History of antibiotic use and risk of non-Hodgkin's lymphoma (NHL)

A population-based, incidence case-control study was conducted among women in upstate New York to determine whether histories of certain infections and antibiotic use are associated with risk of non-Hodgkin's lymphoma (NHL). Our study involved 376 cases of NHL identified through the New York State Cancer Registry and 463 controls selected from the Medicare beneficiary files and state driver's license records. Information about use of common medications including antibiotics, history of selected infectious diseases and potential confounding variables was obtained by telephone interview. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using an unconditional logistic regression model. There was a progressive increase in risk of NHL with increasing frequency and duration of systemic antibiotic use, as assessed over the period of 2-20 years before the interview. The ORs for the highest exposure categories, >/=36 episodes and >/=366 days of use, were 2.56 (95% CI 1.33-4.94) and 2.66 (95% CI 1.35-5.27), respectively. These associations were primarily due to antibiotic use against respiratory infections and dental conditions. Moreover, the association with frequency of antibiotic use for respiratory infections was pronounced for marginal zone B-cell lymphoma and for respiratory tract lymphoma. Analyses by class of antibiotics did not suggest that a general cytotoxic effect of antibiotics was responsible for these increased risks. Although recall bias and selection bias remain potential concerns in our study, the results are generally consistent with the hypothesis that persistent infection/inflammation predisposes individuals to the development of NHL. However, a direct role of antibiotics in NHL induction has not been ruled out.     

Proteasome inhibition as a therapeutic strategy for hematologic malignancies

The ubiquitin–proteasome pathway is a principal intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies since several cell cycle regulators and modulators of apoptosis are degraded through this pathway. The current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the US Food and Drug Administration for the treatment of advanced multiple myeloma, is reviewed. Particular emphasis is placed on the preclinical research data that became the basis for eventual clinical applications of proteasome inhibitors, an overview of the clinical development of this exciting drug class in multiple myeloma, and an appraisal of possible uses in other hematologic malignancies, such as non-Hodgkin’s lymphomas.     

Pharmacokinetic profile and first preliminary clinical evaluation of bendamustine in Taiwanese patients with heavily pretreated indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Prior studies found bendamustine is efficacious in patients with indolent B‐cell non‐Hodgkin lymphoma (NHL). To date, no studies have reported the efficacy of bendamustine in a Chinese population. This multicentre phase II trial evaluated the pharmacokinetics (PK), safety and efficacy of bendamustine monotherapy in Chinese patients in Taiwan with pretreated indolent B‐cell NHL or mantle cell lymphoma (MCL). For PK assessments, patients were randomized (n = 16; 11 with indolent B‐cell NHL and five with MCL) to 90 or 120 mg/m² of bendamustine for the first cycle. Plasma levels of bendamustine and its two metabolites were analyzed. For efficacy and safety evaluations, bendamustine 120 mg/m² was given to all patients every 3 weeks starting at cycle 2 for a minimum of a total of six cycles. The median age of patients was 61.7 years, and the majority were men (75%). The median number of prior treatments was 4 (range, 1–9 regimens), and all patients were previously treated with rituximab. Bendamustine plasma concentration peaked near the end of infusion and was rapidly eliminated with a mean elimination half‐life (t_1/2) of 0.67–0.8 h. Of the evaluable patients (n = 14), the overall response rate was 78.6%, including 7.2% of patients having a complete response. Mean progression‐free survival was 27.5 weeks. The most common grade 3–4 adverse events were leucopenia (56.3%), neutropenia (56.3%) and thrombocytopenia (25%). In conclusion, bendamustine was efficacious and well tolerated in Taiwanese patients with indolent NHL and MCL with a similar PK profile to that of other populations. Copyright © 2014 John Wiley & Sons, Ltd.     

Hepatitis C infection is not associated with systemic HIV-associated non-Hodgkin's lymphoma: a cohort study

Immunosuppression induced by the human immunodeficiency virus (HIV) increases the risk of developing non-Hodgkin's lymphoma (NHL). As the hepatitis C virus (HCV) has been implicated in the development of B cell lymphomas, we compared the incidence of systemic NHL during HIV infection compared to HIV and HCV co-infection. Of 5,832 individuals studied during the era of highly active anti-retroviral therapy (HAART), 102 patients were diagnosed with systemic NHL. The incidence of systemic NHL was 6.9 of 10(4) patient years during HIV infection compared to 7.1 of 10(4) patient years during HIV alone (p = 0.9). In this immunocompromised patient population, there was no association between HCV infection and an increased risk of lymphoma.     

