case-control study in Sydney, Australia., Participants and Methods: Two hundred and nineteen patients with AIDS-related NHL were compared with 219 HIV-infected controls without NHL, matched for CD4 positive cell count and date of specimen collection. Data on demographic, infectious, treatment-related and immunological factors were abstracted by medical record review. The association between demographic factors, sexually transmissible diseases, HIV-related opportunistic infections, anti-viral therapy, duration of immune deficiency and indices of immune stimulation and risk of NHL were derived for these groups., Results: In a multivariate model, there were two independent groups of predictors of NHL risk. The first was duration of immunodeficiency, as measured by longer time since seroconversion (P for trend 0.008), and lower CD4 positive cell count 1 year prior to the time of NHL diagnosis (P for trend 0.009). The second predictor was B-cell stimulation, as indicated by higher serum globulin (a surrogate marker for serum immunoglobulin, P for trend 0.044) and HIV p24 antigenaemia [odds ratio (OR) for p24 positivity, 1.82; 95% confidence interval (CI), 1.15-2.88]. Indices of B-cell stimulation preceded the diagnosis of NHL by several years. Factors not related to NHL risk included clinical indices of Epstein-Barr virus infection and receipt of individual nucleoside analogue antiretroviral agents. Combination therapy with these agents was associated with a non-significant reduction in NHL risk (OR, 0.68; 95% CI, 0.39-1.18)., Conclusions: Markers of long-standing immune deficiency and B-cell stimulation were associated with an increased risk of developing NHL. Unless the strongest risk factor for NHL, immune deficiency, can be reversed, NHL is likely to become proportionately more important as a cause of morbidity and mortality in people with HIV infection.

Objective: Based on animal studies and anecdotal case reports, high-dose therapy and autologous blood stem cell rescue have been proposed as an experimental treatment for severe, refractory rheumatoid arthritis (RA). This study aimed to establish the toxicity of this treatment and obtain preliminary efficacy data upon which to base future clinical trials., Methods: Two cohorts of 4 patients who fulfilled criteria for severe, active, treatment-resistant RA were recruited into a dose-escalation study of cyclophosphamide (CYC) (100 mg/kg or 200 mg/kg) followed by unmanipulated peripheral blood stem cell rescue. Patient treatment was managed according to a standard supportive care protocol. Disease-modifying drugs were discontinued before treatment, but corticosteroids were maintained and later tapered where possible. Patients' conditions were assessed using World Health Organization toxicity criteria and standard parameters for rheumatic disease., Results: Dose-dependent differences in hematologic toxicity were observed between cohorts 1 and 2, although toxicity was similar for other systems and was most significant in the gastrointestinal system. Patients in cohort 1 had only transient responses to therapy, lasting 2-3 months. Substantial improvements were sustained beyond 17-19 months in cohort 2, including steroid-independent disease remission for 1 patient, although the procedure did not completely abolish disease activity., Conclusion: High-dose CYC and unmanipulated autologous blood stem cell rescue has acceptable dose-dependent toxicity in severe, treatment-resistant RA, and 200 mg/kg of CYC induces substantial clinical responses. Refinement of this intensive approach might include further intensification of the preparation regimen, graft manipulation, and posttransplant immunomodulation.

High-dose chemotherapy with autologous stem cell rescue has been proposed as an intensive therapy for severe rheumatoid arthritis (RA). In view of previous observations of abnormal haemopoiesis in RA patients, the composition and function of peripheral blood stem cell harvests (PBSCH) was investigated. Compared with PBSCH from healthy allogeneic donors mobilized with the same dose of G-CSF (filgrastim; 10 microg/kg/d, n = 14), RA PBSCH (n = 9) contained significantly fewer mononuclear cells (375 v 569 x 10(6)/kg, P = 0.03) and CD34+ cells (2.7 v 5.8 x 10(6)/kg, P = 0.003). However, there were increased proportions of CD14+ cells (P = 0.006) and CD14+ CD15+ cells (the phenotype of previously described 'abnormal' myeloid cells, P = 0.002) in the RA PBSCH which translated into 3.5- and 7-fold increases respectively on a per CD34+ cell basis. There were no differences in T-cell activation status as judged by proportions of CD4+ and CD8+ expressing CD45RA, CD45RO, HLA-DR and CD28 (RA PBSCH, n = 7, donor PBSCH, n = 5, P = 0.2-0.7). Phytohaemagglutinin responses determined fluorocytometrically with induction of CD69 expression were reduced in CD4+ and CD8+ cells following filgrastim administration in 3/3 RA patients tested. Compared with bone marrow as a potential source of CD34+ cells, PBSCH contained 11-fold more T cells (P < 0.0005), 8-fold more B cells (P < 0.0005) and 4-fold more monocytes (P = 0.02). In short-term methylcellulose culture there were no differences in colony counts (CFU-GM, CFU-GEMM, BFU-E) per CD34+ cell from PBSCH from RA patients (n = 11) and healthy donors (n = 10). Long-term culture initiator cells were cultured successfully from cryopreserved PBSCH from RA patients (n = 9). In conclusion, PBSCH from RA patients differed significantly in composition from normal individuals, but in vitro studies support normal stem and progenitor cell function. Changes in T-cell function occur during mobilization in RA patients. This work provides reassurance for the use of PBSCH as haematological rescue and baseline data for clinical trials of graft manipulation strategies in patients with RA.

