Life-threatening interaction between antiretroviral therapy and vinblastine in HIV-associated multicentric Castleman's disease

BACKGROUND: HIV-infected patients still present a high risk of developing lymphoproliferative malignancies, despite the fact that their prognosis has been considerably improved by highly active antiretroviral therapy (HAART). Potential interactions exist between antiretroviral drugs, in particular protease inhibitors, and anti-neoplastic ones, but their impact in terms of clinical and haematological adverse events remains unclear. METHODS: We report a case of potentially life-threatening interaction between vinblastine and antiretroviral therapy in a patient presenting with HIV-associated multicentric Castleman's disease (MCD). RESULTS: A 55-year-old HIV-1 infected patient was diagnosed with MCD while being treated with a salvage HAART regimen consisting of zidovudine, lamivudine, abacavir, nevirapine and ritonavir-boosted lopinavir. Vinblastine was prescribed as a monotherapy at the usual dose of 6 mg/m2 (i.e. 10 mg) every 3 weeks. The first vinblastine course was performed without HAART with no adverse event. Antiretroviral therapy was resumed for the two following courses which were associated with unexpected severe digestive and haematological toxicities, and moderate renal failure. Vinblastine was then administered alone at increasing doses without toxicity. HAART was finally resumed and we assessed that a decreased vinblastine dose of 2 mg/m2 was well tolerated, with a complete response of MCD. CONCLUSIONS: HAART regimen comprising protease inhibitors, which are potent inhibitors of cytochrome P450 and P-gp, could interfere with anti-neoplastic drugs, as demonstrated with vinblastine in our case report.     

Multicentric Malignant Gastrointestinal Stromal Tumor

Malignant gastrointestinal stromal tumor (GIST) is a rare type of sarcoma that is found in the digestive system, most often in the wall of the stomach. Multiple GISTs are extremely rare and usually associated with type 1 neurofibromatosis and familial GIST.We report here a case of a 70-year-old woman who reported pain in the abdomen, loss of appetite, and weight loss for six months. Ultrasound examination showed a small bowel mass along with multiple peritoneal deposits and a mass within the liver. Barium studies were suggestive of a neoplastic pathology of the distal ileum. A differential diagnosis of adenocarcinoma/lymphoma with metastases was entertained. Perioperative findings showed two large growths arising from the jejunum and the distal ileum, along with multiple smaller nodules on the serosal surface and adjoining mesentery of the involved bowel segments. Segmental resection of the involved portions of the intestine was performed. Histopathological features were consistent with those of multicentric malignant GIST-not otherwise specified (GIST-NOS). Follow-up examination three months after surgery showed no evidence of recurrence.     

Predictors of response to anti-IL6 monoclonal antibody therapy (siltuximab) in idiopathic multicentric Castleman disease: secondary analyses of phase II clinical trial data

Siltuximab is the only US Food and Drug Administration-approved treatment for idiopathic multicentric Castleman disease (iMCD), a rare haematological disorder associated with substantial morbidity and mortality. Although siltuximab induces a response in a significant proportion of iMCD patients via interleukin 6 (IL6) neutralization, it is not universally effective. To develop a predictive model of response, we performed an in-depth analysis of 38 baseline laboratory parameters in iMCD patients from the phase II siltuximab trial who met criteria for treatment response or treatment failure. Univariate analyses identified eight baseline laboratory parameters that were significantly different between responders and treatment failures: albumin, immunoglobulin G (IgG), immunoglobulin A, C reactive protein (CRP), fibrinogen, haemoglobin, sodium and triglycerides. Stepwise logistic regression analysis of these candidate parameters identified a top performing model that included fibrinogen, IgG, haemoglobin and CRP. Based on cross-validation of the final multivariate logistic regression model, the model accurately discriminated responders from those who failed treatment (area under the receiver operator characteristic curve 0·86, 95% confidence interval: 0·73–0·95). All four laboratory parameters associated with response to siltuximab have biological relationships with IL6 and acute inflammation. Our model suggests that iMCD patients with laboratory evidence of an inflammatory syndrome are the best candidates for siltuximab therapy.     

