Second autologous stem cell transplantation as salvage therapy for multiple myeloma: impact on progression-free and overall survival

The role of a second autologous stem cell transplant (ASCT) as salvage therapy is unclear, particularly with the availability of novel agents to treat progressive multiple myeloma (MM). We retrospectively reviewed all MM patients who received a second ASCT as salvage therapy at our center from March 1992 to December 2009. Eighty-one MM patients received a second ASCT for relapsed MM. The median time to relapse after first transplant was 39 months (9.83-100). All patients received reinduction therapy before the second ASCT. The high-dose regimen given before the second ASCT consisted of melphalan (MEL) alone in the majority. Complete response, very good partial response, and partial response were seen in 7.7%, 39.7%, and 50%, respectively, at day 100 post-ASCT; the median time to relapse after the second ASCT was 19 months. Early deaths occurred in 2.6%. Median progression-free survival (PFS) based on the time to myeloma relapse after first ASCT was 9.83 months (relapse ≤ 24 months) and 17.3 months (relapse ≥ 24 months) (P < .05). Median overall survival (OS) was 28.47 months (relapse ≤ 24 months) and 71.3 months (relapse >24 months) (P = .006). Second ASCT is a feasible and safe option for salvage therapy in MM. The best outcome was observed in patients whose time to progression was >24 months after first ASCT, as these patients had a subsequent PFS lasting over 1 year and an OS of almost 6 years.     

PD1 distribution pattern,regardless of the cell origin,is an independent microenvironmental prognostic factor for progression-free survival in follicular lymphoma

Follicular lymphoma (FL) is a well-studied microenvironment-dependent hematological malignancy, but the crosstalk between various involved cell subtypes is still not fully understood. Recent promising results of immunotherapy in recurrent FL warrant the need for an in-depth analysis of the expression and role of immune system-related proteins in the FL microenvironment.Seventy-one patients with FL and available diagnostic paraffin blocks were enrolled in the retrospective analysis. Histopathological diagnoses were revised according to the World Health Organization recommendations. Patients were either observed (watch and wait/W&W group) or immediately treated with chemo(immuno)therapy regimens according to their clinical status. Immunohistochemical assessment of PD1, PDL1, CD4, CD8, CD163, CD68-KP1, CD68-PGM1 was performed. The scoring methods included both semi-quantitative estimation of positive cells and architectural pattern distribution. The differences between PD1 staining distribution and intensity were classified as intra/perifollicular vs. interfollicular/diffuse cells and presented bright vs. dim immunoreactivity, respectively. No statistically significant differences in the density distribution of the immunohistochemical stainings were found between W&W and chemo(immuno)therapy groups. Interfollicular/diffuse pattern of PD1 expression had significantly decreased progression-free survival when analyzing the whole cohort and patients on chemo(immuno)therapy (p = 0.014 and p = 0.07, respectively). The high dependence was not significant in the W&W group. PD1 positivity of cells did not correlate with CD4 or CD8 immunophenotype. Morphologically FL neoplastic cells were entirely PDL1 negative, but granular and membranous staining was detected in the FL microenvironment.In line with previous studies, PD1/PDL1 expression was predominantly localized in the FL microenvironment, indicating that FL cells might not be the direct target for anti-PDL1 therapy. However, we show that the localization of PD1 expression could be a viable progression-free survival biomarker for FL.     

Peroxiredoxin 4 as an independent prognostic marker for survival in patients with early-stage lung squamous cell carcinoma

Objectives: Peroxiredoxin 4 (Prx 4) is a newly emerging antioxidant protein that has been studied in several human cancers. Recently, it was revealed that Prx 4 is highly expressed in human lung cancer and is needed for the promotion of lung cancer progression in vitro. However, there are no clinical data regarding the association of Prx 4 and prognosis in lung cancer. Materials and methods: The Prx 4 expression state as a prognostic indicator was assessed by immunohistochemical staining in 142 patients with stage II non-small cell lung cancer (NSCLC) who had undergone curative surgery between 2006 and 2010. The association between the degree of Prx 4 expression and several clinicopathologic parameters was then evaluated by statistical analyses. Results: The degree of Prx 4 expression was associated with histology and recurrence in the overall NSCLC patient group, with the proportion of patients with positive Prx 4 expression significantly higher for the adenocarcinoma subtype (39/70, 56%) than the squamous cell carcinoma subtype (23/72, 32%) (P = 0.004). However, when subgroup analyses according to histopathology were performed in terms of recurrence, positive Prx 4 expression was significantly correlated with higher recurrence rates (P = 0.003) and shorter disease-free survival (DFS) (P = 0.003, hazard ratio = 3.910) in patients with squamous cell carcinoma. In contrast, no meaningful relationship was observed between the level of Prx 4 expression and DFS in the adenocarcinoma subgroup. Conclusion: Positive Prx 4 expression is significantly correlated with recurrence and shorter DFS in patients with early-stage lung squamous cell carcinoma.     

