Psychosocial QOL is an independent predictor of overall survival in newly diagnosed patients with multiple myeloma

Only few studies have analyzed quality of life (QOL) and its association with prognosis in patients with multiple myeloma. We studied QOL at start of conventional treatment to evaluate the impact of symptomatic myeloma on QOL and to determine the prognostic significance of various dimensions of QOL. Our study provided further evidence of the significant impairment of QOL in patients with multiple myeloma at onset of therapy. Furthermore, our data showed a closer correlation between the more physical QOL scales such as pain, fatigue, physical functioning and global QOL with the activity of the disease than between psychosocial dimensions such as role, emotional, social, and cognitive functioning and the status of the disease. Multivariate analyses including each a QOL scale and known prognostic parameters (response to therapy, creatinine level, calcium, LDH, Hb, beta2-microglobulin, and albumin) revealed a marked difference in the prognostic significance between psychosocial and other QOL scales. All psychosocial dimensions of QOL were found to be independent prognostic factors, while physical QOL and global QOL were eliminated by disease-associated prognosticators. Taken together, QOL was found to be significantly impaired in myeloma patients at start of therapy. Psychosocial, but not physical dimensions of QOL were found to be independent prognostic factors.     

Multivariate analysis of prognostic factors in CLL: clinical stage,IGVH gene mutational status,and loss or mutation of the p53 gene are independent prognostic factors

This study evaluates the prognostic significance of genetic abnormalities (detected at or shortly after presentation), clinical stage, lymphocyte morphology, CD38 expression, and IGVH gene status in 205 patients with chronic lymphocytic leukemia (B-CLL). Deletion of chromosome 11q23, absence of a deletion of chromosome 13q14, atypical lymphocyte morphology, and more than 30% CD38 expression are significantly associated with the presence of unmutated IGVH genes. Advanced stage, male sex, atypical morphology, more than 30% CD38 expression, trisomy 12, deletion of chromosome 11q23, loss or mutation of the p53 gene, and unmutated IGVH genes are all poor prognostic factors in a univariate analysis. However, only 98% or more homology of IGVH genes to the germline sequence, loss or mutation of the p53 gene, and clinical stage retain prognostic significance in a multivariate analysis. The median survival of patients with mutated IGVH genes, unmutated IGVH genes, and loss or mutation of the p53 gene regardless of IGVH gene status is 310, 119, and 47 months, respectively. These data should facilitate the design of new trials for the management of patients presenting with advanced disease or poor prognosis early stage disease.     

Expression of multidrug resistance-associated ABC transporters in B-CLL is independent of ZAP70 status

Purpose  

To assess whether the poor prognosis of ZAP70-positive B-cell chronic lymphocytic leukemia (CLL) is associated with the overexpression of ABC transporter genes that are responsible for pleiotropic drug resistance.     

High absolute basophil count is a powerful independent predictor of inferior overall survival in patients with primary myelofibrosis

Objectives: To investigate the clinical and prognostic significance of absolute basophil count (ABC) in patients with primary myelofibrosis (PMF).

Methods: We retrospectively investigated 58 patients with PMF treated in our institution in the period from 2006 to 2017. ABC was obtained in addition to other hematological and clinical parameters. Patients were separated into high and low ABC groups using the Receiver operating characteristic curve analysis.

Results: ABC was higher in PMF patients than in healthy controls (P?P?P?=?0.035), higher lactate dehydrogenase (P?P?P?=?0.030) and massive splenomegaly (P?=?0.014). ABC was also positively correlated with absolute monocyte count (AMC) (P?P?P?=?0.009) in a multivariate Cox regression model adjusted for age, gender, Dynamic International Prognostic Scoring System (HR 2.6, P?=?0.001) and AMC (HR 8.45, P?=?0.002).

Discussion: High ABC reflects higher disease activity and stronger proliferative potential of disease. ABC and AMC independently predict survival and therefore seem to reflect different underlying pathophysiologic processes. Hence, both have a potential for improvement of current prognostic scores.

