Osman Manavoglu

Response to Neoadjuvant Chemotherapy in Breast Cancer Could be Predictable by Measuring a Novel Serum Apoptosis Product, Caspase-Cleaved Cytokeratin 18: A Prospective Pilot Study

The M30-monoclonal antibody recognizes a neo-epitope of cytokeratin 18 which is formed after caspase-cleavage during apoptosis. Caspase-cleaved cytokeratin 18 is released from apoptotic cells into circulation. The aim of this study was to evaluate the relationship between M30-antigen level and chemotherapy response in neoadjuvant treatment of breast cancer. Forty-two patients with invasive breast carcinoma received 4 cycles of anthracycline based neoadjuvant chemotherapy. Serum samples were obtained for assessment of M30-antigen levels before the administration of first chemotherapy cycle (baseline), and then after 24 and 48 hours for determination of chemotherapy induced apoptosis. M30-antigen levels at 24 and 48 hours were found to be significantly higher than baseline (p < 0.001, p = 0.003, respectively). M30-antigen levels in responders showed statistically significant increases at 24 and 48 hours (p < 0.001; p = 0.004, respectively), while statistically significant increases were not observed in nonresponders. Percentage change of M30-antigen levels was significantly higher in responders than nonresponders at 24 hours (p = 0.020). In conclusion, our study revealed a significant relationship between increases of M30-antigen levels in serum and overall response to therapy.

Protective Effect of Amifostine Against Toxicity of Paclitaxel and Carboplatin in Non-small Cell Lung Cancer

AbstractAim: In this study we determined the protective role of amifostine against the side effects of the combination of paclitaxel and carboplatin in patients with non-small cell lung cancer (NSCLC). Patients and Methods: Chemo-naive patients with NSCLC were eligible. Thirty-eight patients were randomized to receive paclitaxel 175 mg/m2 and carboplatin AUC=6 with amifostine 910 mg/m2 (group B) or chemotherapy alone (group A). The occurrences of hematologic, neurologic, cardiologic toxicities, and ototoxicity were evaluated. Results: All patients completed the six scheduled cycles of therapy. A total of 114 cycles of chemotherapy was given in both groups. Neutropenia grade 3–4 was observed in 11 cycles (9.6%) in group A and 19 cycles (16.6%) in group B (p=0.16). Paresthesia grade 1 or 2 was observed in 18 of 19 patients of group A and in 8 of 19 patients of group B, following the sixth cycle of chemotherapy (p=0.018). Two patients of group B and nine patients of group A suffered from sensory motor impairment grade 2 (p=0.029). There was no clinical evidence in any patient for deterioration in cardiac function. Asymptomatic and transient sinus bradycardia or ventricular premature beats developed in four patients. None of the patients reported vertigo, tinnitus, or hearing loss. Conclusion: The addition of the amifostine to the combination of paclitaxel and carboplatin may prevent or reduce the incidence of neurotoxicity in the treatment of NSCLC. Amifostine does not appear to have a preventive role in neutropenia.

Single-agent irinotecan as second-line treatment for advanced gastric cancer

Aim To investigate the activity and toxicity of irinotecan (CPT-11) as a single agent in patients with advanced gastric cancer after failure of previous 5-fluorouracil-based combination chemotherapy. Patients and methods Sixteen patients with advanced gastric received CPT-11, 350 mg/m2 every 21 days. The median age of the patients was 54.6 years; ECOG performance status was 0-1 in 14 patients and 2 in 2 patients. Dominant metastatic sites included liver, lung, lymph nodes and peritoneum. Results No complete response was observed. Two patients (12.5%) achieved a partial response to treatment. One patient (6.25%) had a minor response. Ten patients (62.5%) had progressive disease on therapy, and 3 patients (18.75%) had stable disease. The median survival of all 16 patients was 5 months. Grade 3 neutropenia was observed in 3 patients (18.75%), grade 4 thrombocytopenia in 1 patient (6.25%), and grade 3 anemia in 1 patient (6.25%). Three patients (18.75%) suffered from grade 3 diarrhea. Conclusions CPT-11 is moderately active and a well-tolerated regimen for selected advanced gastric cancer patients who experience disease progression after receiving first-line treatment.