Complex karyotype in mantle cell lymphoma is a strong prognostic factor for the time to treatment and overall survival,independent of the MCL international prognostic index

Mantle cell lymphoma (MCL) is usually an aggressive disease. However, a few patients do have an “indolent” evolution (iMCL) defined by a long survival time without intensive therapy. Many studies highlight the prognostic role of additional genetic abnormalities, but these abnormalities are not routinely tested for and do not yet influence the treatment decision. We aimed to evaluate the prognostic impact of these additional abnormalities detected by conventional cytogenetic testing, as well as their relationships with the clinical characteristics and their value in identifying iMCL. All consecutive MCL cases diagnosed between 1995 and 2011 at four institutions were retrospectively selected on the basis of an informative karyotype with a t(11;14) translocation at the time of diagnosis. A total of 125 patients were included and followed for an actual median time of 35 months. The median overall survival (OS) and survival without treatment (TFS) were 73.7 and 1.3 months, respectively. In multivariable Cox models, a high mantle cell lymphoma international prognostic index score, a complex karyotype, and blastoid morphology were independently associated with a shortened OS. Spleen enlargement, nodal presentation, extra‐hematological involvement, and complex karyotypes were associated with shorter TFS. A score based on these factors allowed for the identification of “indolent” patients (median TFS 107 months) from other patients (median TFS: 1 month). In conclusion, in this multicentric cohort of MCL patients, a complex karyotype was associated with a shorter survival time and allowed for the identification of iMCL at the time of diagnosis. © 2013 Wiley Periodicals, Inc.     

Rictor is an independent prognostic factor for endometrial carcinoma

Early-stage endometrial carcinoma (EC) patients have a high cure rate; however, those with high-risk factors may have poor prognosis. Thus, there is an urgent need for searching for new prognostic molecules to more accurately predict survival of patients. We detected the Rictor mRNA expression level in 30 fresh EC tissue and 17 normal endometrial tissue samples with real-time quantitative RT-PCR and Rictor protein expression level in 134 (test cohort) and 115 (validation cohort) paraffin tissue samples by immunohistochemistry, analyzed the correlation between variables and overall survival (OS) using Cox proportional hazards regression, compared the prognostic accuracy of Rictor with other clinicopathological risk factors by logistic regression. The results showed that Rictor mRNA expression of EC is higher than that of normal endometrium; Rictor protein expression level was closely correlated with FIGO stage, grade and vascular invasion in both cohorts; a univariate analysis showed that the pathological type, stage, grade, vascular invasion, lymphatic metastasis and Rictor were predictors of OS in both cohorts; furthermore, multivariate Cox proportional hazards regression analysis indicated that vascular invasion and Rictor were independent prognostic factors for EC in both cohorts; an ROX curve comparison showed that the area under the curve (AUC) for Rictor combined with other clinicopathological prognostic factors was higher than any individual factor or other clinicopathological prognostic factors’ combination. Based on the above data, we concluded that Rictor is an independent prognostic factor for EC. It combined with other clinicopathological risk factors was a stronger prognostic model than individual risk factor or their combination.     

