Bortezomib,thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma

BACKGROUND:

This single‐center retrospective study determined the efficacy of bortezomib, thalidomide, and dexamethasone (BTD) as induction for patients with multiple myeloma (MM) who were eligible for autologous stem cell transplantation (ASCT).

METHODS:

Patients with symptomatic MM who had received BTD induction before stem cell collection at Winship Cancer Institute were included. BTD induction comprised up to 8 3‐week cycles of bortezomib 1.3 mg/m² on Days 1, 4, 8, and 11; thalidomide 100 mg daily; and dexamethasone 40 mg on Days 1 through 4 and Days 9 through 12. Stem cell mobilization involved granulocyte‐colony–stimulating factor and/or cyclophosphamide. Response was assessed according to European Group for Blood and Marrow Transplantation criteria.

RESULTS:

Review of medical records identified 44 eligible patients (34 patients who were treated in the front‐line setting and 10 patients who were treated for recurrent disease) who received a median of 4 BTD cycles. The overall response rate (ORR) was 91%, which included a greater than or equal to very good partial response (≥VGPR) rate of 57% (including 20% stringent complete responses/complete response [sCR/CR] rate). In front‐line patients, the ORR was 94%, which included a 56% ≥VGPR rate (24% sCR/CR). The median CD34‐positive stem cell collection was 10.67 × 10⁶/kg. The ORR after ASCT in 34 patients who were evaluable for response was 100%, including a 76% ≥VGPR rate (53% sCR/CR). Among all 44 patients, the median progression‐free survival (PFS) was 27.4 months. The median overall survival (OS) was not reached after a median follow‐up of 25 months, and the 2‐year OS rate was 82%. There were no significant differences in PFS (27.4 months vs 23.5 months) or in 2‐year survival (80% vs 90%) between patients who did and did not undergo ASCT, respectively. Twenty patients (45%) developed neuropathy, including 4 (9%) with grade 3 neuropathy episodes, and 1 patient developed deep vein thrombosis.

CONCLUSIONS:

BTD was highly effective and well tolerated as induction for MM patients who were eligible for ASCT. Long‐term outcomes appeared to be similar with or without ASCT consolidation. Cancer 2010. © 2010 American Cancer Society.     

Proliferative activity of plasma cells is the most relevant prognostic factor in elderly multiple myeloma patients

Although multiple myeloma (MM) is predominantly a disease of the elderly, few studies have focused on the identification of prognostic factors in this group of patients. Four hundred twenty five MM patients >65 years were uniformly treated with chemotherapy (MP or VCMP/VBAD). Multivariate analysis identified 4 factors with independent unfavorable prognostic influence: high percentage of S-phase bone marrow plasma cells (>2.5%); elevated beta(2) microglobulin (B2M) (>4 mg/L); age >80 years old; and LDH serum levels (above normal limit). The S-phase value was the most powerful independent prognostic factor to discriminate subgroups of patients with different prognosis. Thus, 3 main risk categories could be identified according to S-phase values: 3%, with median survivals of 34, 22 and 12 months, respectively (p < 0.0001). Our study also proved the value for elderly patients of the recently developed International Score System (ISS) based on B2M and albumin. Furthermore, the number of S-phase cells helped to subdivide the ISS III Group identifying a subset of patients with very poor prognosis defined by an additional high S-phase, who displayed a median survival of only 8 months. These results demonstrate that elderly patients can be accurately classified according to prognosis, which may be particularly valuable when comparing the efficacy of new treatment strategies. Moreover, our results underline the high prognostic value of proliferative activity of PC, a parameter that should be considered in routine laboratory investigations of MM.     

