Search

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10 -8 ) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10 -7 ). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival., Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed., Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P &lt; 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant., Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS., Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma., (©2022 American Association for Cancer Research.)

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a rare, cutaneous lymphoma involving subcutaneous adipose tissue. SPTL is associated in less than 20% with hemophagocytic syndrome (HPS). A 5-year overall survival rate is inferior in patients with SPTL and HPS (46%) as compared with 91% in patients without HPS. No standardized therapy for SPTCL has yet been established. This is a case of 35-year-old Caucasian man with a one-month history of B symptoms with the suspicion of Still's disease, at admission with leucopenia, high LDH, ferritin, sIl-R2, and triglycerides levels, hepatosplenomegaly, small right supraclavicular nodule, and irregular thickening of trunk subcutaneous tissue. The abdomen MRI showed generalized thickening of mesentery and colonic mucosa. In the patient, diagnosis of SPTCL was established with secondary HPS. CHOEP chemotherapy and modified HLH 2014 protocol were applied with subsequent high dose chemotherapy (BEAM) supported by autologous stem cells transplantation. Treatment was complicated by pancytopenia and pneumonia. The outcome of the disease treated by intensive protocol seems to be good.

There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 × 10 -15 for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 × 10 -13 for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population., (© 2021. The Author(s).)

Acute myeloid leukemia (AML) in older unfit patients is a therapeutic challenge for clinical hematologists. We evaluated the efficacy and safety of a novel low-intensity regimen consisting of low-dose cytarabine and cladribine (LD-AC+cladribine) in first-line treatment of elderly (≥60 years) AML patients not eligible for intensive chemotherapy (IC) who had either the Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 or the hematopoietic cell transplantation comorbidity index (HCT-CI) score ≥3. The induction phase included two cycles of LD-AC+cladribine. Patients who achieved at least partial remission (PR) received maintenance treatment with LD-AC alone. Overall, 117 patients with a median age of 70 years were enrolled. Adverse cytogenetics, ECOG PS ≥2 and HCT-CI score ≥3 was observed in 43.5%, 60%, and 58% of patients, respectively. The response rate (≥PR) was 54% (complete remission [CR], 32%; CR with incomplete hematologic recovery [CRi], 5%). A median overall survival (OS) was 21 and 8.8 months in CR/CRi and PR group, respectively. Advanced age (≥75 years) and adverse cytogenetics had a negative impact on OS. The 56-day mortality rate was 20.5%. In conclusion, LD-AC+cladribine is a beneficial therapeutic option with a predictable safety profile in elderly AML patients not eligible for IC.

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10 -7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

We evaluated the association between germline genetic variants located within the 3'-untranlsated region (polymorphic 3'UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We performed a case-control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recruited from eight countries. We selected p3UTR of six genes known to act in different pathways relevant in MM pathogenesis, namely KRAS (rs12587 and rs7973623), VEGFA (rs10434), SPP1 (rs1126772), IRF4 (rs12211228) and IL10 (rs3024496). We found that IL10-rs3024496 was associated with increased risk of developing MM and with a worse overall survival of MM patients. The variant allele was assayed in a vector expressing eGFP chimerized with the IL10 3'-UTR and it was found functionally active following transfection in human myeloma cells. In this experiment, the A-allele caused a lower expression of the reporter gene and this was also in agreement with the in vivo expression of mRNA measured in whole blood as reported in the GTEx portal. Overall, these data are suggestive of an effect of the IL10-rs3024496 SNP on the regulation of IL10 mRNA expression and it could have clinical implications for better characterization of MM patients in terms of prognosis., (© 2020 Union for International Cancer Control.)

Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 × 10 -6 for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.