Efficacy of lower dose capecitabine in patients with metastatic breast cancer and factors influencing therapeutic response and outcome.

Objective: Capecitabine exerts considerable therapeutic efficacy in metastatic breast cancer (MBC) patients previously treated with anthracyclines and taxanes. Materials and Methods: In this study, the efficacy and safety of lower dose capecitabine (2000 mg/m2/d) in patients with anthracycline- and taxane-pretreated MBC were studied with a special emphasis on the potential predictors of time to tumor progression (TTP) and response to the capecitabine treatment. Results: The overall response rate (ORR) was 17%. The median TTP was 5 months. Among various factors analyzed, univariate analysis showed that a performance status (PS) of 2 and the presence of visceral metastases were inversely correlated with TTP. Multivariate analysis showed that a poor PS score was associated with impaired TTP. Conclusions: Our study indicates that lower dose capecitabine has substantial antitumor activity and a favorable safety profile in the treatment of anthracycline- and taxane-pretreated MBC. Also, only performance score was demonstrated to be a significant parameter affecting TTP.

Comparison of uroprotective efficacy of mesna and amifostine in Cyclophosphamide- induced hemorrhagic cystitis in rats

BACKGROUND Hemorrhagic cystitis (HC) is a dose limiting side effect of cyclophosphamide (CYP). AIM In this study, we aimed to investigate the role of amifostine in the protection of CYP-induced HC and compare its efficacy with mesna. SETTING AND DESIGN This animal study was conducted in the Experimental Animals Breeding and Research Center of the Medical Faculty of Uludag University. MATERIALS AND METHODS Male Wistar rats (150-200 g; 10 rats per group) were randomly assigned to four groups. Group I (control group) received no drugs, group II received CYP (200 mg/kg, i.p.) alone, group III received amifostine (200 mg/kg, i.p.) and CYP, and group IV received CYP and mesna (40 mg/kg, i.p.) immediately and 4 and 8 h after administration of CYP. Bladders of animals were assessed macroscopically and histologically 24 h later. Gross assessment for presence of edema and hemorrhage and histological evaluation of damage to the bladder were scored according to Grays criteria. STATISTICAL ANALYSIS USED For macroscopic and microscopic data, we used statistical evaluation by Kruskal-Wallis nonparametric analysis of variance followed by the Mann-Whitney U-test. RESULTS All the animals in group II had evidence of HC. Significant histological damage and macroscopic changes were present in this group compared to control group (P<0.001). The median scores for bladder damage in group III and IV were significantly lower compared to group II (P<0.001). When the median scores for bladder damage of group I, III, and IV were compared, there was no significant difference among these groups. CONCLUSION This study demonstrated the efficacy of amifostine in prevention of cyclophosphamide-induced hemorrhagic cystitis.

Small cell carcinoma of the urinary bladder. A clinicopathologic study of five cases

Aims and Background Small cell carcinoma of the bladder (SCCB) is a rare entity characterized clinically by an aggressive behavior with a high incidence of systemic metastases. We report the clinicopathologic findings of five cases. Methods We reviewed five consecutive patients with SCCB treated at our institute. In each case the following clinical data were recorded: age, sex, presenting symptoms, endoscopically determined location of the tumor, clinical staging, node involvement (if any), site of metastases (if any), treatment, follow-up and outcome. Results There were four male and one female patients, age range 42 to 68 years, mean 57.6 years. The clinical presentation was not different from conventional transitional cell carcinoma, with hematuria being the most frequent complaint (four cases). Microscopic examination revealed oat cells in three cases and an intermediate variant in one. At the time of diagnosis the tumors were staged as T3bN2M0, T2N2M0, T4N0M0, T3aN0M0, and T2N0M0. Primary therapy consisted of radical cystectomy alone (one case), transurethral resection (TUR) alone (one case), TUR with chemotherapy (two cases), or TUR with chemotherapy and radiotherapy (one case). Four patients died of progressive disease, with survival from the time of diagnosis ranging from 7 to 16 months (mean, 12.2 months). One patient died of myocardial infarction (unrelated to the primary disease) one month after diagnosis. Conclusion Our study indicates that primary small cell carcinoma of the urinary bladder is as aggressive as its pulmonary counterpart and the overall prognosis of this tumor is very poor.