Circulating angiopoietin-1 to angiopoietin-2 ratio is an independent prognostic factor for survival in newly diagnosed patients with multiple myeloma who received therapy with novel antimyeloma agents

The circulating levels of several angiogenic cytokines [angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), angiogenin and basic fibroblast growth factor (bFGF)] were evaluated in 174 consecutive patients with newly diagnosed, symptomatic, multiple myeloma (MM). Circulating levels of Ang-1/Ang-2 were reduced in myeloma patients compared to controls, whereas VEGF and angiogenin levels were increased. Reduced angiopoietin-1/angiopoietin-2 ratio correlated with advanced disease features including international staging system (ISS)-3 stage, renal impairment and extensive bone disease. Based on immunohistochemical results in 20 patients (10 with the higher and 10 with the lower values of circulating angiopoietin-2) we found that angiopoietin-2 is expressed by myeloma cells and correlates with increased microvessel density in subsets of patients. Furthermore, Ang-1/Ang-2 ratio correlated with survival. Patients with circulating Ang-1/Ang-2 below or equal to the median value (6.03) had a median survival of 26.3 months compared to 53 months of all others (p = 0.002). Interestingly, this was mainly observed in patients who received first-line therapy with novel agent-based regimens (65% of our patients). Furthermore, a subset of ISS-3 patients with serum Ang-1/Ang-2 above the median value had favourable prognosis (median survival: 45 months versus 17 months of all others; p = 0.0001). The multivariate analysis revealed that low Ang-1/Ang-2 ratio could independently predict for inferior survival in our cohort of patients (relative risk (RR) 2.07, 95% CI 1.50-2.42; p < 0.001). These results highlight the role of angiopoietins pathway in the biology of MM and reveal novel targets for the development of antimyeloma agents.     

The combination of intermediate doses of thalidomide and dexamethasone reduces bone marrow micro-vessel density but not serum levels of angiogenic cytokines in patients with refractory/relapsed multiple myeloma

The aim of the study was the evaluation of anti-angiogenic activity of the combination of intermediate doses of thalidomide and dexamethasone in patients with refractory/relapsed myeloma. Twenty-five patients were included in the study. Microvessel density (MVD) was evaluated in marrow biopsies before and after treatment. Serum levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), tumor necrosis factor-alpha (TNF-alpha), which have angiogenic potential and interleukin-6 (IL-6), IL-1beta, soluble IL-6 receptor (sIL-6R), and transforming growth factor-beta (TGF-beta) which are involved in the disease biology, were measured before treatment and then every 2 weeks for 8 weeks. Pretreatment levels of MVD, VEGF, b-FGF, IL-6, sIL-6R were increased in the patients compared to controls. The overall response rate to therapy was 72%. The administration of the combined regimen produced a significant reduction in MVD in responders. However, an increase in serum levels of VEGF, b-FGF, IL-6, sIL-6R was observed post-treatment in responders. In contrast, serum levels of TNF-alpha, TGF-beta, IL-1beta did not differ between patients and controls and remained unchanged during the study. These results suggest that the combination of thalidomide plus dexamethasone is an effective treatment for myeloma reducing MVD marrow levels but not serum levels of angiogenic cytokines or cytokines implicated in myeloma biology.     

Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy

BACKGROUND: Recently, the authors reported improved time to disease progression (TTP) with a combination of pegylated liposomal doxorubicin (PLD) and bortezomib compared with bortezomib alone in a phase 3 randomized trial in patients with recurrent/refractory multiple myeloma (MM). In the current analysis, they determined 1) the efficacy of PLD plus bortezomib versus bortezomib alone in patients with MM who had failed on prior thalidomide/lenalidomide (immunomodulatory drug [IMiD]) treatment and 2) the efficacy and safety profile of PLD plus bortezomib in IMiD-exposed and IMiD-naive patients. METHODS: This prespecified analysis included 646 patients who were randomized to receive either PLD with bortezomib (n=324; 194 IMiD-naive patients and 130 IMiD-exposed patients) or bortezomib alone (n=322; 184 IMiD-naive patients and 138 IMiD-exposed patients). The primary efficacy endpoint was TTP, and secondary endpoints included overall survival, response rate, and safety. RESULTS: The median TTP was significantly longer with PLD plus bortezomib compared with bortezomib alone in IMiD-exposed patients (270 days vs 205 days). No statistical difference was noted with respect to TTP between IMiD-naive (295 days) versus IMiD-exposed (270 days) subgroups who received PLD plus bortezomib. A sustained trend favoring combination therapy was observed in analyses of overall survival. In patients who achieved a response, the response duration was comparable for IMiD-naive patients and IMiD-exposed patients in the combination treatment group and lasted a median of 310 days and 319 days, respectively. The incidence of grade 3/4 adverse events was similar with PLD plus bortezomib regardless of prior IMiD exposure. CONCLUSIONS: A significantly prolonged TTP was observed with combined PLD plus bortezomib combination therapy compared with bortezomib alone despite prior IMiD exposure. For the combination treatment arm in the IMiD-naive and IMiD-exposed subgroups, TTP was comparable. Similarly, the safety profile of the PLD plus bortezomib combination was unaltered by prior IMiD exposure.     