Consolidative involved field radiotherapy after high dose chemotherapy and autologous stem cell transplantation for non-Hodgkin's lymphoma: a case-control study

The role of involved field radiation therapy (IF-RT) after high dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) for non-Hodgkin's lymphoma (NHL) has not been conclusively defined. It has been hypothesized that HDC might obviate the need of consolidative IF-RT. A retrospective matched-pair analysis of patients undergoing HDC and ASCT with or without consolidative IF-RT has been performed. Fifteen patients treated with IF-RT after ASCT were compared with 15 patients without IF-RT, identical for histology, stage and treatment response to HDC/ASCT as well as comparable for international prognostic index (IPI) score, age and gender. After a mean follow-up time of 65 +/- 45 months, none of the patients with consolidative IF-RT following HDC and ASCT relapsed within the involved field compared to six patients without consolidative IF-RT (IF-failure risk at 5 years: 0% vs. 40%; p < 0.005). In most of the cases, local relapse was seen in patients with bulky disease. The 5-year risk for loco-regional failure was 7% after consolidative IF-RT and 38% in patients without IF-RT (p = 0.02) while the 5-year risk for developing distant recurrences was similar in both groups (30% with IF-RT vs. 35% non-IF-RT; p = 0.7). Overall survival at 5 years was similar with 79% (IF-RT) and 65% (non-IF-RT), respectively (p = 0.2). Acute toxicity due to consolidative IF-RT was mild in most cases and severe acute toxicity was noticed in only one patient (7%). Long-term toxicities observed after IF-RT were coronary artery disease, secondary malignancy unrelated to the RT-field, angina abdominalis, hypothyroidism and teeth decay. Recurrence of NHL at sites of macroscopic disease remains common despite HDC. IF-RT achieves excellent local regional control and consolidative IF-RT after ASCT seems indicated, particularly in patients with bulky disease. In the absence of a prospective randomized trial and proven impact on survival rates, IF-RT can be recommended as an option post-ASCT to enhance local disease control.     

Proteasome inhibition and combination therapy for non-Hodgkin's lymphoma: from bench to bedside

Although patients with B-cell non-Hodgkin's lymphoma (NHL) usually respond to initial conventional chemotherapy, they often relapse and mortality has continued to increase over the last three decades in spite of salvage therapy or high dose therapy and stem cell transplantation. Outcomes vary by subtype, but there continues to be a need for novel options that can help overcome chemotherapy resistance, offer new options as consolidation or maintenance therapy postinduction, and offer potentially less toxic combinations, especially in the elderly population. The bulk of these emerging novel agents for cancer treatment target important biological cellular processes. Bortezomib is the first in the class of proteasome inhibitors (PIs), which target the critical process of intracellular protein degradation or recycling and editing through the proteasome. Bortezomib is approved for the treatment of relapsed or refractory mantle cell lymphoma. The mechanisms of proteasome inhibition are very complex by nature (because they affect many pathways) and not fully understood. However, mechanisms of action shared by bortezomib and investigational PIs such as carfilzomib, marizomib, ONX-0912, and MLN9708 are distinct from those of other NHL treatments, making them attractive options for combination therapy. Preclinical evidence suggests that the PIs have additive and/or synergistic activity with a large number of agents both in vitro and in vivo, from cytotoxics to new biologicals, supporting a growing number of combination studies currently underway in NHL patients, as reviewed in this article. The results of these studies will help our understanding about how to best integrate proteasome inhibition in the management of NHL and continue to improve patient outcomes.     

