Salvage treatment with upfront melphalan 100 mg/m2 and consolidation with novel drugs for fulminant progression of multiple myeloma

Patients (pts) with fulminant progression (FPG) of multiple myeloma (MM) after autologous stem cell transplantation (ASCT) have poor prognosis. Pancytopenia, extramedullary disease, and/or renal impairment are often present, and treatment options are limited. We have retrospectively evaluated 31 pts with FPG of MM after ASCT who were treated upfront salvage therapy with melphalan 100 mg/m² (MEL 100) followed by PBSC support and consolidation therapy using regimens containing thalidomide (n?=?16) or bortezomib (n?=?15). The overall response rate (ORR) was 58% (18/31). After MEL 100, one patient achieved complete remission (3%), 26% of pts very good partial remission, 29% of pts partial remission, and 42% of pts stable disease. Progression within 3 months after MEL 100 occurred in 35% of pts. The median follow-up from MEL 100 was 8 months. The median TTP was 5 months (range, 2–15 months), and the median OS was 8 months (range, 3–23 months). There were no treatment-related deaths. In fulminant progression of MM, upfront MEL 100 is a safe salvage regimen with good response rate (ORR, 58%). Treatment with upfront MEL 100 followed by a thalidomide- or bortezomib-based regimen can prolong overall survival to more than 12 months in 33% of pts with fulminant progression of MM.     

Contribution of the β-ureidopropionase (UPB1) gene alterations to the development of fluoropyrimidine-related toxicity

BackgroundAn impairment of the 5-fluorouracil (5-FU) catabolic pathway, represented by alterations in the dihydropyrimidine dehydrogenase (DPYD) gene, is considered a crucial factor contributing to the development of 5-FU-related toxicity. The β-ureidopropionase (BUP1) enzyme catalyzes the final step in the 5-FU catabolic pathway; however, alterations in the UPB1 gene coding for the BUP1 enzyme have not yet been analyzed in fluoropyrimidine (FP)-treated patients suffering from 5-FU-related toxicity.MethodsWe have performed a mutation analysis of the entire coding sequence of UPB1 based on denaturing high-performance liquid chromatography in 113 cancer patients treated by FP-containing regimes. These patients included 67 individuals suffering from severe 5-FU-related toxicity and 46 individuals with excellent tolerance of chemotherapy.ResultsNine UPB1 variants were detected in the subpopulation of patients with severe toxicity, including a novel mutation affecting the coding sequence (c.872_873 + 11del13). An analysis of UPB1 variants on 5-FU-related toxicity in the population of all analyzed patients revealed an association between the c.-80C > G (rs2070474) variant and gastrointestinal toxicity. A strong positive correlation was found between the carriers of the c.-80 GG genotype and the development of severe (grade 3–4) mucositis (OR = 7.5; 95% CI = 2.60 – 21.60; p = 0.0002).ConclusionOur results suggest that UPB1 variants may contribute to the development of 5-FU-related toxicity in some FP-treated patients; however, the role of UPB1 alterations is probably less significant than that of DPYD alterations.     

Analysis of point mutations in the SMN1 gene in SMA patients bearing a single SMN1 copy

Spinal muscular atrophy (SMA) is caused by homozygous deletion of the SMN1 gene in approximately 96% of cases. Four percent of SMA patients have a combination of the deletion or conversion on one allele and an intragenic mutation on the second one. We performed analysis of point mutations in a set of our patients with suspicion of SMA and without homozygous deletion of the SMN1 gene. A quantitative test determining SMN1 copy number (using real-time PCR and/or MLPA analysis) was performed in 301 patients and only 1 SMN1 copy was detected in 14 of them. When these 14 patients were screened for the presence of point mutations we identified 6 mutations, p.Y272C (in three patients) and p.T274I, p.I33IfsX6, and p.A188S (each in one case). The mutations p.I33IfsX6 and p.A188S were found in two SMAI patients and were not detected previously. Further, evaluation of the relationship between mutation type, copy number of the SMN2 gene and clinical findings was performed. Among our SMA patients with a SMN1 homozygous deletion, we found a family with two patients: the son with SMAII possesses 3 SMN2 copies and the nearly asymptomatic father has a homozygous deletion of SMN1 exon 7 and carries 4 SMN2 copies. Generally, our results illustrate that an increased SMN2 gene copy number is associated with a milder SMA phenotype.     

Marker profiling of normal keratinocytes identifies the stroma from squamous cell carcinoma of the oral cavity as a modulatory microenvironment in co-culture

PURPOSE: The microenvironment established by stromal cells may or may not influence phenotypic aspects of epithelial cells and may be relevant for tumor and stem cell biology. We address this issue for keratinocytes using tumor-derived stromal cells in a co-culture system. MATERIALS AND METHODS: We isolated stromal cells from human squamous cell carcinoma tissue and studied their effect on phenotypic characteristics of normal human interfollicular keratinocytes in vitro. RESULTS: Stromal fibroblasts significantly influence immuno- and lectin cytochemical properties of co-cultured normal keratinocytes. Expression of keratins 8 and 19, the nucleolar protein nucleostemin, parameters related to adhesion/growth-regulatory galectins and the epithelial-mesenchymal transition were altered. This biological activity of tumor-derived stromal cells, which did not require cell contact, appeared to be stable, because it was maintained during passaging of keratinocytes in the absence of cancer cells. CONCLUSIONS: Tumor-derived stromal fibroblasts acquire distinct properties to shape a microenvironment conducive to altering the phenotypic characteristics of normal epithelial cells in vitro.     