Lack of genotoxicity in medical oncology nurses handling antineoplastic drugs: Effect of work environment and protective equipment

OBJECTIVE In this study we aimed to investigate the genotoxic effects of antineoplastic agents in occupationally exposed oncology nurses. Genotoxic effects mean the disruptive effects in the integrity of DNA and they are associated with cancer development. Biomonitoring of health care workers handling antineoplastic agents is helpful for the evaluation of exposure to cytostatics. PARTICIPANTS The study included an exposed and two control groups. The exposed group (n=9) was comprised of oncology nurses. The first (n=9) and second (n=10) control groups were comprised of subjects who did not come into contact with antineoplastic drugs working respectively in the same department with oncology nurses and in different departments. METHODS Genotoxicity evaluation was performed using SCE analysis. After applying culture, harvest and chromosome staining procedures, a total of 25 metaphases were analyzed per person. Kruskal Wallis test was used to perform statistical analysis. RESULT A statistically significant difference of sister chromatid exchange frequencies was not observed between the exposed and control groups. CONCLUSION Lack of genotoxicity in medical oncology nurses might be due to good working conditions with high standards of technical equipment and improved personal protection.

Phase II Study of Gemcitabine Plus Paclitaxel in Metastatic Breast Cancer Patients with Prior Anthracycline Exposure

Chemotherapy provides palliation and modest prolongation of symptom-free survival in metastatic breast cancer. Taxane containing regimens are commonly considered to be among the initials in metastatic setting due to earlier use of anthracyclines in the course of breast cancer. Therefore, we conducted this Phase II study to assess efficacy and safety of gemcitabine plus paclitaxel (GT) combination therapy in anthracycline pretreated metastatic first-line setting. Patients and Methods: The study enrolled 26 women with pathologically confirmed and measurable metastatic breast cancer who were previously treated with anthracycline but no prior chemotherapy for metastatic disease. Twenty six and twenty four patients were eligible for toxicity and efficacy evaluations respectively. Mean age was 47.3 years and median ECOG performance status was 0. Twenty patients (76.9 percent) had visceral metastases, most commonly located in liver and lung. Treatment schedule was as follows: paclitaxel 175 mg/m2 was administered intravenously in 3 hours on Day 1 and gemcitabine 1000 mg/m2 was administered intravenously in 30 minutes on Day 1 after paclitaxel application, and on Day 8 every 21 days. Results: Objective response rate was 41.7 percent (95 percent CI: 21.9–61.4) with 16.7 percent (95 percent CI: 1.7–31.6 percent) CR, and 25.0 percent (95 percent CI: 7.6–42.3 percent) PR. Median time to progression and overall survival were 9.6 and 14.5 months, respectively. Grade 3–4 toxicity was observed in 34.6 percent (9) patients. Treatment of two patients was discontinued due to toxicity, consisting of Grade 3 hypersensitivity reactions and Grade 4 infections in one patient each. Dose reductions due to myelotoxicity were performed in 4 (15.3 percent) patients. Hematologic toxicities were generally manageable with appropriate dose modifications and supportive care. Conclusion: Gemcitabine and paclitaxel combination regimen is effective and has manageable toxicity profile as first line metastatic setting.

Primary small cell carcinoma of the breast: report of seven cases and review of the literature

AIMS AND BACKGROUND The aim of the study was to analyze the clinicopathological characteristics, treatment modalities, and clinical outcome of patients with primary small cell carcinoma of the breast. METHODS Fifty-three cases of primary small cell carcinoma of the breast were identified; 7 cases in this series and 46 from the English-language medical literature. RESULTS There were 52 females and 1 male. The mean age was 53 years. Tumor size ranged from 1 to 18 cm (mean, 4.53). Axillary node metastasis was present in 61.7%. Only one patient had distant metastases at presentation. The presence of hormone receptors was reported in 24.5% of the tumors. Modified radical mastectomy was the most common surgical procedure and was performed in 50.9% of the patients. Adjuvant radiotherapy was administered to 39.6% of the patients, and 69.8% underwent chemotherapy. Thirteen percent of patients received adjuvant tamoxifen therapy. The mean follow-up was 20.75 months (range, 3-60), and 10 of 53 cases (18.9%) died of metastatic disease. CONCLUSIONS The prognosis of primary small cell carcinoma of the breast largely depends on the initial stage of the disease. Multimodality treatment including surgery, radiotherapy and chemotherapy seems to be the most appropriate strategy for early disease. Chemotherapy is usually unsuccessful in treating metastatic disease.