Growth inhibition of experimental non-Hodgkin's lymphomas with the targeted cytotoxic somatostatin analogue AN-238

The cytotoxic analogue of somatostatin, AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201), a superactive derivative of doxorubicin (DOX), linked to somatostatin analogue carrier RC-121 binds with high affinity to receptors for somatostatin and can be targeted to tumors that express these receptors. Because somatostatin receptors are found in a high percentage of human non-Hodgkin's lymphomas (NHLs), we evaluated the antitumor effect of AN-238 in 2 human NHL cell lines in vivo. Nude mice bearing xenografts of RL and HT human NHL were treated with AN-238 or its components at equimolar doses, and antitumor effects were determined. Expression of mRNA for somatostatin receptor subtypes was measured by RT-PCR, and the presence of somatostatin receptors was determined by radioligand binding. Toxicity was evaluated by following white blood cell count (WBC) and body weight. AN-238 significantly (p < 0.05) inhibited growth of RL and HT xenografts and prolonged the tumor doubling time. Cytotoxic radical AN-201, the unconjugated mixture of somatostatin analogue RC-121 and AN-201 or RC-121 alone had no significant effects. Blockade of somatostatin receptors by excess RC-121 abolished the effect of AN-238, demonstrating targeting. Expression of somatostatin receptors was not changed after repeated treatment with AN-238. AN-201, but not AN-238, significantly lowered the WBC and caused a greater decrease in body weight than AN-238. Our findings demonstrate that targeted chemotherapy with AN-238 can strongly inhibit the growth of NHL cells, which express somatostatin receptors. AN-238 could be considered for the treatment for patients with NHL.     

Radioimmunotherapy with (131)I-rituximab for patients with relapsed/refractory B-cell non-Hodgkin's lymphoma (NHL)

Aim: To evaluate the efficacy and safety of radioimmunotherapy (RIT) with radioiodinated human/murine chimeric anti‐CD20 monoclonal antibody rituximab (¹³¹I‐rituximab) for treating Korean patients with relapsed or refractory B‐cell non‐Hodgkin's lymphomas (NHL). Methods: All patients received unlabeled rituximab 70 mg immediately prior to the administration of a therapeutic dose (median dose: 7.3 GBq) of ¹³¹I‐rituximab. The tumor response was evaluated 1 month later by contrast enhanced ¹⁸F‐fludeoxyglucose positron emission tomography‐computed tomography. Results: Between May 2004 and October 2006, 24 patients received single treatment with ¹³¹I‐rituximab. The overall response rate (ORR) was 29%; 46% (three complete responses, two partial responses (PR) for patients with low grade B‐cell NHL (LGL) and 9% (one PR) for patients with diffuse large B‐cell lymphoma (DLBCL). After a median follow‐up of 55 months, the median progression‐free survival (PFS) for all the patients was 2.2 months. The median overall survival (OS) was 11.3 months. There were statistically significant differences between the LGL and the DLBCL for the median PFS (4.5 months vs 1.3 months, respectively, P = 0.0007) and the median OS (30.3 months vs 6.5 months, respectively, P = 0.0295). Grades 3–4 thrombocytopenia and neutropenia occurred in 33% (8/24) and 21% (5/24) of the patients, respectively. Conclusion: RIT with ¹³¹I‐rituximab seems to be effective and tolerable for patients with refractory LGL, although this treatment had modest activity in patients with refractory DLBCL. Further studies are warranted to determine the efficacy of ¹³¹I‐rituximab for treating the patients with DLBCL.     

Family history of cancer in children with acute leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma: the ESCALE study (SFCE)

The role of a family history of cancer in the etiology of childhood hematopoietic malignancies was investigated using the data from the ESCALE study. ESCALE, a population-based case-control study, was carried out in France over the period, 2003-2004. A total of 773 cases of acute leukemia (AL), 130 of Hodgkin's lymphoma (HL), 163 of non-Hodgkin's lymphoma (NHL) and 1,681 population-based controls were included. The controls were randomly selected from the French population and were frequency matched with the cases on age and gender. Cancer history in first- and second-degree relatives was reported by the mothers in a structured telephone questionnaire that was the same for the cases and controls. Odds ratios (ORs) were estimated using an unconditional regression model taking into account the stratification variables and potential confounders. A family history of cancer was associated with an increased risk of HL (OR = 1.5 [1.0-2.2]) and NHL (OR = 1.8 [1.3-2.5]), but not AL (OR = 1.0 [0.9-1.2]). The ORs were higher when at least 2 relatives had a history of cancer or when 1 case occurred before age 46 years. Only HL was significantly associated with a family history of hematopoietic malignancies (OR = 2.0 [1.0-3.8]), mainly because of a significant association with a history of HL (OR = 5.4 [1.3-22]). In conclusion, the study findings support the hypothesis of familial susceptibility to childhood lymphoma, but do not suggest familial susceptibility to childhood AL.     