Beta2-microglobulin induces caspase-dependent apoptosis in the CCRF-HSB-2 human leukemia cell line independently of the caspase-3, -8 and -9 pathways but through increased reactive oxygen species

Exogenous beta(2)-microglobulin (beta(2)m) induces significant apoptosis in the CCRF-HSB-2 human lymphoblastic leukemia cell line as detected by DNA fragmentation, DAPI staining and annexin V binding assay. beta(2)m treatment induced the release of cytochrome c and apoptosis-inducing factor (AIF) from the mitochondria, but no change in mitochondrial membrane potential (DeltaPsim) was observed during apoptosis, suggesting that cytochrome c may be released through a mechanism independent of mitochondrial permeability transition (MPT) pore formation. Moreover, the beta(2)m-induced release of cytochrome c and AIF from the mitochondria in CCRF-HSB-2 cells was caspase-independent, since Z-VAD-fmk, a general inhibitor of caspases, did not block the release of these factors. However, Z-VAD-fmk treatment significantly blocked beta(2)m-induced apoptosis, while Western blot analysis revealed that caspases-1, -2, -3, -6, -7, -8 and -9 are not activated during beta(2)m-induced apoptosis in these cells. These results collectively indicate that a post-mitochondrial caspase-dependent mechanism is involved in beta(2)m-induced apoptosis. Moreover, beta(2)m significantly enhanced the production of reactive oxygen species (ROS) during 12-48 hr treatment, and beta(2)m-induced apoptosis was almost totally inhibited in cells pre-treated with the antioxidant N-acetylcysteine (NAC), providing evidence that beta(2)m-induced apoptosis in CCRF-HSB-2 cells is ROS-dependent. Therefore, these results reveal that beta(2)m-induced apoptosis in CCRF-HSB-2 cells may occur through an unknown caspase-dependent and ROS-dependent mechanism(s) that is associated with cytochrome c and AIF release from mitochondria, but is independent of the caspase -3, -8 and -9 pathways.     

Beta2-microglobulin aberrations in diffuse large B-cell lymphoma of the testis and the central nervous system

Human leukocyte antigen (HLA) class I molecules are expressed on the surface of all nucleated cells and present antigenic peptides to cytotoxic T cells, thereby playing an important role in initiating the cellular anti-tumor immune response. We previously reported that loss of HLA class I expression in diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS) and the testis is a common event. Loss of expression and mutations of the light chain of the HLA class I molecule, beta(2)-microglobulin (beta(2)m) have been described in a variety of human tumors and cell lines. In our study, we screened 15 DLBCL cases with a combined loss of HLA class I and beta(2)m expression for mutations in the latter gene by direct sequencing. Frame shift mutations in repetitive sequences within the beta(2)m gene leading to loss of functional beta(2)m were detected in 2 cases. Loss of heterozygosity (LOH) and fluorescent in situ hybridization (FISH) analysis for chromosome 15 exhibited loss of the remaining copy of the beta(2)m gene in both cases but also hemizygous deletions and monosomies in 6 additional cases. Since similar mutations in the beta(2)m gene have been associated with microsatellite instability (MSI), we used 8 markers to study MSI involvement in DLBCL. Low MSI was more frequent (33%) as compared to nodal DLBCL (n=15) but did not correlate with the beta(2)m mutations. Our data indicate that multiple mechanisms lead to downregulation of beta(2)m and concomitant loss of HLA class I expression in DLBCL.     