Conclusion: Basophils represent a part of malignant clone in PMF and are associated with unfavorable disease features and poor prognosis which is independent of currently established prognostic scoring system and monocytosis.     

White blood cell count at diagnosis and immunoglobulin variable region gene mutations are independent predictors of treatment-free survival in young patients with stage A chronic lymphocytic leukemia

A comprehensive panel of clinical-biological parameters was prospectively evaluated at presentation in 112 patients with chronic lymphocytic leukemia (<65 years), to predict the risk of progression in early stage disease. Eighty-one percent were in Binet stage A, 19% in stages B/C. Treatment-free survival was evaluated as the time from diagnosis to first treatment, death or last follow up. In univariate analysis, advanced stage, hemoglobin, platelets, white blood cell, leukemic lymphocyte count, raised beta 2-microglobulin and LDH, unmutated immunoglobulin variable region genes, CD38, del(17p), del(11q) and +12, were significantly associated with a short treatment-free survival; the T/leukemic lymphocyte ratio was associated with a better outcome. Multivariate analysis of treatment-free survival in stage A patients selected a high white blood cell count and unmutated immunoglobulin variable region genes as unfavorable prognostic factors and a high T/leukemic lymphocyte ratio as a favorable one. At diagnosis, these parameters independently predict the risk of progression in stage A chronic lymphocytic leukemia patients.     

Early post-transplantation positron emission tomography in patients with Hodgkin lymphoma is an independent prognostic factor with an impact on overall survival

The aim of the present study was to investigate the prognostic role of pre- and/or early post-autologous stem cell transplantation (ASCT) ¹⁸F-flourodeoxyglucose (FDG) positron emission tomography (PET) in patients with relapsed/refractory Hodgkin lymphoma. Forty-three consecutive patients were enrolled in this study. FDG-PET/CT was performed following salvage chemotherapy within 6 weeks of undergoing ASCT and at the first month after ASCT. FDG-PET positivity was found in 26 patients before ASCT and in 13 patients after ASCT. The patients who had negative PET scan before or after ASCT had significantly better outcomes in terms of overall survival (OS) and progression-free survival (PFS). Pre- and post-ASCT FDG-PET positivity was found to be independently associated with PFS while post-ASCT FDG-PET was an independent factor with an impact on OS in multivariate analysis. ¹⁸F-flourodeoxyglucose positron emission tomography imaging may be useful in predicting prognosis after ASCT. Furthermore, effective treatment options including allogeneic stem cell transplantation might be considered in patients with positive FDG-PET scan after salvage chemotherapy and ASCT.     

Mutations in ligands and receptors of the leptin-melanocortin pathway that lead to obesity

Obesity is associated with increased morbidity and mortality from cardiovascular disease, diabetes mellitus and certain cancers. The prevalence of obesity is increasing rapidly throughout the world and is now recognized as a major global public-health concern. Although the increased prevalence of obesity is undoubtedly driven by environmental factors, the evidence that inherited factors profoundly influence human fat mass is equally compelling. Twin and adoption studies indicate that up to 70% of the interindividual variance in fat mass is determined by genetic factors. Genetic strategies can, therefore, provide a useful tool with which to dissect the complex (and often heterogeneous) molecular and physiologic mechanisms involved in the regulation of body weight. In this Review, we have focused our attention on monogenic disorders, which primarily result in severe, early-onset obesity. The study of these genetic disorders has provided a framework for our understanding of the mechanisms involved in the regulation of body weight in humans and how these mechanisms are disrupted in obesity. The genes affected in these monogenic disorders all encode ligands and receptors of the highly conserved leptin-melanocortin pathway, which is critical for the regulation of food intake and body weight.     