Systemic mastocytosis (SM) is a rare clonal disorder with multi-organ involvements and shortened life expectancy. To date, no curative treatment for SM exists. Cladribine (2-CdA) is a purine analogue showing activity against neoplastic mast cells and its use was found to be effective in some patients with SM. Nine patients (six males and three females) with advanced SM at median age of 63 years (range 33-67) who received at least one course of 2-CdA were included in a retrospective analysis. Study patients were classified as having aggressive SM (ASM; n  = 7) and SM with an associated hematological neoplasm (SM-AHN; n  = 2). The "C" findings were as follows: (1) absolute neutrophil count (ANC) < 1 × 10 9 /l ( n  = 1) and/or hemoglobin level < 10 g/dl ( n  = 4) and/or platelet count < 100 × 10 9 /l ( n  = 4); (2) hepatomegaly with ascites ( n  = 4); (3) skeletal involvement ( n  = 2); (4) palpable splenomegaly with hypersplenism ( n  = 3) and (5) malabsorption with weight loss ( n  = 5). Treatment consisted of 2-CdA at dose 0.14 mg/kg/day intravenously over a 2-h infusion for 5 consecutive days. Median dose per cycle was 45 mg (range 35-60). Median number of cycles was 6 (range 1-7). Overall response rate (ORR) was 66% (6/9 pts) including three partial responses and three clinical improvements. ORR was 100% and 66% for SM-AHN and ASM, respectively. Median duration of response was 1.98 years (range 0.2-11.2). At the last contact, five patients died, four have little disease activity, but remain treatment- free. 2-CdA seems to be beneficial in some patients with SM, however the response is incomplete., Competing Interests: Conflict of interestAll authors declare that they have no conflict of interest., (© The Author(s) 2020.)

Cereblon (CRBN) is crucial for antiproliferative and immunomodulatory properties of immunomodulatory drugs. The objective of this study was to verify whether germline single nucleotide polymorphisms (SNPs) in the CRBN gene may influence response to lenalidomide in multiple myeloma (MM). Fourteen tagging SNPs covering the genetic variability in the CRBN gene region were genotyped in 167 Polish patients with refractory/relapsed MM treated with lenalidomide-based regimens. We found that carriers of minor alleles of two studied CRBN SNPs rs1714327G > C (OR = 0.26; 95% CI = 0.1-0.67; p  = .0055, Bonferroni corrected p  = .033) and rs1705814T > C (OR = 0.22; 95% CI = 0.07-0.65; p  = .0063, Bonferroni corrected p  = .037) were significantly associated with lower probability of achievement at least partial remission while treated with lenalidomide-based regimens, using the dominant inheritance model. Moreover, one of these SNPs, namely rs1705814T > C, was correlated with shorter progression-free survival (HR = 2.49; 95%CI = 1.31-4.74, p  = .0054, Bonferroni corrected p  = .033). It is suggested that selected germline CRBN allelic variants (rs1714327G > C and rs1705814T > C) affect lenalidomide efficacy in patients with relapsed/refractory MM.

The present retrospective analysis evaluated the efficacy and safety of the VTD (bortezomib, thalidomide, dexamethasone) regimen in 205 newly-diagnosed patients with multiple myeloma (MM) eligible for high dose therapy and autologous stem cell transplantation (HDT/ASCT) in routine clinical practice. With a median of 6 cycles (range, 1-8), at least partial response was achieved in 94.6% and at least very good partial response (VGPR) was achieved in 67.8% of patients. Peripheral neuropathy (PN) grade 2-4 was observed in 28.7% of patients. In 72% of patients undergoing stem cell mobilization one apheresis allowed the number of stem cells sufficient for transplantation to be obtained. Following HDT/ASCT the sCR rate increased from 4.9 to 14.4% and CR from 27.8 to 35.6%. The results demonstrated that VTD as an induction regimen was highly efficient in transplant eligible patients with MM with increased at least VGPR rate following prolonged treatment (≥6 cycles). Therapy exhibited no negative impact on stem cell collection, neutrophils and platelets engraftment following ASCT. Therapy was generally well tolerated and PN was the most common reason of dose reduction or treatment discontinuation., (Copyright: © Hus et al.)