Soluble HLA-DR is a potent predictive indicator of disease progression in serum from early-stage melanoma patients

Despite numerous therapeutic options, the prognosis of malignant melanoma, once metastasized, is still poor. Thus, the search for reliable methods to identify patients with high risk of disease progression as early as possible is of major importance. In our study, we analyzed the predictive value of soluble HLA-DR (sHLA-DR) in comparison to S100-beta in serum from 183 melanoma patients of different stages of disease and with or without current therapy using immunosorbent assays. sHLA-DR serum levels of 121 healthy individuals served as controls. We found significantly (p < 0.0005) reduced sHLA-DR serum levels in melanoma patients (0.70 +/- 0.08 SEM microg/ml) compared to controls (1.49 +/- 0.10 SEM microg/ml). Reduced sHLA-DR and increased S100-beta levels were associated with advanced disease stages and tumor load. S100-beta was increased under cytostatic therapy (p < 0.0005), whereas sHLA-DR was not influenced by therapy modalities. Univariate analysis showed an association of sHLA-DR < 0.3 microg/ml and S100-beta > 0.12 microg/l with poor overall (p = 0.021 and p = 0.0009) and progression-free survival (p < 0.0005 and p = 0.0025). Multivariate analysis revealed disease stage (p = 0.0093) and tumor burden (p < 0.0005) as independent predictive factors for overall survival, and sHLA-DR (p = 0.0007) and tumor burden (p = 0.0015) for progression-free survival. In contrast to S100-beta, sHLA-DR serum concentrations < 0.3 microg/ml were strongly associated (p = 0.0001) with poor progression-free survival in a subgroup of 60 nonmetastasized patients. In conclusion, our results suggest sHLA-DR as a potent prognostic serum marker in melanoma patients superior to S100-beta in helping to identify early-stage patients at high risk of disease progression.     

The efficacy and safety of bortezomib and dexamethasone as a maintenance therapy in patients with advanced multiple myeloma who are responsive to salvage bortezomib-containing regimens

BACKGROUND:

Although treatment for multiple myeloma (MM) has considerably improved in the past decade, MM continues to be an incurable hematological malignancy that causes most patients to eventually relapse and die from their illness. Thus, the identification of effective salvage strategies remains a priority.

METHODS:

In this trial, the authors evaluated the safety and efficacy of bortezomib and dexamethasone [V: on days 1 and 15 (1.3 mg/mq); D: on days 1‐2 and 15‐16, every 28‐day cycle until progression (20 mg/d)] as maintenance therapy (MT) in patients with advanced MM who responded to salvage therapy that used a bortezomib‐containing regimen.

RESULTS:

Forty‐nine MM patients were enrolled in this study between October of 2004 and April of 2008. All patients who were included in this study were responsive to a prior salvage therapy with bortezomib and had a measurable disease. The bortezomib and dexamethasone MT improved the quality of responses to complete remission in 4 patients and very good partial response in 3 patients. In addition, 10 patients experienced at least a 50% improvement in their symptoms. The median time to progression (TTP) was 16 months with a progression‐free survival of 61% after 1 year. The overall response after 1 year was 76%, and the cumulative incidence of death due to disease progression, which was adjusted for competitive risk events, was 14%. Non‐dose‐limiting toxicities included neuropathy (predominantly grade 1), herpes zoster reactivation, pneumonia, and gastrointestinal affections (constipation and diarrhea). Three patients developed grade 2 neuropathy, which required a bortezomib dose reduction to 1.0 mg/mq. No grade 3 or 4 toxicities were recorded.