Genomic aberrations and immunohistochemical markers as prognostic indicators in multiple myeloma

As patients with multiple myeloma (MM) have a variable clinical course, predictive markers would help determine the appropriate treatment strategy. Clinical staging is commonly used to predict outcome, but tumour marker expression and the underlying genetic changes are increasingly used to assess the biological aggressiveness of the disease. Recent studies have demonstrated the utility of immunohistochemistry in detecting prognostic markers, including fibroblast growth factor receptor 3, cyclin D1, c-maf and p53, which have been associated with various genetic aberrations, including t(4;14), t(11;14), t(14;16) and del(17p). While t(4;14), t(14;16) and del (17p) have been documented to confer a poor prognosis, t(11;14) appears to be a neutral or even favourable factor in some studies. CD56, CD33, CD20 and CXCR4 are promising surface markers due to their roles in MM progression, but further studies of larger cohorts are necessary to assess their prognostic relevance. In this review, the biological function and clinical relevance of the main prognostic markers in MM is discussed, and also the role of immunohistochemistry in the stratification of patients into appropriate risk categories.     

Modified Glasgow prognostic score is an independent prognostic factor in patients with cervical cancer undergoing chemoradiotherapy

Objectives: There is increasing evidence that the presence of an inflammation-based prognostic score (modified Glasgow prognostic score, mGPS) could predict survival in patients with advanced cancer. The aim of this study was to investigate the prognostic value of mGPS in patients with cervical cancer. Methods: We included 238 consecutive patients with cervical cancer in our study. The albumin and serum C-reactive protein (CRP) were measured before initiation of treatment. The relationships between the mGPS and other clinical parameters including body mass index (BMI), white blood cell count, lymphocyte, platelet, hemoglobin, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) were analyzed. Overall survival (OS) and progression-free survival (PFS) were calculated. Significant prognostic factors were identified using univariate and multivariate analyses. Results: The 5-year OS rate for all patients was 52.1% and 5-year PFS rate was 42.3%. Patients with mGPS of 0, 1 and 2 were 138, 71, 29, respectively. Higher mGPS was related to more advanced disease, including higher FIGO stage, lymph node metastases and lower lymphocyte counts, BMI and hemoglobin level. Performance status (PS), FIGO stage, lymph nodal status and mGPS were independent prognostic indicators for OS and PFS in the multivariate analysis. Conclusions: Higher mGPS is associated with advanced cervical cancer. The mGPS is an easily measurable biomarker which can be used in combination with conventional FIGO stage to predict survival in patients with cervical cancer undergoing chemoradiotherapy.     

Lymph node ratio,an independent prognostic factor for patients with stage II-III rectal carcinoma

BackgroundIdentification of the proper surgical method and the most reliable prognostic parameters of rectal carcinomas is a challenging issue. The aim of this paper was to determine the possible prognostic role of the number of harvested lymph nodes versus lymph node ratio (LNR) in patients with rectal carcinomas, and the proper value of LNR that can be used as prognostic parameter.Materials and methodsA retrospective study was performed in 186 consecutive patients with rectal carcinomas that underwent surgical resection. The LNR was calculated for cases from stage II-III, and was correlated with classic prognostic parameters and overall survival (OS).ResultsA statistically significant difference was found between LNR of 0.15 and OS (p = 0.03), respectively LNR > 0.15 and TNM stage (p < 0.0001), but also tumor infiltration level (p < 0.05). The number of harvested lymph nodes was not correlated with the tumor stage (r = 0.148, p = 0.06) and this parameter did not influence the OS, when the number of 12 or 14 lymph nodes was used as the ideal value (p = 0.6 and p = 0.66, respectively).ConclusionIn patients with rectal carcinomas that underwent preoperative chemoradiotherapy, a LNR of 0.15 is a parameter with independent prognostic value, comparing with the number of harvested lymph nodes. The specific LNR should be calculated in larger cohorts.     

ATM mutations as an independent prognostic factor and potential biomarker for immune checkpoint therapy in endometrial cancer

The morbidity and mortality of endometrial cancer has been increasing over years. Ataxia telangiectasia mutated (ATM) gene, encoding a protein kinase participated in the response to DNA damage, is frequently mutated in endometrial cancer patients. However, the potential relationship between ATM mutations and the progression of endometrial cancer remains unclear. We performed an integrative bioinformatics analysis to investigate the relationship between ATM mutational status with clinical outcomes and tumor microenvironment in endometrial cancer patients. The whole exome sequencing data, RNA sequencing data and clinical information were collected from The Cancer Genome Atlas (TCGA) dataset. We found that mutation in the ATM gene was an independent prognostic factor for endometrial cancer. Antitumor immune pathways were enriched in endometrial tumors with ATM mutations. The tumor-infiltrating T lymphocytes, especially cytotoxic lymphocytes, were generally more abundant in tumors with ATM mutations. Furthermore, patients with ATM mutations exhibited higher tumor mutational burden, higher neoantigen load and increased expression levels of some immune checkpoints. In conclusion, the present study indicated that ATM mutations were linked to longer overall survival of endometrial cancer. Our findings may add better understanding for potential immunotherapy of endometrial cancer.     

