Hüseyin Engin

Old antihypertensives as novel antineoplastics: angiotensin-I-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists

Angiogenesis, cellular growth and invasion of a cancer cell are attractive targets for new treatment strategies of malignancies in recent years. The evidences are accumulating that ACE inhibitors and angiotensin II type 1 antagonists could be novel anti-angiogenic, anti-invasive, and even anti-growth agents against neoplastic tissues: The renin-angiotensin system promotes angiogenesis directly or indirectly and growth of neoplastic cell. Some tumors carry angiotensin II type 1 receptors. Angiotensin II antagonists and angiotensin-I-converting enzyme inhibitors have shown some anti-neoplastic actions. Angiotensin II receptor blocker losartan antagonises platelets, which are thought to modulate via vascular endothelial growth factor. They may even protect the patient from the major toxicity of chemotherapy and/or radiotherapy, myelotoxicity, enabling us to give higher doses and end up with higher success rate. We believe that these agents can be useful on clinical grounds and suggest their incorporation into clinical studies.

Generalized lymphadenopathy: a rare presentation of disseminated prostate cancer.

Prostate cancer most often metastases to regional lymph nodes and bones by hematogenous or lymphatic spread. Metastases to the supradiaphragmatic nodes are rare. A 56-yr-old male smoker with generalized lymphadenopathy was referred to our center with the complaints of weight loss of 15 kg and severe back and leg pain. On computed tomography of the thorax and abdomen, massive mediastinal, intra-abdominal, retroperitoneal, and inguinal lymphadenopathies with hydroureteronephrosis of the left kidney were noted. Excisional biopsy of left cervical lymph node revealed metastasis of prostatic adenocarcinoma and transrectal biopsy of the prostate disclosed poorly differentiated adenocarcinoma. Bone marrow aspiration biopsy, done for the differential diagnosis of anemia, also showed infiltration with prostate-specific antigen positive neoplastic cells. Supradiaphragmatic spread of prostate cancer has been postulated to be by a hematogenous route via the vertebral venous system, or Batson’s plexus, accessible via direct extension from the primary cancer site.

Tumor lysis syndrome following a single dose of capecitabine

1. Kaklamani VG, Vaiopoulos G, Kaklamanis PG. Behcet’s disease. Semin Arthritis Rheum 1998;27:197-217. 2. Turan B, Gallati H, Erdi H, Gurler A, Michel BA, Villiger PM. Systemic levels of the T cell regulatory cytokines IL-10 and IL-12 in Behcet’s disease; soluble TNFR-75 as a biological marker of disease activity. J Rheumatol 1997;24:128-32. 3. Sfikakis PP, Theodossiadis PG, Katsiari CG, Kaklamanis P, Markomichelakis NN. Effect of infliximab on sight-threatening panuveitis in Behcet’s disease. Lancet 2001;358:295-6. 4. Joseph A, Raj D, Dua HS, Powell PT, Lanyon PC, Powell RJ. Infliximab in the treatment of refractory posterior uveitis. Ophthalmology 2003;110: 1449-53. 5. Muñoz-Fernandez S, Hidalgo V, Fernandez-Melon J, Schlincker A, Martin-Mola E. Effect of infliximab on threatening panuveitis in Behcet’s disease (letter). Lancet 2001;358:1644.

Interleukin-2-induced reversible hyperbilirubinemia and cholestasis in a patient with Gilbert's syndrome

