Do baseline Cereblon gene expression and IL-6 receptor expression determine the response to thalidomide-dexamethasone treatment in multiple myeloma patients?

Immunomodulatory drugs (IMiDs) are key components of treatment for hematologic malignancies, especially multiple myeloma (MM). Cereblon (CRBN) expression was described to be essential for the activity of thalidomide. Furthermore, IMiD binding to CRBN is cytotoxic to multiple myeloma cells and absence of CRBN confers IMiDs resistance. Interleukin-6 (IL-6) is a potent pleiotropic cytokine that regulates plasma cell (PC) growth via the IL-6 receptor (IL-6R). IL-6/IL-6R autocrine activity is implicated in the development and progression of cancers including cervical cancer, prostate cancer, and multiple myeloma. The aim of the study was to evaluate CRBN and IL-6R expressions and their impact on clinical efficacy of dexamethasone-thalidomide therapy in multiple myeloma (MM) patients, in addition to their association with other clinical and prognostic parameters. Forty-six newly diagnosed MM patients were enrolled in the study. We measured CRBN expression prior to therapy initiation by real-time polymerase chain reaction in 46 bone marrow (BM) aspiration samples of patients and controls. In addition, IL-6R expression was evaluated on BM biopsies of patients and controls by immunohistochemistry (IHC). Twenty-eight males (60.9%) and 18 females (39.1%) were enrolled. The mean age was 65.11 ± 7.3 yr (range 39-77 yr). Median CRBN expression in 46 BM samples of MM patients was significantly higher than in controls (P < 0.001). Among established prognostic parameters, international staging system (ISS), serum beta-2-microglobulin (B2M), and serum albumin correlated reversely with CRBN expression. IL-6R expression was significantly higher in patients than in controls. IL-6R expression was significantly associated with response to treatment (P < 0.001), B2M (P = 0.032), and ISS (P = 0.028). Strong intensity expression was associated with low CRBN expression (P = 0.001).In conclusion, CRBN expression may provide a biomarker to predict response to IMiD in patients with MM and its high expression can serve as a marker of good prognosis. Strong IL-6R expression is associated with poor response to therapy in multiple myeloma patients and may be used as a prognostic marker.

Assessing DcR3 expression in relation to survivin and other prognostic factors in B cell non-Hodgkin's lymphoma.

UNLABELLED: The soluble decoy receptor 3 (DcR3) is a member of the tumor necrosis factor receptor superfamily whose overexpression has been observed in several human malignancies. Survivin is one of the inhibitors of apoptosis proteins that are thought to play an important role in the pathogenesis of malignancies. We aimed to evaluate the expression of DcR3 in relation to survivin in B cell non-Hodgkin`s lymphoma (NHL) and then we focused on patients with diffuse large B cell non-Hodgkin's lymphoma (DLBCL) (50 cases) and correlated DcR3 expression with survivin expression and other prognostic parameters. Fifteen subjects with reactive lymphoid hyperplasia were included as controls. The expression of DcR3 and survivin were analyzed by immunohistochemistry on formalin-fixed paraffin-embedded lymph node sections from 80 cases of B cell NHL and 15 controls. Bone marrow biopsy sections of patients were also immunostained with the previous markers. RESULTS: DcR3 expression was found in 32.5% of B cell NHL patients versus 6.7% of controls (p <0.001) and was associated with the aggressive/highly aggressive subtypes. DcR3 was strongly expressed in 30% of DLBCL patients, where it was associated with survivin expression, high international prognostic index (IPI), the presence of extra nodal disease, ECOG performance status >1, reduced remission rates and shorter event-free survival. The expression of survivin was 40% in B cell NHL patients versus 13.3% in the control group (p <0.001). The expression of survivin in aggressive/highly aggressive B cell NHL was significantly higher than that in indolent B cell NHL. Survivin expression has been detected in 44% of the DLBCL patients and was associated with their clinical stage and shorter event-free survival (p = 0.026). Bone marrow biopsy sections from DLBCL patients showed significant DcR3 and survivin over expressions in sections with infiltration by lymphoma cells than sections with no infiltration. CONCLUSION: DcR3 expression was associated with other prognostic factors including survivin, reduced remission rates, and shorter event-free survival. Survivin is closely related to aggressive/highly aggressive subtypes of B cell NHL and is associated with shorter event-free survival. Both DcR3 and survivin expressions on bone marrow sections can be of help in diagnosing bone marrow infiltration.

The prognostic value of glucocorticoid receptors for adult acute lymphoblastic leukemia.

