Ayşen Timurağaoğlu

Effect of iron deficiency anemia on the levels of hemoglobin A1c in nondiabetic patients.

The major form of glycohemoglobin is hemoglobin A1c (HbA1c). The HbA1c fraction is abnormally elevated in chronic hyperglycemic diabetic patients and correlates positively with glycemic control. Previous studies suggest that iron deficiency anemia (IDA) affects the levels of HbA1c. The aim of this study was to determine the effect of IDA on HbA1c levels in nondiabetic patients. The population studied consisted of 50 patients (30 women, 20 men, mean age 35.7 ± 11.9 years) with IDA and 50 healthy subjects that were matched for age and sex. Patients who had glucose tolerance abnormalities (impaired glucose tolerance or diabetes mellitus), hemoglobinopathies, hemolytic anemia, chronic alcohol ingestion and chronic renal failure were excluded from the study. Hematologic investigations, fasting and postprandial glucose and HbA1c levels were measured in all subjects before iron therapy. All patients with IDA were treated with iron 100 mg/day for 3 months. We repeated the laboratory investigation after iron therapy. Before iron treatment, the mean HbA1c (7.4 ± 0.8%) level in patients with IDA was higher than in a healthy group (5.9% ± 0.5) (p < 0.001). In patients with IDA, HbA1c decreased significantly after iron treatment from a mean of 7.4% ± 0.8 to 6.2% ± 0.6 (p < 0.001). Iron deficiency must be corrected before any diagnostic or therapeutic decision is made based on HbA1c.

Iron Deficiency Anemia in the Elderly: Prevalence and Endoscopic Evaluation of the Gastrointestinal Tract in Outpatients

Iron deficiency anemia (IDA), mostly due to chronic occult bleeding from the gastrointestinal tract, is a common problem in the elderly. This study aimed to determine the prevalence of IDA in the elderly and to investigate the gastrointestinal tract in elderly patients with IDA. 1,388 patients over 65 years were prospectively evaluated for IDA in our outpatient clinic. IDA was defined if decreased hemoglobin concentrations (<13 g/dl for men and <12 g/dl for women) were associated with low serum ferritin levels (<15 ng/ml in men and <9 ng/ml in women). We evaluated the gastrointestinal system of all patients with IDA by upper gastrointestinal endoscopy and colonoscopy regardless of fecal occult blood loss. The prevalence of anemia was found to be 25% (n = 347) in our study population, and 30.5% (n = 106) of these patients with anemia had iron deficiency. Upper gastrointestinal endoscopy and colonoscopy were performed in 96 patients with IDA. Fifty-eight upper gastrointestinal system lesions (55 patients, 57.3%) and 27 colonic lesions (26 patients, 27.1%) were detected. We diagnosed gastrointestinal malignancy in 15 (15.6%) elderly patients with IDA (8 colon, 1 esophageal and 6 gastric cancers). IDA is a common problem in elderly patients; consequently, before iron replacement therapy, patients should be thoroughly investigated regarding a possible association with gastrointestinal malignancy.

Methylenetetrahydrofolate reductase C677T polymorphism in adult patients with lymphoproliferative disorders and its effect on chemotherapy

Methylenetetrahydrofolate reductase (MTHFR) is one of the most critical enzyme in folic acid metabolism, and it converts 5,10-MTHF to 5-MTHF. 5,10-MTHF is required for conversion of uridilate to thymidylate. On the other side, MTHFR enzyme causes methylation of homocysteine into methionine, leading to methylation of DNA. Chemotherapeutic agents have different effects, but DNA is the target for most of them. Because folate is the cornerstone in DNA synthesis, we analysed herein if the polymorphisms in MTHFR gene can alter the susceptibility of lymphoproliferative disease risk and if it has an effect on chemotherapy response. One hundred fifty-six patients with lymphoid malignancies and 82 healthy controls were included into the study. Neither gene frequencies nor allel frequencies were found to increase lymphoproliferative disease risk significantly in both overall group and subgroups. Although it was not statistically significant, we found a 2.7-fold increased risk in acute lymphocytic leukaemia (ALL)/Burkitt lymphoma patients with TT genotype [odds ratio (OR), 2.7; 95% confidence interval (CI), 0.88–8.2] than CC genotype but a 1.7-fold decreased risk with TT genotype in diffuse large B-cell lymphoma (DLBCL; OR, 0.58; 95% CI, 0.17–1.88) and a 1.8-fold decreased risk in Hodgkin’s lymphoma with TT genotype (OR, 0.55; 95% CI, 0.10–2.87) than CC genotype. The chemotherapy response was analysed in DLBCL, Hodgkin’s lymphoma and ALL/Burkitt’s lymphoma because these patients received standard chemotherapy protocols. No significant difference was detected between responder and non-responders according to MTHFR T677C polymorphism, but the patients who had TT genotype respond 1.75-fold worse than CC (OR, 0.57; 95% CI, 0.07–4.64) in ALL patients (p=0.59), and in DLBCL, CT genotype revealed a 1.8-fold worse response than CC genotype (OR, 0.54; 95% CI, 0.17–1.7), but TT genotype revealed 2.6-fold better response rates than patients with CC genotype (OR, 2.6; 95% CI, 0.26–26.8). As a conclusion, MTHFR C677T polymorphism does not increase the risk of lymphoproliferative disease, and it does not have an effect on chemotherapy response significantly; however, the patients with TT genotype have a slightly increased risk for ALL, and they also respond worse than CC genotype. TT genotype slightly decreases the risk of DLBCL, and the patients have much favorable response rates.