Decreased expression of HOXB9 is related to poor overall survival in patients with gastric carcinoma

BackgroundStudies have demonstrated the implication of HOXB9 in tumorigenesis, but its role in gastric carcinoma remains unknown.AimsTo investigate the expression and prognostic value of HOXB9 in patients with gastric carcinoma.MethodsThe localization and expression of HOXB9 in gastric cancer cells lines were detected by immunofluorescence and western blot. The mRNA and protein expression level of HOXB9 was detected in subjects with gastric carcinoma and paired non-cancerous tissues. Correlation between HOXB9 expression and clinicopathological parameters, the association of HOXB9 expression with the patients’ survival rate was also assessed.ResultsHOXB9 was predominantly localized in the cell nucleus. A significant decrease in HOXB9 intensity in poorly differentiated gastric cancer cells is evident (P < 0.01). A lower mRNA and protein expression level of HOXB9 was detected in gastric carcinoma (P < 0.01). Decreased expression of HOXB9, poorly differentiation status and the presence of lymph node metastasis predict shorter overall survival (P < 0.05). Patients without HOXB9 expression had a lower overall survival rate (P < 0.01). Multivariate Cox regression analysis showed HOXB9 was an independent prognostic factor in gastric carcinoma (P < 0.01).ConclusionsHOXB9 is down-regulation in gastric carcinoma and may be a novel prognostic marker for poorer clinical outcome for patients with gastric carcinoma.     

CD49d expression is an independent predictor of overall survival in patients with chronic lymphocytic leukaemia: a prognostic parameter with therapeutic potential

In vitro studies have demonstrated that surface expression of CD49d on chronic lymphocytic leukaemia (CLL) B cells facilitates leukaemic cell-stromal interactions by binding to fibronectin. This interaction reduces both spontaneous and drug-induced apoptosis. The present study measured CD49d expression by flow cytometry in a cohort of untreated CLL patients previously accrued to a prospective observational study and evaluated the relationship with overall survival (OS). Among the 158 CLL patients tested, the percentage of leukaemic B cells expressing CD49d ranged from 0 to 100%. When all risk factors were treated as continuous variables, CD49d expression showed moderate correlation with expression of ZAP-70 (r = 0.54; P < 0.0001) and CD38 (r = 0.58; P < 0.0001) but not %IGHV mutation. As a continuous variable, CD49d expression strongly correlated with OS (P < 0.0001). Recursive partitioning analysis suggested the 45% threshold of CD49d expression best predicted OS. Multivariate analysis, controlling for disease stage, ZAP-70, IGHV status and fluorescent in situ hybridization defects identified CD49d as an independent predictor of OS and was a better predictor of clinical outcome than ZAP-70, IGHV, or cytogenetics. This observational cohort study suggests that CLL B-cell expression of CD49d is an easily measurable and independent predictor of OS and CD49d expression in CLL. Importantly, anti-CD49d antibodies are already approved for treatment of other human diseases. Clinical testing of anti-CD49d therapy in CLL appears warranted.     

Despite aggressive histopathology survival is not impaired in young patients with colorectal cancer

Purpose  

Colorectal carcinoma (CRC) is generally a disease of persons older than 50 years. Concerning younger patients, controversies still exist regarding features and prognosis of CRC. We performed this study to characterize CRC in young patients (≤50 years) as well as to evaluate outcome in comparison with older patients (>50 years) with CRC.     

Bone marrow angiogenesis magnetic resonance imaging in patients with acute myeloid leukemia: peak enhancement ratio is an independent predictor for overall survival