CONCLUSIONS:

The use of bortezomib and dexamethasone as MT in advanced MM was effective and well tolerated. The twice‐monthly bortezomib infusion appeared to reduce the incidence of grade 3 and 4 neuropathies in comparison to similar experiences in other settings. Cancer 2011. © 2010 American Cancer Society.     

Correlation between the tumoral expression of beta3-integrin and outcome in cervical cancer patients who had undergone radiotherapy

Integrins are cell-surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Besides playing an important role in tumour angiogenesis, beta3-integrin is also expressed in several types of epithelial cancer cells. It was the purpose of the present study to evaluate the prognostic value of beta3-integrin expression in patients with cervical cancer. Biopsies were taken from 82 patients with squamous cell or adenocarcinomas of the uterine cervix who had undergone external-beam radiotherapy with or without brachytherapy. These tissue samples were analysed immunohistochemically for the expression of beta3-integrin. The impact of immunoreactivity for beta3-integrin on survival end points was assessed by univariate and multivariate analyses, and its correlation with clinicopathological characteristics evaluated by crosstabulations. beta3-integrin was expressed in 61% (50 of 82) of the patients. Kaplan-Meier curves revealed local progression-free survival, distant metastasis-free survival and cause-specific survival to be significantly shorter (P-values according to the log-rank test: 0.002, 0.04 and 0.01, respectively) in patients with beta3-integrin expression. The prognostic impact of this parameter was even higher than for other well-known prognostic parameters and remained statistically significant in the multivariate analyses. beta3-integrin, which is expressed in the majority of patients with advanced cervical cancer, has a significant prognostic impact on outcome according to univariate and multivariate analyses.     

Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia

BACKGROUND: The prevalence of chronic lymphocytic leukemia (CLL) increases with age. Although chemoimmunotherapy (CIT) has dramatically improved response rates in patients with CLL, some CIT regimens are not well tolerated by many patients >or=70 years of age. METHODS: Sixty-four previously untreated patients with CLL and serum creatinine <1.5 times the upper limit of normal who met National Cancer Institute (NCI) 96-WG criteria for treatment received pentostatin (2 mg/m(2)), cyclophosphamide (600 mg/m(2)), and rituximab (375 mg/m(2)). The authors measured performance status at study entry and used age, weight, and baseline creatinine to calculate creatinine clearance (CrCl). RESULTS: Eighteen of 64 (28%) patients were ages >or=70 years. Although individuals ages >or=70 years were more likely to have delayed treatment cycles (28% vs 7%; P=.03), there were no significant differences in the number of cycles administered, need for dose reductions, or grade 3-4 hematologic, infectious, or other toxicities. No significant differences in overall response rate, complete response rate, or progression-free survival were observed by age. Twenty-five (39%) patients had a CrCl < 70 mL/min (range, 34-67). Although individuals with CrCl < 70 were more likely to require dose reduction (24% vs 5%; P=.05), there were no significant differences in the number of cycles administered or grade 3-4 hematologic, infectious, or other toxicities. No significant difference in overall response rate, complete response rate, or progression-free survival were observed between patients with CrCl >or= 70 mL/min and those with CrCl < 70 mL/min. CONCLUSIONS: In this clinical trial, the PCR regimen was well tolerated by older patients and individuals with CrCl 相似文献   

Circulating estradiol, but not testosterone, is a significant predictor of high-grade prostate cancer in patients undergoing radical prostatectomy

BACKGROUND:

The objective of this study was to assess the association between preoperative circulating levels of 17β‐estradiol (E₂) and high‐grade prostate cancer (HGPCa) (Gleason grade ≥4 + 3) at the time patients underwent radical retropubic prostatectomy (RRP).