Rhabdomyosarcoma of the perianal region presenting as acute leukemia

Rhabdomyosarcoma (RMS) is the most common malignant soft tissue tumor in adolescence and childhood, which becomes manifest by the locally destructive growth of the primary tumor or its metastases. Sometimes no discernible primary lesion can be detected despite widespread dissemination or in some rare cases the disease may be confined to the marrow. Although approximately 60% of soft tissue sarcomas of children are RMS, it constitutes only 2–5% of all soft tissue sarcomas in adults [1–3]. A 25-year-old female presented with pain and mass of the perianal region, fatigue, fever, and weight loss. Her history revealed that she had developed a papular lesion in her perianal region 4 months before her admittance, which enlarged and acquired a large mass with time. Concomitantly she had symptoms of anemia and weight loss. One month before her admittance, she underwent drainage of the mass as an abscess and had five erythrocyte transfusions at that time. Two weeks before admission, she developed dizziness, epistaxis, and 38°C fever and was referred to our unit with a diagnosis of acute leukemia. Physical examination revealed severe pallor, petechiae on the lower extremities, lymph node with dimension 2×2 cm in the right inguinal region, and a hyperemic, ulcerated, and infected mass with dimensions of 15×10 cm in the lower right gluteus. Her hematologic findings were: hemoglobin 5.3 g/dl, hematocrit 15.3%, mean corpuscular volume (MCV) 80 fl, mean corpuscular hemoglobin (MCHb) 28 pg, WBC 7.69×10/l with 53% polymorphonuclear cells, 16% bands, 18% lymphocytes, 9% monocytes, and 4% blasts, and platelets 107×10/l. Bone marrow smear showed that 90% of marrow cells were tumor cells. They were characterized by vacuolated cytoplasm and the propensity to form pairs, clusters, and multinucleated forms (Fig. 1a–c). Flow cytometric studies of the bone marrow cells revealed no lineage markers for B cells, T cells, or myeloid cells. Trephine biopsy showed complete replacement of marrow (Fig. 1d) and infiltration of the mass by small round cells (Fig. 1e), which stained positively for actin, desmin, and vimentin, but negatively for leukocyte common antigen (LCA) and cytokeratin. The diagnosis of alveolar rhabdomyosarcoma (ARMS) was established. Abdominopelvic computed tomography showed a mass with dimensions of 14×12×10 cm in the medial region of right gluteus and the other masses with 4×3 cm near the inferior ramus pubis and in the anterior part of the right piriform muscle (Fig. 1f). The patient underwent a combined regimen of chemotherapy. Initially the neoplasm responded to chemotherapy, but disease progressed after 4 months. The histological diagnosis of tumor often remains difficult in a variety of solid tumors characterized by round cell morphology including RMS, neuroblastoma, Ewing’s sarcoma, and some cases of non-Hodgkin’s lymphoma [3]. Relatively few conditions spuriously may mimic a hematological disease such as acute leukemia; one of these is ARMS. ARMS in cases of bone marrow involvement is easily confused with acute leukemia and also the clinical picture may mimic the similar systemic symptoms of acute leukemia. The cells of ARMS resemble hematologic blasts (particularly lymphoblasts) and are difficult to differentiate from leukemic cells [2, 4]. R. Ali (*) . F. Özkalemkaş . Ü. Ozan . T. Özçelik . V. Özkocaman . A. Tunalı Department of Internal Medicine, Division of Hematology, Uludağ University School of Medicine, Bursa, Turkey e-mail: ridvanali@uludag.edu.tr Tel.: +90-224-4428400 Fax: +90-224-4428060