Characteristics and survival of patients with non-Hodgkin's lymphoma with and without acquired immunodeficiency syndrome

Our objective was to determine the characteristics and survival of patients with non-Hodgkin's lymphoma (NHL) with and without acquired immunodeficiency syndrome (AIDS). A cancer registry and AIDS registry linkage for San Diego County was performed in October 1998 as part of a national multicentre study. We performed Kaplan-Meier analysis to compare survival in NHL patients with and without AIDS, after matching for age, sex, and race/ethnicity. We performed logistic regression to determine which patient and tumour characteristics were significantly associated with 1-year survival. Of the 4361 cases of NHL, 324 (7%) had AIDS and 4037 (93%) were not known to have AIDS. Patients with AIDS were more likely to have extranodal, high-grade, and disseminated NHL diagnosed by non-histologic means and were less likely to have received chemotherapy. Patients with AIDS and NHL who survived at least 1 year had less advanced disease stage and received chemotherapy. The median survival in patients with AIDS was 4 months (95% confidence interval (CI): 4-5) and 95 months (95% CI: 58-157) in patients without AIDS (P<0.001). Although these patients with AIDS-related NHL were unlikely to survive, the highly active antiretroviral agents currently used may improve outcomes in future patients.     

Childhood Hodgkin's lymphoma, non-Hodgkin's lymphoma and factors related to the immune system: the Escale Study (SFCE)

The study investigated the role of factors considered related to the early stimulation of the immune system in the aetiology of childhood lymphoma. The national registry-based case-control study, Escale, was carried out in France over the period 2003-2004. Population controls were frequency matched with the cases on age and gender. Data were obtained from structured telephone questionnaires administered to mothers. Odds ratios (ORs) were estimated using unconditional regression models adjusted for potential confounders. Data from 128 cases of Hodgkin's lymphoma (HL) aged 5-14 years, 164 cases of non-Hodgkin's lymphoma (NHL) aged 2-14 years and 1,312 controls were analyzed. Negative associations were observed between HL and day care attendance [OR = 0.5 (0.2-1.2)] and between HL and repeated early common infections among non-breastfed children [OR = 0.3 (.2-0.7), p = 0.003] [OR for breastfed children: 1.0 (.5-2.1)], but not for the other factors investigated. Negative associations were observed between NHL and birth order 3 or more [OR = 0.7 (0.4-1.1)], prolonged breastfeeding [OR = 0.5 (0.3-1.0)], regular contact with farm animals [OR = 0.5 (0.3-1.0)], frequent farm visits in early life [OR = 0.6 (0.4-1.1)] and history of asthma [OR = 0.6 (0.3-1.1)]. In conclusion, the results partly support the hypothesis that an abnormal maturation of the immune system may play a role in childhood HL or NHL, and call for further investigations.     

Ophthalmologic and intraocular non-Hodgkin's lymphoma: a large single centre study of initial characteristics, natural history, and prognostic factors

The aims of this study were to define the initial characteristics, natural history, and prognostic factors of patients with ophthalmologic and intraocular malignant lymphoma. All patients treated at the Institut Curie for lymphoma with ophthalmologic (orbit and/or adnexa) or intraocular involvement were retrospectively reviewed. A pathological review of all cases was performed according to the WHO classification. One hundred and forty-five patients were selected for the study. Pathological review showed 36% MALT type lymphoma, 22% lymphoplasmocytic lymphoma, and 15% diffuse large B-cell lymphoma. Ophthalmologic and ocular sites were intra-orbital in 61 cases (42%) and conjunctival in 51 cases (35%), with bilateral involvement in 10% of cases. Stage IV was found in 32% of cases, with bone marrow involvement in 12%. With a median follow-up of 90 months, the 5-year DFS and OS were 64 and 79% for low-grade NHL, and 43 and 50% for high-grade NHL. On multivariate analysis, age greater than 59 years, elevated LDH level, stage IV, high-grade histological subgroup, and presence of B-symptoms had a negative impact on OS for the overall population. In conclusion, with a median follow-up of 7.5 years, our large cohort of patients represents one of the largest published series on primary ophthalmologic and intraocular malignant lymphoma.     