bilirubin level was 1.87mg/dl (normal range [NR] 0.10– 1.20 mg/dl), with the indirect bilirubin fraction being 1.56 mg/dl (NR, 0.10–0.70mg/dl). Results for all other liver function tests, including levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrognase (LDH), and gamma-glutamyl transferase (GGT) were within normal limits. He was started on IL-2, 36 106 IU, given by continous i.v. infusion. On the second day, the following laboratory parameters were obtained: total bilirubin 4.06 mg/dl, with indirect fraction of 2.44mg/dl; AST, 56 U/l (NR, 8–33U/l); ALT, 56U/l (NR, 5–40 U/l); ALP, 391 mg/dl (NR, 91–258mg/dl); and GGT, 95 U/l (NR, 5–40U/l). Treatment was then immediately stopped. Two days after the cessation of treatment, all the abnormal laboratory parameters had normalized (total bilirubin, 1.22mg/dl). Gilbert’s syndrome, a hereditary, chronic, mild, unconjugated hyperbilirubinemia resulting from impaired hepatic bilirubin clearance and otherwise normal liver function, is arguably the most common hepatobiliary syndrome known in humans. Recent molecular genetic studies have determined that the clinical phenotype can be described by a dinucleotide polymorphism in the TATA box promoter of the bilirubin uridine diphosphate-glucuronosyl transferase (UGT-1A1) gene, most frequently (TA)7TAA, which affects up to 36% of Africans, but only 3% of Asians. However, a second common heterozygous mutation in the coding exon 1 of the UGT-1A1 gene (G71R) can also cause the Gilbert’s phenotype in Japanese and other Asians. The clinical phenotype may not be apparent as frequently as the determined genotype, because of environmental factors such as alcohol-induced hepatic bilirubin glucuronidation. Gilbert’s disease is a contributory factor in prolonged neonatal jaundice in breast-fed infants and may precipitate jaundice when coinherited with other disorders of haem metabolism. The genetic variation described as GS may lead to pharmacological variation To the Editor: Interleukin-2 (IL-2) is a form of therapy that has been shown to induce remissions in patients with renal cell carcinoma (RCC) and melanoma. However, at present, the toxicity of most IL-2 regimens is severe, and the treatment is prohibitive for clinicians not intimately familiar with the myriad of side effects associated with it. In a nonrandomized retrospective and prospective analysis,1 IL-2 based immunotherapy was found to be associated with profound reversible cholestasis and hyperbilirubinemia. A return to normal levels of bilirubin was noted within 5.6 days of cessation of IL-2. Tissue ultrasound examinations revealed a mean scatterer spacing (MSS) increase compared with baseline, suggestive of hepatic edema or an infiltrative process. Further, computerized hepatobiliary nuclear magnetic resonance scans revealed a delay in the uptake and excretion of technetium-99m-labeled disofenin. Microscopic examination of the liver during IL-2induced hyperbilirubinemia shows features of acute multifocal hepatitis with necrosis and acute pericholangitis, in agreement with findings in animal studies.2–4 Recently, we observed a 50-year-old man with metastatic RCC and Gilbert’s syndrome (GS) who during i.v. IL-2 administration, developed hyperbilirubinemia and cholestasis, which were reversible after discontinuation of the therapy. He first presented, in 1992, with a mass in the right kidney, and right radical nephrectomy was performed, leading to a diagnosis of clear cell adenocarcinoma. After a 2-year course of treatment with interferon alpha, medroxyprogesterone acetate, and vinblastine, he remained in complete remission until 2001, when metastatic lesions in the parenchyma of the left lung were observed; these were confirmed, on biopsy, to be RCC metastases. On admission to hospital, his total

Myasthenia Gravis and Lymphoblastic Lymphoma Involving the Thymus: A Rare Association

Myasthenia gravis (MG) is an autoimmune neuromuscular junction disease. An association between thyrnic epithelial neoplasms and MG is well known. However, it is rarely associated with hematologic malignancies. In particular, very few cases of lymphoblastic lymphoma involving the thymus and MG have been reported. Here we report a case T-cell lymphoblastic lymphoma involving the thymus who developed MG after the initial diagnosis. The patient initially presented with a mediastinal mass which was diagnosed as lymphoblastic lymphoma. MG was diagnosed during leukemic relapse in this patient and was based on clinical presentation and neurophysiologic studies including single fiber electromyography (EMG) and repetitive nerve stimulation tests. In contrast to the other cases with such an association, the myasthenic symptoms presented nine months after the diagnosis of lymphoma by thymectomy. The patient had a highly aggressive clinical course and was resistant to various chemotherapy regimens.

Embryonal rhabdomyosarcoma of the larynx.

m t ore than 95% of laryngeal tumors in adults are squamous cell carcinoma. Laryngeal involvement by rhabomyosarcoma in adults is extremely rare. A 28-year-old male atient with the complaint of hoarseness presented with a aryngeal mass. Biopsy revealed embryonal rhabdomyosaroma. Combination chemotherapy was initiated consisting of yclophosphamide, doxorubicin, cisplatin, and vincristine. Folowing induction chemotherapy, clinical and radiological comlete response was obtained. Radiotherapy was applied after nduction chemotherapy. Squamous cell carcinoma is the most ommon histology among the laryngeal malignancies, making p more than 95% of laryngeal tumors. Mesenchymal tumors onstitute less than 1% of the cases, primarily in children. Of hem, rhabdomyosarcoma is the least common and the larynx s a primary localization is extremely unusual. In children, the ost common variety of laryngeal rhabdomyosarcoma is the mbryonal type, whereas in adults, pleomorphic rhabdomyoarcoma is the most common variety encountered. Rhabdoyosarcoma of the larynx tends to be less aggressive than habdomyosarcoma elsewhere in the head and neck region. lthough it is the most common soft tissue sarcoma in chilren, it ranks third in adults. Herein we report a case of mbryonal rhabdomyosarcoma involving the larynx as the nitial site of involvement.