Quantification of human herpesvirus 8 by real-time PCR in blood fractions of AIDS patients with Kaposi's sarcoma and multicentric Castleman's disease

Few studies have assessed human herpesvirus 8 (HHV8) viremia levels in different HHV8-related pathologies, using sensitive and reproducible molecular assays. Our objective was to compare the HHV8 DNA load in serial blood samples (collected every 3 months for 1 year) from acquired immunodeficiency syndrome (AIDS) patients with Kaposi's sarcoma (KS) and multicentric Castleman's disease (MCD). The HHV8 viral load was determined in both peripheral blood mononuclear cells (PBMC) and plasma fractions, using a competitive real-time polymerase chain reaction (PCR) assay developed in a LightCycler instrument (Roche Diagnostics). In six subjects with limited or extensive KS while on highly active antiretroviral therapy, the HHV8 DNA load was either undetectable (<50 copies/10(5) cells) or low (1,000 copies in at least one of the samples from the two subjects with both KS and MCD. HHV8 DNA was detected in plasma only when the cellular viral load was >10,000 copies/10(5) cells. After chemotherapy, the HHV8 DNA load became undetectable in the MCD patients despite no changes in CD4 T-cell counts or highly active antiretroviral therapy (HAART) regimens. These results suggest that the pathogenesis of the two HHV8-associated diseases (i.e., KS and MCD) might be different, as only the latter was associated with important viremia in our patients.     

Heterogeneous versus homogeneous genetic nature of multiple foci of in situ carcinoma of the breast

The vast majority of in situ breast cancers represent focal lesions all derived from a single clone and requiring local treatment alone. We focused our attention on rare cases of multicentric in situ carcinomas affecting different quadrants, which required mastectomy. Defining the origin from single- or multiple-cell clones of separate independent neoplastic foci in the breast may be of pathogenetic interest and of importance in deciding the type of therapy to be administered. We employed a molecular assay based on loss of heterozygosity (LOH) and human androgen receptor assay (HUMARA) analysis of microdissected samples from 19 mastectomies. Two or more tissue samples were obtained from 7 patients with multicentric lobular in situ carcinoma (LCIS), either classical or large-cell variety; and 12 patients with multicentric ductal in situ carcinomas (DCIS), either low-grade (7 cases) or high-grade (5 cases) variety. Separate foci of high-grade (comedonic) DCIS were found to be monoclonal in nature. On the contrary, definite evidence favoring the origin from different cell clones of separate carcinomatous foci within the same breast was obtained in 2 cases of low-grade DCIS and in 6 cases of LCIS. A genetic imbalance might be the factor favoring the development of multifocal heterogeneous foci of in situ breast cancer. Such a small subgroup of in situ cancers affecting diffusely the entire breast and originating from independent foci presents both clinical and pathogenetic interest.     

Determination of the molecular relationship between multiple tumour nodules in hepatocellular carcinoma differentiates multicentric origin from intrahepatic metastasis

The purpose of this study was to determine the molecular relationship between multiple tumour nodules in hepatocellular carcinoma (HCC) within individual patients and to evaluate their clonality, which may bear prognostic significance. In 25 HCC nodules from 11 patients with multiple HCCs, the clonal relationships of the nodules within individual patients were determined using DNA fingerprinting with loss of heterozygosity (LOH) assay, comparative genomic hybridization (CGH), and hepatitis B virus (HBV) integration pattern. Both LOH assay and CGH indicated that in four (36%) of the 11 patients, the multiple HCCs had different clonalities and hence were of multicentric origin, whereas in the remaining seven (64%) patients, the multiple HCCs had similar clonal relationships and were intrahepatic metastases. In selected cases, the HBV integration pattern helped to confirm the clonality results. Gross appearance, size, location, and histology of the tumours could not accurately predict their clonal origin in every case. Assessment of DNA alterations allows precise determination of the clonality of multiple HCCs within one patient. Of these molecular methods, LOH analysis can be used to evaluate tumour clonality in most patients even before surgical resection, since this assay can be readily applied routinely to either liver biopsies or fine needle aspirates.     