Objective: To determine the effectiveness and safety of splenectomy for patients with human immunodeficiency virus (HIV)-related immune thrombocytopenia, using the results of splenectomy for patients with non-HIV immune thrombocytopenic purpura as a control group for comparison., Design: Retrospective study., Setting: Tertiary care university hospital., Patients: Fourteen patients who underwent splenectomy for symptomatic, medically refractory HIV-related immune thrombocytopenia at this hospital from 1988 to 1997. During the same period, 20 patients had splenectomy for treatment of non-HIV immune thrombocytopenic purpura., Intervention: Splenectomy., Main Outcome Measures: Platelet response, need for postsplenectomy medical therapy, progression of HIV disease, and complications., Results: All patients with HIV-related thrombocytopenia had a complete early platelet response to splenectomy, with an elevation of the platelet count to greater than 100X10(9)/L. After a median follow-up of 26.5 months, all but 1 patient had a sustained complete remission with no need for medical therapy for thrombocytopenia. Splenectomy was more effective in the HIV-related thrombocytopenia group than in the non-HIV immune thrombocytopenic purpura group, with significantly higher platelet counts at 1 week and 1 month after splenectomy in the HIV group (t test, P=.02 and P=.009, respectively). There were significantly fewer patients needing medical therapy for thrombocytopenia after splenectomy in the HIV group (chi2 test, P=.02). There were no remarkable short- or long-term complications in the patients with HIV infection, including no overwhelming postsplenectomy infections. Three patients have died, and 2 patients have developed AIDS since operation., Conclusions: Splenectomy is effective treatment for patients with symptomatic HIV-related thrombocytopenia that is resistant to medical therapy. The effectiveness of this treatment suggests that the predominant mechanism of thrombocytopenia in HIV-infected patients is increased destruction of platelets because of platelet-associated immunoproteins.

Microsporidia are zoonotic protozoa which were rare human pathogens prior to 1985, when Enterocytozoon bieneusi was described in human immunodeficiency virus-infected patients with chronic diarrhea. Another species, Encephalitozoon (Septata) intestinalis, is associated with diarrhea and chronic sinusitis, and approximately 25 cases have been reported in the literature. However, other microsporidial infections in human immunodeficiency virus-infected patients remain extremely rare. We report the first case of a Pleistophora sp.-like microsporidian infection presenting as a progressive severe myosotis associated with fever and weight loss. The organism was demonstrated by light microscopy and electron microscopy in corneal scrapings, skeletal muscle, and nasal discharge. Electron microscopy showed an electron-dense surface coat with "sunflare"-like projections surrounding all stages of development of meronts (two to four nuclei, dividing by binary fission), sporonts, and sporoblasts. Division of sporonts, in which sporonts separate from the thick outer coat, creating a sporophorous vesicle, is by binary fission, differentiating this organism from Pleistophora sp. The spore measures 4.0 by 2.5 microns and has a rugose exospore. A new genus and species, Trachipleistophora hominis, has been established for this parasite. The patient was treated with albendazole, sulfadiazine, and pyrimethamine, and the clinical symptoms resolved.

Treating systemic malignancies requires specialist skill and experience, with active treatment often providing the best initial palliation of symptoms. A full management plan involving general practitioner, patient and others is essential at this stage of HIV disease.