BACKGROUND: Therapeutic protocols used in adult acute lymphoblastic leukemia (ALL) are widely variable, and glucocorticoids (GCs) are essential components in ALL treatment. Therefore, this study aimed to evaluate the distribution of prominent glucocorticoid receptor (GR) gene polymorphic variants among adult ALL patients. We also investigated the association between GR messenger ribonucleic acid (mRNA) isoform expressions and the response to chemotherapy. METHODS: Fifty-two newly diagnosed Philadelphia-negative adult ALL patients and 30 healthy control subjects were enrolled in this study. Genotyping was carried out using a polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis. GR mRNA isoform expressions were assayed by quantitative real-time PCR. RESULTS: ALL patients in this study had a median age of 34 years (range, 18-75). GRα expression was associated with complete remission (P=0.03), while GRγ mRNA expression was significantly higher in GC resistant patients (P=0.032) and in non-responders (P=0.019). However, there were no significant associations with GC resistance. The BclI polymorphic variant of the GR gene was the most frequent in adult ALL patients and was not associated with the GC response. Both higher GRα expression and lower GRγ expression were associated with achievement of complete remission, while higher GRγ expression was associated with GC-resistance. CONCLUSION: Our data suggest that the level of GR isoform expression may be useful in predicting GC response, achievement of complete remission, and better event-free survival in ALL patients. However, further evaluation with a larger cohort of patients is warranted.

Do SLCO1B3 (T334G) and CYP3A5*3 polymorphisms affect response in Egyptian chronic myeloid leukemia patients receiving imatinib therapy?

BACKGROUND: Imatinib has so far been the first-choice treatment in chronic myeloid leukemia (CML) with excellent results. However, only a proportion of patients achieve major molecular response. Hence, the need to find whether there are some factors that affect the response to treatment is essential. This study aimed to investigate the allele and genotype frequencies of single nucleotide polymorphisms (SNPs) of SLCO1B3 (T334G) and CYP3A5*3 in CML patients undergoing imatinib treatment and to determine whether SNPs of these two genes could predict the response of imatinib therapy in CML patients. SUBJECTS AND METHODS: We investigated SLCO1B3 (T334G) and CYP3A5*3 polymorphisms by Polymerase Chain Reaction-restriction fragment length polymorphism in 86 Philadelphia positive newly diagnosed Egyptian CML patients (78 patients in chronic phase and 8 patients in accelerated phase). All patients received imatinib therapy and were followed for at least one and half years. The response to imatinib therapy was evaluated by recording the hematological response, cytogenetic response, and molecular response according to the European Leukemia Net criteria. RESULTS: This study included 86 Philadelphia positive newly diagnosed CML patients, 78 in the early chronic phase and 8 in the accelerated phase. In the chronic phase patients, no association between SLCO1B3 (T334G) exon 3 polymorphism and response to imatinib therapy was detected (P = 0.938) while CYP3A5*3 gene polymorphism was associated with inferior outcome (P < 0.001). In the group of accelerated phase patients, the SLCO1B3 polymorphic variants (TG) and (GG) were detected equally with none of the patients in this group having the homozygous wild form (TT). The homozygous state for the CYP3A5*3 allele was the most frequent (50%) and the homozygous state for the CYP3A5*1 allele was the least frequent (12.5%) in this group. CONCLUSION: CYP3A5*3 polymorphism was associated with imatinib efficacy while the SNP SLCO1B3 (T334G) was not associated with the response to imatinib treatment in Egyptian patients with CML in chronic phase. These results prompt us to explore the effect of CYP3A5*3 in CML patients taking imatinib in a larger scale study.

Importance of serum IL-18 and RANTES as markers for breast carcinoma progression.

BACKGROUND: Interleukin-18 (IL-18), a cytokine that plays an important role in the T-cell-helper response, acts as an angiogenic factor and a tumor suppressor. RANTES (regulated upon activation normal T-cells expressed and secreted) is a member of the C-C chemokine family with chemoattractant activity for a variety of cell types. High incidence and intensity of RANTES were noted in advanced breast carcinoma. AIM OF THE STUDY: To correlate the levels of RANTES and IL-18 in serum of breast cancer patients with bone or other organ metastasis compared to breast cancer patients without metastasis and healthy controls and to estimate the role of each of them as a prognostic marker for the progression of the disease. PATIENTS AND METHODS: The study was conducted on 60 breast cancer patients (25 cases with no metastasis and 35 cases with metastasis) who were admitted to the outpatient clinic of the NCI, Cairo University during the period from March 2004 to September 2004 and 30 apparently healthy controls who were volunteers at the blood bank of the NCI, Cairo University. RESULTS: Showed that there was a statistically significant difference between the level of IL-18 in breast cancer patients without metastasis and the control group (p<0.05) while there was a highly significant difference between the metastatic group and the control group (p<0.001). There was a significant increase in IL-18 levels between metastatic and non-metastatic cases (p<0.01). RANTES showed a significant increase in breast cancer cases with no metastasis and the control group (p<0.05) and it showed a highly significant increase in metastatic patients compared to controls (p<0.001). There was no significant increase in the level of RANTES in metastatic compared to non-metastatic patients (p>0.05). CONCLUSIONS: IL-18 is an important non invasive marker suspecting metastasis. Even though RANTES levels were higher in cancer patients compared to controls, its role in staging of breast cancer was not clear in this study.