METHODS:

Serum total testosterone (tT), sex hormone‐binding globulin (SHBG), and E₂ levels were measured the day before surgery (8‐10 AM ) in a cohort of 655 consecutive Caucasian‐ European patients who underwent RRP at a single institution. Logistic regression models were used to test the association between predictors (including age, body mass index, prostate‐specific antigen [PSA], clinical tumor classification, biopsy Gleason sum, tT, SHBG, and E₂) and HGPCa. Serum E₂ was included in the model as both a continuous variable and a categorized variable (according to the most informative cutoff: 50 pg/mL).

RESULTS:

Pathologic HGPCa was identified in 156 patients (23.8%). Patients with HGPCa had significantly higher PSA, clinical tumor classification, and biopsy Gleason sum than those without HGPCa (all P < .001). No other significant differences were observed between groups. At univariate analysis, continuously coded E₂ was not associated significantly with HGPCa (odds ratio [OR], 1.009; P = .25), whereas patients with E₂ levels ≥50 pg/mL had a 3.24‐fold increased risk of HGPCa (P < .001). At multivariate analysis, E₂ was associated significantly with HGPCa both as a continuous predictor (OR, 1.02; P = .04) and as a categorical predictor (OR, 3.94; P < .001) after accounting for other variables. Conversely, tT and SHBG levels were not associated significantly with HGPCa.

CONCLUSIONS:

E₂ was associated significantly with pathologic HGPCa, whereas SHBG and tT failed to demonstrate any association with HGPCa in patients who underwent RRP. Cancer 2011;. © 2011 American Cancer Society.     

A new prognostic score system in patients with advanced hepatocellular carcinoma not amendable to locoregional therapy: implication for patient selection in systemic therapy trials

BACKGROUND: Advanced hepatocellular carcinoma (HCC) patients who are not candidates for surgery or locoregional therapy are the focus of clinical trials of systemic therapy, as their overall prognosis remains poor. However, the current prognostic systems cannot reliably select appropriate candidates for systemic therapy trials based on the probability of 3-month survival. In this study, the authors constructed a new prognostic score system, the Advanced Liver Cancer Prognostic System (ALCPS), which can objectively predict the probability of 3-month survival. METHODS: Between 1990 and 2005, 1470 patients with advanced HCC who were not amendable to surgery or locoregional therapy were included in the analysis. The prognostic score system was developed from the multivariate Cox model through a point system and validated in an independent set. Okuda staging and Cancer of the Liver Italian Program (CLIP) score were also applied to the validation set to compare their predictive accuracy. RESULTS: The ALCPS was based on 11 prognostic factors with different weights: ascites, abdominal pain, weight loss, Child-Pugh grade, alkaline phosphatase, total bilirubin, alpha-fetal protein, urea, portal vein thrombosis, tumor size, and presence of lung metastases. It stratified patients in both training and validation sets to different prognostic groups with significant difference in 3-month overall survival (P < .0001). By using the patients in the validation set with known 3-month survival status, the ALCPS showed significantly better predictive power (area under the curve [AUC], 0.77) than Okuda score (AUC, 0.66; P < .001) and CLIP score (AUC, 0.71; P = .002). CONCLUSIONS: The new prognostic system can objectively help the clinicians to select appropriate candidates for evaluation of treatment efficacy in systemic therapy trials for advanced HCC.     

Hypoxia inducible factor-1alpha is a prognostic marker in premenopausal patients with intermediate to highly differentiated breast cancer but not a predictive marker for tamoxifen response