Emerging evidence suggests that progression of hematologic malignancies is associated with angiogenesis. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can provide global and functional imaging of tumor angiogenesis. In this study, we performed bone marrow DCE-MRI prospectively at diagnosis and after induction chemotherapy in 78 de novo acute myeloid leukemia (AML) patients and correlated it with treatment outcome. An algorithm to assess bone marrow angiogenesis by measuring the DCE-MRI time-intensity curve pixel by pixel was developed using 3 distinct parameters: peak enhancement ratio (Peak) to indicate tissue blood perfusion; amplitude (Amp) to reflect vascularity; and volume transfer constant (K trans) to indicate vascular permeability. The Peak and Amp decreased significantly at remission status after induction chemotherapy. Patients with higher Peak or Amp at diagnosis had shorter overall survival and disease-free survival than others. Cox multivariate analysis identified higher Peak value (hazard ratio, 9.181; 95% confidence interval, 1.740-48.437; P = .009) as an independent predictor for overall survival in addition to unfavorable karyotype and old age. Our findings provide evidence that increased bone marrow angiogenesis measured by DCE-MRI can predict adverse clinical outcome in AML patients. DCE-MRI may help to select high-risk phenotype AML patients for tailored antiangiogenic therapy and to monitor treatment response.     

Serum sodium and hydration status predict transplant-free survival independent of MELD score in patients with cirrhosis

Background and Aim: Serum sodium may have prognostic value in addition to the model for end‐stage liver disease (MELD) score for prediction of early mortality in patients listed for liver transplant. In patients with cirrhosis, over‐hydration is a common feature but its prognostic value has not been evaluated. This study examines the independent prognostic significance of MELD, serum sodium and hydration status on long‐term survival in patients with cirrhosis. Methods: Serum sodium and hydration (total body water as a percentage of fat‐free mass) were measured in 227 consecutive cirrhotic patients (146 male, 81 female; median age 49 years, range 19–73 years; median MELD score 13, range 6–36). Patients with hepatocellular carcinoma or listed for liver transplantation at the time of initial assessment were excluded. A competing risks Cox proportional hazards analysis was performed to evaluate the influence of MELD, sodium and hydration on risk of death or transplant. Results: Median follow‐up was 52 (range 4–93) months. Serum sodium and hydration were each associated with reduction in time to death or transplant on univariate analysis (sodium: hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.87–0.94, P < 0.0001; hydration: HR 1.20, 95% CI 1.10–1.30, P < 0.0001). On multivariate analysis, MELD, serum sodium and hydration were independently predictive of death or transplant (MELD: HR 1.12, 95% CI 1.06–1.19, P < 0.0001; sodium: HR 0.93, 95% CI 0.87–0.99, P = 0.04; hydration: HR 1.17, 95% CI 1.02–1.33, P = 0.02). Conclusions: In non‐waitlisted patients with cirrhosis, serum sodium is predictive of transplant or death independent of MELD score.     

KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival

Mutations in codon D816 of the KIT gene represent a recurrent genetic alteration in acute myeloid leukemia (AML). To clarify the biologic implication of activation loop mutations of the KIT gene, 1940 randomly selected AML patients were analyzed. In total, 33 (1.7%) of 1940 patients were positive for D816 mutations. Of these 33 patients, 8 (24.2%) had a t(8;21), which was significantly higher compared with the subgroup without D816 mutations. Analyses of genetic subgroups showed that KIT-D816 mutations were associated with t(8;21)/AML1-ETO and other rare AML1 translocations. In contrast, other activating mutations like FLT3 and NRAS mutations were very rarely detected in AML1-rearranged leukemia. KIT mutations had an independent negative impact on overall (median 304 vs 1836 days; P = .006) and event-free survival (median 244 vs 744 days; P = .003) in patients with t(8;21) but not in patients with a normal karyotype. The KIT-D816V receptor expressed in Ba/F3 cells was resistant to growth inhibition by the selective PTK inhibitors imatinib and SU5614 but fully sensitive to PKC412. Our findings clearly indicate that activating mutations of receptor tyrosine kinases are associated with distinct genetic subtypes in AML. The KIT-D816 mutations confer a poor prognosis to AML1-ETO-positive AML and should therefore be included in the diagnostic workup. Patients with KIT-D816-positive/AML1-ETO-positive AML might benefit from early intensification of treatment or combination of conventional chemotherapy with KIT PTK inhibitors.     

Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells

Notch signaling is involved in tumorigenesis, but its role in B-chronic lymphocytic leukemia (B-CLL) pathogenesis is not completely defined. This study examined the expression and activation of Notch receptors in B-CLL cells and the role of Notch signaling in sustaining the survival of these cells. Our results show that B-CLL cells but not normal B cells constitutively express Notch1 and Notch2 proteins as well as their ligands Jagged1 and Jagged2. Notch signaling is constitutively activated in B-CLL cells, and its activation is further increased in B-CLL cells, which resist spontaneous apoptosis after 24-hour ex vivo culture. Notch stimulation by a soluble Jagged1 ligand increases B-CLL cell survival and is accompanied by increased nuclear factor-kappa B (NF-kappaB) activity and cellular inhibitor of apoptosis protein 2 (c-IAP2) and X-linked inhibitor of apoptosis protein (XIAP) expression. In contrast, Notch-signaling inhibition by the gamma-secretase inhibitor I (GSI; z-Leu-Leu-Nle-CHO) and the specific Notch2 down-regulation by small-interfering RNA accelerate spontaneous B-CLL cell apoptosis. Apoptotic activity of GSI is accompanied by reduction of NF-kappaB activity and c-IAP2 and XIAP expression. Overall, our findings show that Notch signaling plays a critical role in B-CLL cell survival and apoptosis resistance and suggest that it could be a novel potential therapeutic target.     

CD24 genetic variants contribute to overall survival in patients with gastric cancer

AIM: To investigate the role of single nucleotide polymorphisms(SNPs) in CD24 gene in susceptibility and overall survival of gastric cancer(GC).METHODS: We genotyped 3 tagging SNPs of CD24-P-534 in the promoter region, P170 in the coding region of exon 2 and P1527 in the 3′ untranslated region- using polymerase chain reaction-restriction fragment length polymorphism in specimens from 679 histologically-confirmed GC cases, 111 gastric atrophy(GA) cases and 976 tumor-free controls. Serumimmunoglobulin G antibodies to Helicobacter pylori(H. pylori) of all subjects were detected by enzyme-linked immunosorbent assay. CD24 expression was evaluated by immunohistochemistry in 131 GC specimens. Correlations between SNPs and risk of GC or GA were shown by P values and odd ratios(ORs) with 95% confidence intervals(95%CI) compared with the most common genotype of each SNP using the unconditional logistic regression model after adjusting for age, sex and H. pylori infection. Survival within each SNP group was plotted by Kaplan-Meier method and compared by log-rank test(recessive model). Hazard ratios with 95%CIs were computed by Cox regression model after adjusting for age, sex, histological type, tumor differentiation, clinical stage and post-operational chemotherapy.RESULTS: All of the three loci were in Hardy-Weinberg equilibrium in the control group. Median followup time for the 600 GC patients included in the survival analysis was 36.2 mo(range, 2.1-66.7 mo; 95%CI: 34.3-36.5 mo). Patients with the P-534 A/A genotype had significantly shorter survival(HR = 1.38, 95%CI: 1.01-1.88, P = 0.042) than did the C/C or C/A genotype carriers after adjusting for age, sex, histological type, tumor differentiation, clinical stage and post-operational chemotherapy. This trend was more evident in patients who lived longer than 2.5 years(HR = 7.55, 95%CI: 2.16-26.32, P = 0.001). The P170 T/T genotype was associated with a shorter lifespan than the non-T/T genotypes, but not significantly so. None of the three genetic variants was found to be associated with risk of GC(including tumor stage, grade and distant metastasis) or with risk of gastric atrophy. Furthermore, no difference of CD24 expression was found among the genotypes.CONCLUSION: The P-534 site in CD24 gene affects the overall survival of gastric cancer and may serve as a prognostic marker for gastric cancer.