Objectives: To determine whether microsporidian infections occur in Australian patients infected with human immunodeficiency virus (HIV), to assess the incidence, and to discuss microscopic detection methods., Design and Patients: 180 consecutive HIV-infected patients (109 with chronic diarrhoea and 71 with other indications) underwent upper gastrointestinal tract endoscopy and pinch biopsies of the second part of the duodenum. The biopsies were handled by a protocol: four levels, with haematoxylin and eosin stain (H&E) at each level, periodic acid Schiff reagent after diastase (DiPAS) and auramine stain at the second level, and Warthin-Starry (WS) stain and cytomegalovirus early antigen immunoperoxidase study at the third level. Electron microscopy was carried out on samples from the first 95 patients, and thereafter from selected patients., Setting: The patients came from the HIV Medicine Unit of a teaching hospital and from the practice of a gastroenterologist., Main Outcome Measures: Diagnosis of microsporidia was to based on the H&E stain, with electron microscopy as the definitive test because the microsporidia are often difficult to see with H&E. Empirically, the WS stain was found to stain the microorganisms and it replaced electron microscopy during the study as the screening diagnostic test., Results: Microsporidia were present in 36 of the 109 patients with diarrhoea (33%) and one of 71 patients without diarrhoea. The WS stain in all cases showed developing spores in the enterocytes and in four cases in macrophages as well. The H&E stain showed non-specific duodenitis and was not diagnostic in some cases. Electron microscopy on samples from the first 95 consecutive patients showed 100% concordance with the WS stain. In 33 cases, electron microscopy showed the multinucleated plasmodia and the spores of Enterocytozoon bieneusi and in the four cases confirmed the spores in macrophages and showed a new Encephalitozoon-like species with a septate parasitophorous vacuole. Other causes of duodenal infection were cytomegalovirus (11 cases), mycobacteria (8), cryptosporidia (8) and Giardia lamblia (5)., Conclusion: E. bieneusi was the commonest microorganism found in our series of 180 consecutive patients. The actual prevalence of the two microsporidia species within the HIV-positive population and general community awaits further study. The WS stain provides a sensitive diagnostic test for the presence of E. bieneusi and the new Encephalitozoon-like species, avoiding the cost and potential sampling error of electron microscopy. The detailed ultrastructure and taxonomy of the new species requires further study.

Although a number of tumors in patients infected with the human immunodeficiency virus have been reported, Kaposi's sarcoma and non-Hodgkin's lymphoma remain the two principal malignancies. This article provides an Australian perspective of the recent advances in research into malignancy in HIV-infected persons.

An 11-year-old boy with acute myeloblastic leukaemia in first remission received an allogeneic mismatched bone-marrow transplant (BMT) from his father in 1979; subsequent HLA typing showed that his haemopoietic system had been repopulated by the donor cells. In 1986 hypereosinophilic syndrome, secondary to a T-cell lymphocytic lymphoma, developed in the father, then aged 45 years. A full haematological remission was obtained by means of standard acute lymphoblastic leukaemia treatment. He then received melphalan, total body irradiation, and a BMT from his son. Graft-versus-host disease was transient in both patients, and father and son remain well and disease-free 20 months and 10 years, respectively, after BMT.

Deep fungal infection in recipients of bone marrow transplants remains a significant cause of morbidity and mortality. Prolonged neutropenia is the major factor predisposing patients to invasive fungal disease. Candida and Aspergillus species remain the two most common pathogens. Prophylaxis against these organisms with the oral polyenes nystatin and amphotericin B has been disappointing. Systemic amphotericin B is too toxic for prophylactic use, yet it remains the mainstay of therapy for suspected or established deep fungal infection. Ketoconazole is contraindicated in patients receiving cyclosporine prophylaxis against graft-vs.-host disease and appears effective only in high doses associated relatively commonly with adverse reactions. This paper reviews results of antifungal prophylaxis and discusses new measures and agents likely to be of value in the prevention of fungal infection in bone marrow transplantation.

The serum level of galactosyltransferase was measured in a group of 218 patients with a variety of solid tumors and most with advanced disease. The pretreatment enzyme level showed little potential as a diagnostic tumor marker, and its change with treatment did not reflect the initial response. There was, however, a significant correlation between the length of survival and the pretreatment enzyme level. Patients with normal levels survived over twice as long as those with elevated levels. When Cox's proportional hazards regression analysis was used to compare the prognostic potential of galactosyltransferase with a number of known clinical indicators of prognosis, the variable most related to survival was performance status (P less than 10(-4) followed by galactosyltransferase (P = 0.01) and then the extent of disease (P = 0.03). The other variables, such as previous therapy, the type, site, and size of primary tumor, did not contribute significantly to the relationship with survival. The pretreatment level of galactosyltransferase is therefore a relatively independent prognosticator of survival and, as such, could be potentially useful in patient management by increasing the accuracy of the initial assessment of prognosis.

Of 101 patients with symptomatic adenocarcinoma or undifferentiated carcinoma of unknown primary site, 95 were evaluable for the effects of two randomized chemotherapy regimens. Forty-eight patients received combination doxorubicin and mitomycin C (DM) and 47 received combination cisplatin, vinblastine and bleomycin (PB). Response rates were not significantly different between the two treatment groups, 42% for DM and 32% for PVB, with an overall response rate of 37.1%. Survival differences for DM and PVB treated groups were not significantly different, with 18 weeks and 25 weeks median survivals respectively. Toxicities were unequal for the two treatment groups with increased haematological toxicity for DM and greater gastrointestinal toxicity for PVB. The authors conclude both therapies were of limited efficacy in the treatment of ACUP patients and emphasize that only symptomatic patients should be considered for such therapies.