Increasing incidence of non-Hodgkin's lymphoma in Canada, 1970-1996: age-period-cohort analysis

Previous studies have shown that the incidence of non-Hodgkin's lymphoma (NHL) has increased in many parts of the world in recent decades. Using data obtained from the Canadian Cancer Registry, the present study examined time trends in NHL incidence in Canada between 1970 and 1996 and the effects of age, period of diagnosis and birth cohort on incidence patterns for each sex separately. Results showed that overall age-adjusted incidence rates increased substantially, from 7.3 and 5.2 per 100,000 in 1970-1971 to 14.0 and 10.0 per 100,000 in 1995-1996 in males and females, respectively. Diffuse lymphoma was the major histological subtype, accounting for approximately 76% of NHL cases over the 27-year period. The data suggest that period effects have played a major role, although birth cohort effects may also have been involved. Sex-specific patterns of the incidence were similar over the time period of diagnosis but were distinct among recent birth cohorts. In conclusion, there is in fact a marked increase in NHL in Canada which cannot be explained in terms of improvements in diagnosis, changes in NHL classification and the increase in AIDS-associated NHL alone. The birth cohort effect in NHL suggests that changes in risk factors may have contributed to the observed increase.     

Tobacco smoking, alcohol drinking and non-Hodgkin's lymphoma: A European multicenter case-control study (Epilymph)

To study the role of tobacco smoking and alcohol drinking in the etiology of non-Hodgkin's lymphoma (NHL), we conducted a multicenter case-control study in Spain, France, Germany, Italy, Ireland and Czech Republic between 1998 and 2004, which included 1,742 cases of NHL and 2,465 controls matched on age, sex and recruitment area. Tobacco smoking was not associated with the risk of NHL overall or with risk of specific histological subtypes. Similarly, there was no association between alcohol drinking and the risk of NHL overall or across histological subtypes. However, a protective effect of alcohol drinking was observed among men (OR = 0.76, 95% CI = 0.62-0.93) and in non-Mediterranean countries (OR = 0.73, 95% CI = 0.61-0.86). There was no evidence of interaction between alcohol drinking and tobacco smoking in NHL etiology. The results of this large-scale European study did not support an association between tobacco and NHL and suggested a protective effect of alcohol on development of NHL for men and in non-Mediterranean countries.     

Patterns of care in a population-based random sample of patients diagnosed with non-Hodgkin's lymphoma

New therapies have enhanced treatment of non-Hodgkin's lymphoma (NHL), but extent of treatment use in community practice is unknown. We conducted a population-based study of NHL patients diagnosed in 1999 with histologically confirmed NHL (n = 947) residing in areas covered by the Surveillance, Epidemiology, and End Results program. We performed analyses to study factors associated with receipt of chemotherapy, radiation, and rituximab, and examine factors associated with mortality. Most patients presented with B-cell lymphoma (n = 828). Approximately 20% of patients received no therapy, over 60% received chemotherapy, and 12% received rituximab, alone or in combination. Patients aged 75 +, and males were less likely to have received chemotherapy (p = 0.01). There were no significant associations between receipt of rituximab and the factors analyzed. Patients who presented with B-symptoms or unknown B-symptom status were less likely to receive radiation (OR = 0.32 and 0.47, respectively, p = 0.0002) than asymptomatic patients. Cause-specific and all-cause mortality were significantly associated with patient age, race/ethnicity, gender, marital status, co-morbid conditions, and histological subgroup. Hispanic and African-Americans, patients age 75 +, males, unmarried patients, or patients with B-symptoms had higher risk of death from NHL and all-cause (p < 0.01). This is the first population-based study examining therapy received for many histological subtypes of NHL.     