Array comparative genomic hybridization analysis of adult acute leukemia patients.

We have performed a retrospective array-based comparative hybridization (array-CGH) study on 41 acute leukemia samples [n=17 acute lymphoblastic leukemia (ALL) patients only at diagnosis, n=3 ALL patients both at diagnosis and relapse; n=20 acute myeloid leukemia (AML) patients only at diagnosis and n=1 AML patient both at diagnosis and relapse] using an Agilent 44K array. In addition to previously detected cytogenetic aberrations, we observed cryptic aberrations in 95% of ALL and 90.5% of AML cases. ALL-specific recurrent abnormalities were RB1 (n=3), PAX5 (n=4), and CDKN2B (n=3) deletions; AML-specific recurrent abnormalities were HOXA9 and HOXA10 (n=2) deletions and NOTCH1 duplication (n=2). Recurrent duplication of the ELK1 oncogene was observed in both ALL (n=2) and AML (n=3) cases. Our results demonstrate that oligo-array CGH (oaCGH) is an effective method for defining copy number alterations and identification of novel recurring unbalanced abnormalities. At least for now, however, the use of oaCGH for routine diagnosis still has some restrictions.

Aspergillus alliaceus and Aspergillus flavus co-infection in an acute myeloid leukemia patient

We report a case of a pulmonary infection caused by Aspergillus flavus and Aspergillus alliaceus in an acute myeloid leukemia patient. These isolates were identified using traditional and sequencing-based molecular methods.

Improvement of Zoledronic Acid-Induced Jaw Osteonecrosis with Bortezomib

month, but the painful mass on her mandible did not recover. The clinical course, CT and biopsy findings suggested that our patient had a zoledronic acid-induced jaw osteonecrosis [3, 4] . Two months after the cessation of antibiotic therapy, MM also relapsed. Bortezomib was started on days 1, 4, 8 and 11 at a dose of 1.3 mg/m 2 as monotherapy. After the first cycle of bortezomib, clinically regression of the mass and pain relief in her left jaw were observed in the absence of dexamethasone, antibiotic or any other drug treatment that could cause the improvement in osteonecrosis. This was an unexpected and surprising finding. If it were a plasmacytoma, it would reasonably respond to bortezomib therapy, but a biopsy specimen of the involved tissue did not reveal plasmacytoma. A control CT after three cycles of bortezomib also showed improvement in the soft tissue mass with a moderate callus formation and, as a result, moderately improved osteonecrosis ( fig. 1 b). In total, four cycles of bortezomib were given without bisphosphonates. The patient responded to bortezomib therapy with a significant decrease in M-protein. She is still on follow-up with no MM-related complaints, but has neuropathic pain due to bortezomib. The exact mechanism of bisphosphonate-induced jaw osteonecrosis has not been elucidated yet, however, the cumulative ischemic effect was suggested to be the causative event. It was reported that osteonecrosis induced by bisphosphonates did not improve following surgical resection or antibiotics [4, 5] . Bortezomib is the first proThe proteasome is an enzyme complex that degrades many targeted intracellular proteins. Inhibition of this enzyme complex affects the levels of various intracellular proteins that regulate the cell cycle, leading to a decrease in cell proliferation. Bortezomib is the first proteasome inhibitor to be used in cancer therapy, especially in multiple myeloma (MM) [1, 2] . However, we report a different effect of bortezomib in a patient with relapsed MM. A 58-year-old female patient was diagnosed as having IgG MM. She received three cycles of VAD (vincristine, adriamycin and dexamethasone) chemotherapy and high-dose melphalan with autologous peripheral blood stem cell support, followed by monthly zoledronic acid. One year after high-dose chemotherapy, she had a tooth extraction from the left jaw and sometime later, she was admitted with gum hyperplasia. Since no clinically associated disease was found to explain the gum hyperplasia, it was surgically resected. Histopathological examination of this material revealed normal histological findings. One year after the tooth extraction, a painful mass appeared on her left jaw and a few days later, an inflammatory material began to drain. Computerized tomography (CT) revealed osteitis and a widespread periosteal reaction in her mandible ( fig. 1 a). Biopsy of the involved bone disclosed osteonecrosis and a mixed inflammatory reaction, but there was no evidence of plasmacytoma. With a clinical suspicion of osteomyelitis, ampicillin/sulbactam therapy was given empirically and zoledronic acid was stopped. The fistula was successfully treated after 1 Received: July 4, 2007 Accepted after revision: September 6, 2007 Published online: November 9, 2007