Background: Despite a significant improvement in treatment outcomes, 30-40% of aggressive non-Hodgkin lymphomas (NHL) patients are refractory or relapse after the first line therapy. Half of them are not eligible to autologous stem cell transplantation (ASCT) due to failure of platinum-based salvage regimens. Pixantrone is conditionally approved in Europe in patients with R/R aggressive NHL failing at least 2 previous lines of therapy. Polish Lymphoma Research Group (PLRG) evaluated the efficacy and tolerability of P[R]EBEN combining pixantrone, etoposide, bendamustine with or without rituximab), a new regimen developed recently by Francesco d'Amore, in real-life experience., Methods: In this retrospective audit, we analyzed the data of consecutive 25 R/R NHL cases, treated with P[R]EBEN regimen in 9 PLRG centers. Safety and efficacy data, including adverse reactions (AE), response rates, progression-free and overall survival (PFS and OS) were collected., Results: Overall response rate (ORR) to P[R]EBEN regimen was 68% (40% CR and 28% PR). Most patients responded, relatively early, by second cycle of therapy. P[R]EBEN was effective in 8 out of 15 patients (53%) refractory to previous platinum-based salvage regimens. In 4 patients (16%) stabilization of disease (SD) during therapy was observed and further 4 patients (16%) progressed during the treatment (PD). Response rates were higher in patients, chemosensitive to their prior regimen (ORR - 87.5%, including 50% CR). At the median follow-up of 7.5 months (range 1-16) the median PFS and OS were not reached. Projected PFS and OS at 12 months are 68% and 78% respectively. The P[R]EBEN regimen was well tolerated and most of patients received it as out-patients. AEs grade ≥3 occurred in 17 patients (68%). Most common grade 3-4 AEs were due to hematological toxicity with febrile neutropenia observed in 5 patients (20%). There were no episodes of septic deaths. Six patients (24%) died during treatment and follow-up period, all of them due to lymphoma progression., Conclusion: Our data suggest good efficiency and tolerability of P[R]EBEN regimen as a rescue therapy in patients with R/R aggressive NHL., (Copyright © 2019. Published by Elsevier B.V.)

A small proportion of patients with multiple myeloma (MM) are diagnosed at a very young age. The clinicopathological characteristics and prognosis of these patients are not well known. This analysis included 52 patients diagnosed with MM at the age of ≤30 years (range: 8-30 years). 68% of patients had International Scoring System (ISS) 1 MM; 22% presented with the light chain-only disease, and 48% with elevated serum lactate dehydrogenase (LDH). 85% of patients were treated with novel agents, and 62% received front-line autologous stem cell transplantation (ASCT). Overall response rate (ORR) to front-line treatment and ASCT were 71% and 90%, respectively. The group was followed-up for the median period of 86 months. The median overall survival (OS) was 166 months (95% CI: 53-222), with 5-year OS rate of 77% (95% CI: 61.0-87.9). This findings suggest that the prognosis in young MM patients may be as good if not better than in the general population of MM patients.

Bendamustine is a cytostatic drug with a unique structure, combining the features of purine nucleoside analogs and alkylating agents. In patients with chronic lymphocytic leukemia (CLL) it is commonly used in combination with rituximab (BR protocol) both in the first-line as well as subsequent lines of therapy, and in clinical trials it is often combined with new targeted therapies. Therefore, the data on its real-life safety and efficacy are of clinical significance. As the Polish Lymphoma Research Group (PLRG), we retrospectively analyzed the efficacy and tolerability of bendamustine monotherapy in 96 patients with CLL. The median number of bendamustine cycles was 5, and 44 patients did not complete the planned 6 cycles (46%). Among the adverse events associated with the earlier termination of bendamustine treatment, infections were the most common (20.5%), followed by neutropenia (15.9%) and thrombocytopenia (15.9%). Dose reductions and/or delays occurred in 31% of treatment cycles (132 of 425) with neutropenia (17.9%) as the most frequent cause. Efficacy analysis showed an overall response rate of 88.2% with complete remission and partial remission achieved in 43.8 and 41.7% of patients, respectively. At the 24th month of follow-up, progression-free survival was 52% and overall survival was 69.7%. Bendamustine in monotherapy was found to be safe and efficacious, at least in terms of early response. Special attention should be paid to infectious complications, and especially that immune disorders are characteristic in the clinical course of CLL. Our observations suggest efforts must be made to ensure the proper timing and proper dose in the administration of the drug, and to avoid the premature termination of the treatment., (© 2019 S. Karger AG, Basel.)

Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 [Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18-1·95, P = 0·00087], and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44-3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2-rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2-rs4148388 and MM outcome that is supported by a plausible biological explanation., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Atypical chronic myeloid leukaemia (aCML) belongs to myelodysplastic/myeloproliferative neoplasms. Because of its rarity and changing diagnostic criteria throughout subsequent classifications, data on aCML are very scarce. Therefore, we at the Polish Adult Leukemia Group performed a nationwide survey on aCML. Eleven biggest Polish centres participated in the study. Altogether, 45 patients were reported, among whom only 18 patients (40%) fulfilled diagnostic criteria. Among misdiagnosed patients, myelodysplastic/myeloproliferative syndrome unclassifiable and chronic myelomonocytic leukaemia were the most frequent diagnoses. Thirteen patients were male, median age 64.6 years (range 40.4-80.9). The median parameters at diagnosis were as follows: white blood cell count 97 × 10 9 /L (23.8-342) with immature progenitors amounting at 27.5% (12-72), haemoglobin 8.6 g/dL (3.9-14.9), and platelet count 66 × 10 9 /L (34-833). Cytoreductive treatment was used in all patients, and 2 patients underwent allogeneic hematopoietic stem cell transplantation. The median overall survival was 14.1 months (95% CI, 7.2), with median acute myeloid leukaemia-free survival of 13.3 months (95% CI, 3.6-22.6). Cumulative incidence of acute myeloid leukaemia transformation after 1 year in aCML group was 12.5% (95% CI, 0%-29.6%). To conclude, aCML harbours a poor prognosis. Treatment options are limited, with allogeneic hematopoietic stem cell transplantation being the only curative method at present, although only a minority of patients are transplant eligible. Educational measures are needed to improve the quality of diagnoses., (Copyright © 2018 John Wiley & Sons, Ltd.)

Multiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA-binding sites in target genes (miRSNPs) may alter the strength of miRNA-mRNA interactions, thus deregulating protein expression. MiRSNPs are known to be associated with risk of various types of cancer, but they have never been investigated in MM. We performed an in silico genome-wide search for miRSNPs predicted to alter binding of miRNAs to their target sequences. We selected 12 miRSNPs and tested their association with MM risk. Our study population consisted of 1,832 controls and 2,894 MM cases recruited from seven European countries and Israel in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. In this population two SNPs showed an association with p < 0.05: rs286595 (located in gene MRLP22) and rs14191881 (located in gene TCF19). Results from IMMEnSE were meta-analyzed with data from a previously published genome-wide association study (GWAS). The SNPs rs13409 (located in the 3'UTR of the POU5F1 gene), rs1419881 (TCF19), rs1049633, rs1049623 (both in DDR1) showed significant associations with MM risk. In conclusion, we sought to identify genetic polymorphisms associated with MM risk starting from genome-wide prediction of miRSNPs. For some mirSNPs, we have shown promising associations with MM risk., (© 2016 UICC.)

We compared the outcomes of multiple myeloma (MM) patients aged 21-40 and 41-60 years in the novel agent era. This case-control study included 1089 patients between 2000 and 2015. Cases and controls were matched for sex, International Staging System (ISS) stage and institution. There were 173 patients in the younger group and 916 patients in the older group. Younger patients presented with a higher incidence of lytic lesions (82% vs. 72%; P = 0·04) and high-risk cytogenetic abnormalities (83% vs. 68%; P = 0·007), but lower rate of elevated lactate dehydrogenase (21% vs. 44%; P < 0·001). Five- and 10-year overall survival (OS) in younger versus older patients was 83% vs. 67% and 56% vs. 39%, respectively (P < 0·001). Similar results were seen when studying the subset of 780 patients who underwent autologous transplantation. Younger patients with ISS stage 1 had a better OS than older patients (P < 0·001). There was no survival difference between younger and older patients with ISS stage 2 or 3. Younger MM patients, aged 21-40 years, treated in the era of novel agents have a better OS than their counterparts aged 41-60 years, but the survival advantage observed in younger patients was lost in more advanced stages of MM., (© 2016 John Wiley & Sons Ltd.)

Our report refers to 58-year old woman, who after 7 years of asthma developed multi system symptoms and sings of Churg-Strauss syndrome; these are polyneuropathy, skin lesions, hypereosinophilia, eosinophilic infiltrates around blood vessels. Biopsy of skin specimen confirmed initial diagnosis and helped with efficient therapy. We consider this report to be important in early diagnosis and proper treatment of Churg-Strauss syndrome.