Elevated expression of cyclooxygenase-2 is a negative prognostic factor for overall survival in intrahepatic cholangiocarcinoma

The production of prostaglandins is regulated by cyclooxygenases (COXs), which also have a role in tumour development and progression in various human malignancies, including cholangiocarcinoma. Limited information is available of the correlation of COX-2 protein expression and prognosis in intrahepatic cholangiocarcinoma (ICC). The aim of the present study was to determine the clinical significance of COX-2 expression in ICC. In addition the correlation of COX-2 expression and apoptosis/proliferation was analysed. COX-2 expression was determined immunohistochemically in 62 resected ICCs. Proliferation was assessed using Ki67-immunohistochemistry, and apoptosis was measured with the TdT-mediated dUTP nick-end-labelling technique. COX-2 was identified as an independent prognostic factor (P = 0.028) in resected ICC by survival analysis. High levels of COX-2 expression were found to be associated both with reduced apoptosis and increased proliferation of tumour cells. This study demonstrates the independent prognostic value of the COX-2 expression in resected ICC, thus, offering a potential additional adjuvant therapeutic approach with COX-2 inhibitors.     

Survivin as a prognostic factor for osteosarcoma patients

PURPOSE: Survivin is one of the apoptosis inhibitor genes and is rarely expressed in adult -tissues. However, survivin expression has been detected in various human cancers and -correlations have been recognized between the level of expression of this gene in tumors and prognosis. In this study, we investigated the correlations between survivin mRNA expres-sion in osteosarcoma tissues and clinicopathological parameters.METHODS: There were 22 osteosarcoma patients in our hospital with paraffin-embedded -tissues which could be extracted from biopsy specimens. We used the RT-PCR method after extracting total RNA and conducted a densitometric analysis to determine the ratio of survivin relative to h-GAPDH as an internal marker.RESULTS: Expression of survivin mRNA was detected in all osteosarcoma samples. Patients with metastasis had high survivin mRNA levels in initial biopsy specimens (p<0.01). Moreover, there was a statistically significant difference in survivin mRNA expression between -patients with and without metastasis (p<0.01).CONCLUSION: We concluded that high levels of survivin mRNA expression suggest poor prognosis for osteosarcoma patients.     

Comparison of serum beta 2-microglobulin and 24 hour urinary creatinine clearance as a prognostic factor in multiple myeloma

A new staging system for multiple myeloma (MM) has utilized serum concentrations of beta2-microglobulin (Sbeta2M) and albumin as important prognostic factors for survival. Since Sbeta2M is an indicator of glomerular filtration rate, we compared the prognostic values of Sbeta2M and 24-hr urinary creatinine clearance (Ccr) in patients with MM. We retrospectively reviewed the records of 170 MM patients from January 1996 to November 2003 whose 24-hr urinary Ccr was available at the time of diagnosis. We found that pretreatment Sbeta2M was inversely related to Ccr (Spearman's correlation coefficient=-0.787). In univariate analysis, the hazard ratio (HR) of death was 1.043 (p<0.001) for Sbeta2M and 0.985 (p<0.001) for Ccr. Multivariate analysis showed that Sbeta2M (HR 1.030, p=0.010) and Ccr (HR 0.993, p=0.059) were significant prognostic factors in patients' survival. In conclusion, 24-hr urinary Ccr may be utilized for staging of patients with MM.     

Prediction and prognostic significance of BCAR3 expression in patients with multiple myeloma

Background

Multiple myeloma (MM) is the plasma cell tumor, which is characterized by clonal proliferation of tumor cells, with high risk of progression to renal impairment, bone damage and amyloidosis. Although the survival rate of patients with MM has improved in the past decade, most people inevitably relapse. The treatment and prognosis of MM are still urgent problems. Breast Cancer Antiestrogen Resistance 3 (BCAR3) is a protein-coding gene that is associated with many tumors. However, there have been few studies on the relationship of BCAR3 and MM.