Microsatellite Instability Is a Common Finding in Multiple Myeloma

PURPOSE Microsatellite instability (MSI) occurs as a result of sliding in the DNA sequences from shortening or elongation of the repeat zones of DNA during replication. Such abnormalities can normally be corrected by the enzymes coded by the DNA mismatch repair (MMR) genes. Therefore, detection of MSI is considered to be a sign of disorder of the MMR genes and is interpreted as a replication error phenotype. PATIENTS AND METHODS We evaluated the MSI in 5 different loci in the 14q32 region of immunoglobulin heavy chain IgH gene in 26 newly diagnosed patients with multiple myeloma (MM). RESULTS Fifty-four percent of the patients disclosed MSI and at least 1 locus but no significant association of MSI was found between different clinical stages and the MM subtype. MSI was not found in 5 light-chain myeloma patients. CONCLUSION Although our case number is small, probably the genomic instability in heavy-chain MM may be a common finding and probably plays a critical role in the MM pathogenesis.

Effects of single-agent bortezomib as post-transplant consolidation therapy on multiple myeloma-related bone disease: a randomized phase II study

This phase II study explored the effects of bortezomib consolidation versus observation on myeloma‐related bone disease in patients who had a partial response or better after frontline high‐dose therapy and autologous stem cell transplantation. Patients were randomized to receive four 35‐day cycles of bortezomib 1·6 mg/m2 intravenously on days 1, 8, 15 and 22, or an equivalent observation period, and followed up for disease status/survival. The modified intent‐to‐treat population included 104 patients (51 bortezomib, 53 observation). There were no meaningful differences in the primary endpoint of change from baseline to end of treatment in bone mineral density (BMD). End‐of‐treatment rates (bortezomib versus observation) of complete response/stringent complete response were 22% vs. 11% (P = 0·19), very good partial response or better of 80% vs. 68% (P = 0·17), and progressive disease of 8% vs. 23% (P = 0·06); median progression‐free survival was 44·9 months vs. 21·8 months (P = 0·22). Adverse events observed ≥15% more frequently with bortezomib versus observation were diarrhoea (37% vs. 0), peripheral sensory neuropathy (20% vs. 4%), nausea (18% vs. 0) and vomiting (16% vs. 0). Compared with observation, bortezomib appeared to have little impact on bone metabolism/health, but was associated with trends for improved myeloma response and survival.

Bacteremia caused by Brevibacterium species in a patient with chronic lymphocytic leukemia.

We report a case of bacteremia caused by Brevibacterium species which is one of the coryneform bacteria, in a patient with chronic lymphocytic leukemia. We conclude that, if a coryneform bacteria is isolated from sterile body sites, it must be carefully evaluated, and especially in immunocompromised patients, Brevibacterium species should be considered as potential pathogens.

Aberrations of Chromosomes 9 and 22 in Acute Lymphoblastic Leukemia Cases Detected by ES-Fluorescence In Situ Hybridization

A reciprocal translocation between chromosomes 9 and 22 creates oncogenic BCR/ABL fusion in the breakpoint region of the derivative chromosome 22. The aim of this study was to evaluate the importance of atypical fluorescence in situ hybridization (FISH) signal patterns in pediatric and adult acute lymphoblastic leukemia (ALL) cases. We evaluated t(9;22) translocation in 208 cases with ALL (294 tests), including 139 childhood and 69 adult cases by FISH technique using BCR/ABL extra signal (ES) probe. FISH signal patterns observed in pediatric ALL cases were as follows; Major-BCR/ABL (M-BCR/ABL) (1.4%), minor-BCR/ABL (m-BCR/ABL) (3.6%), trisomy 9 (4.3%), trisomy 22 (4.3%), trisomy or tetrasomy of both chromosomes 9 and 22 (2.9%), monosomy 9 (1.4%), monosomy 22 (0.7%), ABL gene amplification (1.4%), derivative chromosome 9 deletion (1.4%), and extra copies of the Philadelphia chromosome (1.4%). FISH signal patterns observed in adult ALL cases were as follows; M-BCR/ABL (5.8%), m-BCR/ABL (11.6%), two different cell clones with major and minor BCR/ABL signal pattern (2.9%), extra copies of Philadelphia chromosome (4.3%), derivative chromosome 9 deletion (1.4%), trisomy 9 (2.9%), tetraploidy (1.4%), monosomy 9 (1.4%), trisomy 22 (1.4%), and coexistence of both trisomy 22 and monosomy 9 (1.4%). Trisomy 9, trisomy 22, and polyploidy of chromosomes 9 and 22 were specific atypical FISH signal patterns for childhood B cell acute lymphoblastic leukemia (B-ALL) patients. However, monosomy 9 and ABL gene amplification were highly specific for childhood T cell acute lymphoblastic leukemia (T-ALL) patients. Our report presents the correlation between atypical FISH signal patterns and clinical findings of a large group of ALL cases.