A Phase II Study on the Safety and Efficacy of 5-Fluorouracil, Epirubicin, Cyclophosphamide (FEC) Followed by Paclitaxel in the Adjuvant Treatment of Breast Cancer

The incorporation of a taxane into an anthracycline-containing regimen in the adjuvant treatment of breast cancer is a promising approach. In this study, we aimed to evaluate the safety and efficacy of four cycles of FEC (fluorouracil 500 mg/m2, epirubicin 70 mg/m2, cyclophosphamide 500 mg/m2, every 3 weeks) followed by four cycles of paclitaxel (175 mg/m2 every 3 weeks) in the adjuvant treatment of node-positive and other high-risk breast cancer patients. A total of 88 female patients were enrolled. Mean age (± SD) of the patients was 47 ± 10 (min: 24; max: 71). The patients were followed for a median of 48 months (min: 20; max: 64). The most common side effects were nausea-vomiting (grade I–II: 91%; grade III: 2%), as well as hematological toxicity (grade I–II: 70%; grade III: 3%). Although all patients experienced some degree of toxicity, it was severe enough to be classified as grade III or IV in only 10 (11%) of the cases. Of note, six (8%) patients had grade I and only one (1%) had grade II cardiotoxicity. No grade III or IV cardiotoxicity was observed. The full eight cycles of study treatment could be administered to 75 patients (85%). Side effects necessitated the reduction of the doses of FEC and paclitaxel in one (1%) and three patients (3%), respectively. Median overall (OS) and disease-free survival (DFS) have not yet been reached. Five-year OS and DFS have been estimated to be 78% and 61%, respectively. We conclude that FEC followed by paclitaxel is a well-tolerated and feasible regimen in the adjuvant treatment of early breast cancer. Its efficacity is comparable with other commonly used regimens and merits evaluation in a phase III study.

Hypereosinophilia and metastatic anaplastic carcinoma of unknown primary

The differential diagnosis of eosinophilia may sometimes be difficult. Eosinophilia may occur in a diverse array of conditions from parasitic infestations to malignacies. Idiopathic hypereosinophilic syndrome has also been described. A 65-year-old male patient presenting with eosinophilia of obscure etiology is described in the present report. Three years after the diagnosis of eosinophilia, metastatic anaplastic carcinoma of unknown primary was detected. Differential diagnosis is disscussed briefly. It is stressed that patients with hypereosinophilia of unknown etiology must be screened for malignancy regularly during follow up.

Is Granulocyte Colony-stimulating Factor Safe in the Treatment of Febrile Neutropenia in Lymphoma Patients with Renal Transplantation?

Garcia-Carbonero et al. showed that granulocyte colony stimulating factors (G-CSF) are helpful in reducing the duration of neutropenia, the duration of antibiotic therapy and hospitalisation and costs in patients with high-risk febrile neutropenia in their publication [1]. As a result of imrnunosuppression, the incidence of rnalignancies in renal-transplanted patients has increased. Since chernotherapy has been used increasingly for renal-transplant patients with neoplastic diseases, the management of the highrisk febrile neutropenia in this group has becorne an important issue. To our knowledge, the safety of G-CSF in renal-transplanted patients with neoplasrns, who also receive potentially nephrotoxic agents, has not been well defined yet. Although there are sorne studies reported [2,3], none of the patients in these studies received cornbination chernotherapy. Here, we would like to report our experience in a renal-transplant case with nonHodgkins lyrnphorna. A 48-year-old fernale patient was adrnitted to the clinic with stage IV non-Hodgkins lyrnphorna (li ver and spleen involvernent) 10 years after the renal transplantation. Standard treatrnent using the well established CHOP regimen (cyclophospharnide, adriarnycin, vinristine, prednisone) was started. Six days after the beginning of chernotherapy, a neutropenic fever with associated grade rn diarrhoea led to hospitalisation. Based on the grade rn diarrhoea, irnrnunosuppression for renal transplantation, recent in-patient status and short latency; we planned to start prophylactic G-CSF. This was based on the advice in the last ASCO guideline where the white blood cell and absolute neutrophil counts drop below 1000/rnrn [4]. G-CSF was not given