Methods

We analyzed 1878 MM patients (1930 samples) from 7 independent datasets. First, we compared the BCAR3 expression level of MM patients in different stages and MM patients with different amplification of 1q21. Second, we analyzed BCAR3 expression levels in MM patients with different molecular subtypes. Finally, we explored the event-free survival rate (EFS) and overall survival rate (OS) of MM patients with high or low BCAR3 expression, including patients before and after relapse, and their therapeutic responses to bortezomib and dexamethasone.

Results

The expression of BCAR3 showed a decreasing trend in stages I, II and III (P?=?0.00068). With the increase of 1q21 amplification level, the expression of BCAR3 decreased (P?=?0.022). Patients with high BCAR3 expression had higher EFS and OS (EFS: P?<?0.0001, OS: P?<?0.0001). The expression of BCAR3 gene before relapse was higher than that after relapse (P?=?0.0045). BCAR3 is an independent factor affecting prognosis (EFS: P?=?5.17E?03; OS: P?=?3.33E?04).

Conclusion

We found that high expression level of BCAR3 predicted better prognosis of MM patients. Low expression of BCAR3 at diagnosis can predict early relapse. BCAR3 is an independent prognostic factor for MM. BCAR3 can be used as a potential biomarker.

     

Rhinitis as an independent risk factor for adult-onset asthma

BACKGROUND: For many years, the association between asthma and rhinitis has primarily been attributed to a common allergic background. Recently, it has been suggested that asthma and rhinitis are associated in the absence of atopy. The nature of this association is not well known. OBJECTIVE: The purpose of this study, which was performed in a large, longitudinal community population, was to determine the extent to which rhinitis is an independent risk factor for adult-onset asthma. METHODS: We carried out a nested case-control study from the longitudinal cohort of the Tucson Epidemiologic Study of Obstructive Lung Diseases. One hundred seventy-three incident patients with physician-confirmed asthma were compared with 2177 subjects who reported no asthma or shortness of breath with wheezing. Potential risk factors, including the presence of rhinitis, were assessed before the onset of asthma (patients) or before the last completed survey (control subjects). RESULTS: Rhinitis was a significant risk factor for asthma (crude odds ratio, 4.13; 95% confidence interval, 2.88-5.92). After adjustment for years of follow-up, age, sex, atopic status, smoking status, and presence of chronic obstructive pulmonary disease, the magnitude of the association was reduced but still highly significant (adjusted odds ratio, 3.21; 95% confidence interval, 2.19-4.71). After stratification, rhinitis increased the risk of development of asthma by about 3 times both among atopic and nonatopic patients and by more than 5 times among patients in the highest IgE tertile. Patients with rhinitis with persistent and severe nasal symptoms and a personal history of physician-confirmed sinusitis had an additional increased risk of asthma development. CONCLUSION: We conclude that rhinitis is a significant risk factor for adult-onset asthma in both atopic and nonatopic subjects. The nature of the association between rhinitis and asthma is open to interpretation.     

Stromelysin 3: an independent prognostic factor for relapse-free survival in node-positive breast cancer and demonstration of novel breast carcinoma cell expression.

Stromelysin 3 (ST3) is a matrix metalloproteinase implicated in mammary carcinoma progression. To date, localization of ST3 expression in breast cancer by in situ hybridization and immunocytochemistry has shown that the expression of the enzyme is limited to only the stromal fibroblasts surrounding the cancer cells. We have immunostained a large group of ductal carcinoma in situ and invasive breast carcinomas using a monoclonal antibody (5ST-4A9) raised against the hemopexin-like domain of human ST3. We show that invasive lobular carcinomas express significantly less ST3 than invasive ductal carcinomas (IDCs) (P = 0.002). We also show, for the first time, that certain breast carcinoma cells that have undergone a degree of epithelial-to-mesenchymal transition, the so-called metaplastic carcinomas, can express ST3 mRNA and protein, which may in part explain the increased metastatic propensity seen in a number of these tumors. In addition, patients with IDC who had moderate to strong ST3 levels had significantly shorter disease-free survival than those with negative or weak ST3 levels (P = 0.02). Furthermore, in node-positive IDC patients, multivariate analysis revealed that ST3 level was a strong, independent prognostic parameter for disease-free survival (P = 0.005).