Hypoxia is common in many solid tumours, including breast cancer. Hypoxia triggers the expression of hypoxia inducible factor-1alpha (HIF-1alpha), and HIF-1alpha has been associated with an impaired prognosis in breast cancer and down-regulation of the oestrogen receptor (ER), potentially affecting the treatment efficiency of antioestrogens. The role of HIF-1alpha regarding prognostic and treatment predictive information in breast cancer has not been established and we therefore analyzed HIF-1alpha using immunohistochemistry in a cohort of 377 premenopausal stage II breast cancers arranged in a tissue microarray. The patients were included in a randomized trial with either 2 years of tamoxifen or no adjuvant treatment. The tamoxifen treatment effect could be studied in subgroups of breast cancer and pure prognostic information could be scrutinized for untreated control patients. HIF-1alpha was scored as positive in 24% of the tumours and correlated positively to tumour size, Nottingham histological grade (NHG), Ki-67, Her2 and cyclin E expression and negatively to lymph node status, cyclin D1, ER and PR (progesterone receptor) expression. Surprisingly, there was no difference in tamoxifen response for patients with high or low HIF-1alpha expressing tumours. In lymph node-positive patients as well as NHG 1/2 tumours, high HIF-1alpha protein expression was significantly associated with an impaired recurrence-free survival (p=0.014, 0.018). When analyzing the subgroup of NHG 1/2 tumours, a high HIF-1alpha expression was the only independent significant prognostic marker in multivariate analysis, including standard prognostic markers, suggesting that HIF-1alpha might be a useful prognostic marker in this subgroup of breast cancer, with a rather good but diverse prognosis.     

Combined treatment with pegylated interferon-alpha-2a and dacarbazine in patients with advanced metastatic melanoma: a phase 2 study

BACKGROUND.: Dacarbazine (DTIC) and pegylated interferon (IFN)-alpha-2a have both demonstrated some efficacy as single agents in metastatic melanoma. To the authors' knowledge, the current study is the first to test a combination of these 2 agents in a phase 2 trial. METHODS.: Twenty-eight patients with stage IV melanoma without brain metastases were treated with DTIC (at a dose of 850 mg/m(2) every 3 weeks) combined with weekly pegylated IFN-alpha-2a at a dose of 180 mug. The study was initiated to evaluate the efficacy and tolerability of the combination. The primary study endpoint was objective response. RESULTS.: Twenty-five patients were evaluable for response. Two patients (8.0%) achieved a complete response that continued for >480 days and 746 days, respectively. Four patients (16.0%) demonstrated a partial response, and another patient experienced stable disease. Six of 7 nonprogressive patients had either not received treatment or had not developed disease progression during adjuvant IFN treatment for stage II/III disease. The median duration of response was 236 days, the median progression-free survival was 56 days, and the overall survival time was 403 days. Few grade 3 toxicities and only 1 grade 4 toxicity were observed (according to National Cancer Institute Common Toxicity Criteria). CONCLUSIONS.: The combination of DTIC and pegylated IFN-alpha-2a was found to be well tolerated in patients with metastatic melanoma. The response rate of 24%, including 2 long-lasting complete responses, is encouraging, but must be confirmed in larger trials. Cancer 2008. (c) 2008 American Cancer Society.     

Overexpression of beta2-microglobulin is associated with poor survival in patients with oral cavity squamous cell carcinoma and contributes to oral cancer cell migration and invasion

beta2-Microglobulin (beta2M), a component of MHC class I molecules, is believed to be associated with tumour status in various cancers. In this study, we examined the expression of beta2M at different malignant stages of oral cavity squamous cell carcinoma (OCSCC). To determine the possible correlation between beta2M expression and various clinical characteristics, 256 samples from patients with OCSCC were evaluated by immunohistochemical staining. Strong beta2M expression was significantly correlated with a relatively advanced tumour stage (P<0.001), positive nodal status (P<0.001), and TNM stage (P<0.001). The cumulative 5-year survival rate was significantly correlated with a relatively advanced tumour stage (P<0.001), positive nodal status (P<0.001), TNM stage (P<0.001), and strong expression of beta2M (P<0.001). Thus, elevated beta2M expression is an indicator of poor survival (P<0.001). In addition, we extended our analysis of beta2M expression to the FaDu and SCC25 oral cancer cell lines. beta2-Microglobulin expression was positively correlated with cell migration and invasion in beta2M-overexpressing transfectants in Transwell chambers. The suppression of beta2M expression using small interfering RNA (siRNA) was sufficient to decrease cell migration and invasion in vitro. Taken together, our results suggest that beta2M expression in the tissues is associated with survival and may be involved in tumour progression and metastasis in OCSCC.