Clinical and mutation profile of multicentric osteolysis nodulosis and arthropathy

​Multicentric osteolysis nodulosis and arthropathy (MONA) is an infrequently described autosomal recessive skeletal dysplasia characterized by progressive osteolysis and arthropathy. Inactivating mutations in MMP2, encoding matrix metalloproteinase‐2, are known to cause this disorder. Fifteen families with mutations in MMP2 have been reported in literature. In this study we screened thirteen individuals from eleven families for MMP2 mutations and identified eight mutations (five novel and three known variants). We characterize the clinical, radiographic and molecular findings in all individuals with molecularly proven MONA from the present cohort and previous reports, and provide a comprehensive review of the MMP2 related disorders. © 2015 Wiley Periodicals, Inc.

     

Human herpesvirus 8-associated multicentric Castleman disease in a patient with advanced HIV infection: A case report

Rational:Multicentric Castleman disease (MCD) is a nonclonal lymphoproliferative disorder that is rarely reported from Southeast Asian countries. Here, we report a case of human herpesvirus 8 (HHV-8)-associated MCD in a patient with advanced human immunodeficiency virus (HIV) infection who presented with prolonged intermittent fever, urticarial rash, hepatosplenomegaly, and generalized lymphadenopathy.Patient concerns:A 34-year-old man with advanced HIV infection who was in good compliance with his antiretroviral treatment regimen presented with intermittent fever, weight loss, marked hepatosplenomegaly, and generalized lymphadenopathy. Recurrent symptoms of high-grade fever, abdominal discomfort, pancytopenia, and high C-reactive protein level occurred for 16 months.Diagnoses:Histopathological findings of left inguinal lymph node revealed diffuse effacement of lymph node architecture with coexpression of HHV-8 latency-associated nuclear antigen 1 from immunohistochemical staining. The HHV-8 viral load was 335,391 copies/mL.Interventions:The patient was treated initially with one dose of intravenous rituximab (375 mg/m²) followed by subcutaneous rituximab (1400 mg) weekly for 5 weeks.Outcomes:The patient''s recurrent systemic symptoms subsided dramatically, and he has now been in remission for almost two years.Lessons:HHV8-associated MCD remains a diagnostic challenge in advanced HIV disease and should be suspected in those with recurrent flares of systemic inflammatory symptoms. Lymph node histopathology is essential for diagnosis and for excluding clonal malignancy. HHV-8 viral load is also useful for diagnosis and for monitoring disease activity.     

Castleman disease: delineating the spectrum

Glanzmann thrombasthenia (GT) is caused by inherited defects of the α_IIbβ₃ platelet glycoprotein. This bleeding disorder can be treated with platelet transfusion therapy, but some patients will be immunized and begin to form anti‐human leucocyte antigen (HLA) and/or anti‐α_IIbβ₃ antibodies. These antibodies can bind and interfere with the function of the transfused platelets, rendering treatment ineffective. However, platelet transfusion refractoriness attributable to HLA antibodies may be managed by the selection of compatible donors, although they are not always readily available, particularly in an emergency. Thus, anti‐α_IIbβ₃ antibodies represent one of the most severe complications in GT. Both genetic and environmental factors may contribute to the risk of anti‐α_IIbβ₃ development, but the underlying pathogenic mechanisms are still unknown. This review will summarize the current knowledge of the risk factors for development of anti‐α_IIbβ₃ antibodies in patients with GT and discuss how these findings may influence the clinical management of patients.