Benefit of combined cardiac rehabilitation on exercise capacity and cardiovascular parameters in patients with type 2 diabetes

Favorable effects of exercise training on cardiovascular prognosis have been reported repeatedly in patients with diabetes mellitus type 2 (DM2). However, little is known about the cardiovascular rehabilitation effects in diabetic patients with coronary artery disease (CAD). This study has evaluated the benefits of combined aerobic-resistance training in two groups of patients--diabetics and non-diabetics--after percutaneous coronary intervention (PCI). Changes in exercise capacity parameters, resting cardiovascular and anthropometrical parameters were evaluated in 77 patients who completed 12-weeks of combined aerobic-resistance training: 32 patients with DM2 (DM) and 45 patients without DM2 (NDM). Significant improvements in exercise capacity (total peak workload [W(peak)], peak workload per kg of body weight [W(peak)/kg], total peak oxygen uptake [VO(2peak)], peak oxygen uptake per kg of body weight [VO(2peak)/kg]) were found in both DM and NDM (p < 0.01 and p < 0.001, respectively). The decrease in resting heart rate (HR(rest)), resting systolic (SBP(rest)) resting diastolic (DBP(rest)) blood pressures, body weight (BW) and BMI in the DM group was not statistically significant. However, there was a statistically significant decrease in SBP(rest), BW and BMI in the NDM group. In conclusion, this study demonstrated similar beneficial effects of combined cardiovascular training on exercise capacity in patients with or without type 2 diabetes mellitus. Our results suggest that the combined cardiac training is well tolerated and useful in secondary prevention in patients with DM2 and CAD.     

Cystic parathyroid adenoma within a multinodular goiter: a rare cause of primary hyperparathyroidism

Parathyroid cysts are uncommon lesions that do not have a specific sonographic appearance. We report a rare case of a functionally active cystic parathyroid adenoma as a cause of primary hyperparathyroidism and discuss the difficulties associated with the diagnosis. In this case, the association with a multinodular goiter made preoperative differentiation from thyroid cysts difficult. Demonstration of a high intact parathyroid hormone level in the aspirated cyst fluid was critical for the correct diagnosis.     

Serum lipids and neopterin in urine as new biomarkers of malnutrition and inflammation in the elderly

ObjectiveLevels of serum lipids are influenced by malnutrition and inflammation. The study aimed to find the relation of the lipidogram to positive and negative markers of inflammation in geriatric patients. Attention was paid to neopterin in urine as a non-protein positive bioindicator of inflammation.MethodsIt was a local, monocentric, prospective clinical study in hospitalized patients older than 80 y. The study included 101 patients (54 women, 47 men). The average age of the entire group was 85.37 ± 4.88 y. The dependence of the values of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triacylglycerols (TAGs) on C-reactive protein (CRP), neopterin in urine, and prealbumin was examined.ResultsWhen we compared CRP and serum lipids, we found a statistically significant negative correlation between levels of CRP and total cholesterol (P < 0.05), HDL (P < 0.01), and LDL (P < 0.05). Also the level of neopterin in urine was negatively correlated with levels of total cholesterol (P < 0.05) and HDL (P < 0.01). A statistically highly significant interaction was demonstrated between levels of prealbumin and total cholesterol (P < 0.001), HDL (P < 0.001), LDL (P < 0.001), and TAG (P < 0.05).ConclusionA significant negative correlation between levels of inflammation markers (neopterin in urine, CRP) and total cholesterol and HDL was found. LDL was influenced to a lesser extent. A close relation between serum lipids and prealbumin was also demonstrated. Total cholesterol, HDL, and LDL can be considered novel biomarkers of malnutrition and inflammation in geriatric patients.     

Establishment, growth and in vivo differentiation of a new clonal human cell line, EM-G3, derived from breast cancer progenitors

A new clonal cell line, EM-G3, was derived from a primary lesion of human infiltrating ductal breast carcinoma. The line consisted of cuboidal cells with occasional appearance of more differentiated branched cells apparently involved in cell-to-cell communication. The EM-G3 cells, population doubling time 34 h, are dependent on the epidermal growth factor. Multicolor fluorescence in situ hybridization (mFISH) analysis demonstrated a stable diploid genome with several genetic changes. Immunocytochemical analysis of EM-G3 in vitro revealed positivity for keratins (K) K5, K14, K18, nuclear protein p63, epithelial membrane antigen (EMA) and other proteins indicative of a pattern of mammary epithelium bipotent progenitors. Detection of integrins α-6, β-1, and protein CD44 by cDNA array also pointed to the character of basal/stem cells. In contrast, dominant cells in the human original tumor showed the luminal character (K18+, K19+, K5−, K14−, and p63−). However, cells with the immunocytochemical profile similar to that of cultured EM-G3 cells were found in minor clusters in the patient’s tumor sections. The EM-G3 cells formed limited tumors in nu/nu mice. The cells in mouse tumors were organized in primitive ductal-like structures consisting of 1–3 large central luminal-like cells (EMA+) surrounded by peripheral myoepithelial-like cells (p63+/EMA−). The large central cells gradually disintegrated, forming a pseudolumen. Apparently, EM-G3 cells are able to partially differentiate in vivo as well as in vitro. Our results indicate that EM-G3 cells were derived from a premalignant population of common progenitors of luminal and myoepithelial cells that were immortalized in an early stage of tumorigenesis.