Inhibition of Lyn is a promising treatment for mantle cell lymphoma with bortezomib resistance

Although proteasome inhibition with bortezomib (BTZ) is a validated treatment for relapsed or refractory mantle cell lymphoma (MCL), many patients show resistance to BTZ. However, the molecular mechanism of BTZ resistance in MCL has not been elucidated. In the present study, we investigated BTZ-resistant MCL cells in vitro and in vivo. We demonstrate that BTZ-resistant MCL cells showed highly increased expression of the B-cell receptor (BCR) components CD79A and CD19. Activation of the BCR signaling pathway enhanced the activity of Src family kinases (SFKs), especially Lyn, and downstream kinases PI3K/AKT/mTOR in BTZ-resistant MCL cells. Depletion of CD79A and Lyn significantly reduced several kinase activities involved in PI3K signaling, leading to inhibition of proliferation. In addition, the SFKs inhibitor dasatinib inhibited the proliferation of BTZ-resistant cells, preventing the binding of CD19 with Lyn and PI3K p85. We also verified our findings with the mouse xenograft tumor model. Dasatinib treatment significantly decreased tumor size in the mouse bearing BTZ-resistant MCL cells, but not in the mouse bearing BTZ-sensitive MCL cells. Collectively, our data show that overexpression of the BCR and its activated signaling confers BTZ resistance in MCL cells. Thus, targeting BCR signaling with dasatinib could be a novel therapeutic approach for patients with MCL that has relapsed or is refractory to treatment with BTZ.     

Obesity and risk of non-Hodgkin's lymphoma: a meta-analysis

Obesity is associated with altered immune and inflammatory responses and it may therefore influence the risk of non-Hodgkin's lymphoma. However, epidemiologic findings on obesity in relation to non-Hodgkin's lymphoma have been inconsistent. We conducted a meta-analysis to summarize the epidemiologic evidence on the association between excess body weight and risk of non-Hodgkin's lymphoma. Relevant studies were identified by searching MEDLINE (1966 to February 2007) and the reference lists of retrieved publications. We included cohort and case-control studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the association of body mass index (BMI) with non-Hodgkin's lymphoma incidence or mortality. A random-effects model was used to combine results from individual studies. Sixteen studies (10 cohorts and 6 case-control studies), with 21,720 cases, met the inclusion criteria. Compared to individuals of normal weight (BMI < 25.0 kg/m(2)), the summary RRs of non-Hodgkin's lymphoma were 1.07 (95% CI, 1.01-1.14) for overweight individuals (BMI between 25 and 30 kg/m(2)) and 1.20 (95% CI, 1.07-1.34) for those who were obese (BMI >/=>/=>/=>/= 30.0 kg/m(2)). Meta-analysis stratified by histologic subtypes showed that obesity was associated with a statistically significant increased risk of diffuse large B-cell lymphoma (RR, 1.40; 95% CI, 1.18-1.66; n = 6 studies) but not of follicular lymphoma (RR, 1.10; 95% CI, 0.82-1.47; n = 6 studies) or small lymphocytic lymphoma/chronic lymphocytic leukemia (RR, 0.95; 95% CI, 0.76-1.20; n = 3 studies). These findings indicate that excess body weight is associated with an increased risk of non-Hodgkin's lymphoma, especially of diffuse large B-cell lymphoma.     

Childhood exposure to simian virus 40-contaminated poliovirus vaccine and risk of AIDS-associated non-Hodgkin's lymphoma

Persons with acquired immunodeficiency syndrome (AIDS) have increased risk for non-Hodgkin's lymphoma (NHL). Recent studies have reported the detection of DNA sequences from simian virus 40 (SV40), a macaque polyomavirus that contaminated early poliovirus vaccines, in a large proportion of AIDS-associated NHLs. To examine the association between SV40 exposure and NHL risk, we analyzed data from a U.S. registry-based cohort study of persons with AIDS (1980-96). We calculated NHL incidence in persons born in 1958-61 (exposed to SV40-contaminated poliovirus vaccine as children, n = 39,468) and in 1964-67 (born after vaccines were cleared of SV40 and thus unexposed, n = 17,340). Among persons with AIDS, NHL incidence was 11.7 per 1,000 person-years in SV40-exposed individuals (616 NHL cases) and 10.1 per 1,000 person-years in SV40-unexposed individuals (230 cases; unadjusted relative risk 1.15, 95% CI 0.99-1.34, p = 0.06). Because of differences in cohorts' birth years and the evolving demographics of the AIDS epidemic, SV40-exposed subjects were older at AIDS onset than unexposed subjects (mean age 32.0 vs. 27.2 years, p < 0.0001), and the cohorts differed by sex (p < 0.0001) and ethnic group (p < 0.0001). Since NHL incidence was relatively high among whites (p < 0.0001) and homosexual males (p < 0.0001) and increased with age (p = 0.09), comparisons required adjustments for these factors. After adjustment, SV40 exposure was not associated with NHL incidence (adjusted relative risk 0.97, 95% CI 0.79-1.20, p = 0.80). We conclude that childhood exposure to SV40 through receipt of contaminated poliovirus vaccine was not associated with increased risk for AIDS-associated NHL. Our findings do not support a role for SV40 in lymphomagenesis among immunosuppressed persons.     

Leukaemia and non-Hodgkin's lymphoma in children of male Sellafield radiation workers

Our objective was to investigate if there was (i) an excess risk of leukaemia/non-Hodgkin's lymphoma among children of male radiation workers at the Sellafield nuclear installation in Cumbria, northwest England; (ii) a dose-response relationship between fathers' preconceptional irradiation and their children's risk of leukaemia/non-Hodgkin's lymphoma; and (iii) whether any observed association could be explained by demographic factors. We performed a cohort study of live births, 1950-1991 in Cumbria, followed up to age 25 years or the end of 1991, comparing the risk of leukaemia/non-Hodgkin's lymphoma among all 9,859 children of male radiation workers to that among all 256,851 children of non-Sellafield fathers. Children of radiation workers had a higher risk of leukaemia/non-Hodgkin's lymphoma than other children [rate ratio (RR) = 1.9, 95% confidence interval (CI) 1.0-3.1, p = 0.05]. Adjustment for population mixing greatly reduced the excess risk in the village of Seascale, adjacent to Sellafield, but had little effect elsewhere. The risk increased significantly with father's total preconceptional external radiation dose (RR(100mSv) = 1.6, 95% CI 1.0-2.2, p = 0.05). This dose-response was not reduced by adjustment for population mixing. Although our 13 exposed cases included 10 considered previously (Gardner et al., BMJ 1990;300:423-34), we used a cohort rather than a case-control design, with wider temporal and geographic boundaries, and confirmed the statistical association between father's preconceptional irradiation and child's risk of leukaemia/non-Hodgkin's lymphoma that they reported. The possibility remains that paternal preconceptional irradiation may be a risk factor for leukaemia/non-Hodgkin's lymphoma, and this effect may not be confined to Seascale.     

Generation of a highly stable, internalizing anti-CD22 single-chain Fv fragment for targeting non-Hodgkin's lymphoma

The generation of a single chain Fv (scFv) fragment derived from the anti-CD22 monoclonal antibody LL2 resulted in a molecule with good antigen binding but very poor stability properties, thus hampering its clinical applicability. Here we report on the construction of an engineered LL2 scFv fragment by rational mutagenesis. The contribution of uncommon wild-type sequence residues for providing stability to the conserved common core structure of immunoglobulins was examined. Aided by computer homology modeling, 3 destabilizing residues within the core of the wild-type VH domain were identified. Owing to the conserved nature of the buried core structure, mutagenesis of these sites to respective consensus residues markedly stabilized the molecule but did not influence its antigen binding properties: the engineered scFv MJ-7 exhibited exceptional biophysical stability with a half-life not reached after 6 days of incubation in human serum at 37 degrees C, while fully retaining the epitope specificity of the monoclonal antibody, and antigen binding affinity of the wild-type scFv. Furthermore, both the monoclonal antibody LL2 and the engineered scFv fragment became fully internalized after only 30 min of incubation at 37 degrees C with CD22+ tumor cells. These properties predict scFv MJ-7 could become a novel powerful tool to selectively deliver cytotoxic agents to malignant CD22+ cells.