Chemopreventive efficacies of rosiglitazone, fenretinide and their combination against rat mammary carcinogenesis.

INTRODUCTION: Peroxisome proliferator-activated receptor gamma (PPAR-gamma) and retinoic acid receptors (RAR/RXR) belong to the nuclear steroid receptor family. In vitro studies have suggested that PPAR-gamma ligands are highly effective in preventing mammary tumours and these effects are enhanced by some retinoids. However, in vivo anti-initiator and anti-promoter efficacies of this combination are not clear. AIM AND METHODS: The present study aimed to investigate the chemopreventive efficacies of the PPAR-gamma ligand rosiglitazone (200 microg/kg/day), synthetic retinoid fenretinide (0.3 mg/kg/day) and their combination on a DMBA-induced rat mammary carcinogenesis model. RESULTS: In the rosiglitazone group, no malignant tumour developed, apart from the lowest proliferative mammary lesions. In the fenretinide group, 30% developed a malignant tumour but there were no benign tumours. Cancer incidences were 61.5% and 10% in the control and combination groups respectively. CONCLUSIONS: Our results showed that the PPAR-gamma ligand rosiglitazone and synthetic retinoid fenretinide have potent chemopreventive properties against in vivo mammary carcinogenesis; however, the efficacies were not enhanced by their combination.

The effect of anthracycline-based (epirubicin) adjuvant chemotherapy on plasma TAFI and PAI-1 levels in operable breast cancer.

An increased incidence of thromboembolic events has been described in women receiving systemic chemotherapy for breast cancer. The effect of anthracycline-based adjuvant chemotherapy regimens on fibrinolytic system markers of plasminogen activator inhibitor-1 (PAI-1) and thrombin activitable fibrinolysis inhibitor (TAFI) was investigated in patients with operable breast cancer. Twenty-four patients with operable breast cancer (median age, 54.5 years; range, 37-72 years) enrolled in our study. Stage I-II and stage IIIA cases received EC (Epirubicin 90 mg/m(2)/d1, I.V. and cyclophosphamide 600 mg/m(2)/d1, I.V.) and FEC (5-fluorouracil 500 mg/m(2)/d1, I.V., epirubicin 100 mg/m(2)/d1, I.V., and cyclophosphamide 500 mg/m(2)/d1, I.V.) as an adjuvant chemotherapy regimen, respectively. Each group consisted of 12 patients. Blood samples were obtained at baseline and just before the third cycle of EC and fourth cycle of FEC chemotherapy regimens. Plasma TAFI antigen and PAI-1 levels did not disclose any statistical difference between basal and postchemotherapy levels within each group and between two groups. Although postchemotherapy D-dimer levels were statistically higher in the FEC group than in the EC group, results in both groups were within normal ranges. More studies concerning the role of fibrinolytic system in breast cancer patients receiving chemotherapy, probably including cases with advanced stage and with different chemotherapy regimens and dose intensities, are needed.

Primary non-hodgkin lymphoma of breast in a patient with rectal carcinoma and magnetic resonance spectroscopic examination.

A 62-year-old woman being treated for stage IIIC rectal adenocarcinoma was diagnosed with primary non-Hodgkin lymphoma of the breast after a 4-year follow-up. This case illustrates the importance of close and long-term follow-up as well as of differential diagnostic procedures for second primary malignancies after the initial diagnosis and treatment of a solid tumor.

Toxicity induced by the chemical carcinogen 7,12-dimethylbenz[a]anthracene and the protective effects of selenium in Wistar rats.

7,12-Dimethylbenz[a]anthracene (DMBA), a polycyclic aromatic hydrocarbon (PAH), has been used extensively as a tool to initiate mammary carcinogenesis and subsequent chemoprevention. On the other hand, selenium (Se) is potentially useful in oncology because this element possesses anticarcinogenic and chemopreventive properties. Se-containing enzymes such as glutathione peroxidase (GPx) play an important role in PAH metabolism and detoxification. In this study, rats were administered a single, oral dose of DMBA (12 mg). In the Se group, rats received 20 microg Se daily via gavage, starting 2 wk before the DMBA administration and continued for 1 wk. One hundred twenty days after DMBA administration the rats were sacrificed and toxicity was evaluated using histopathological and biochemical criteria. Five rats (30%) died in the DMBA group within the study period, whereas no death occurred in the DMBA-Se-treated group. Malignant tumor frequency was 33% in the DMBA group, while no malignant tumors occurred in the DMBA-Se-treated group. Some inflammatory changes rather than epithelial changes were found upon histopathological examination. GPx activity and blood urea nitrogen levels were higher and kidney GST activity was lower in the DMBA-Se-treated group compared to DMBA alone. In conclusion, Se appears to be effective in preventing some of the adverse effects associated with DMBA.

False negative bone scintigraphy in a patient with primary breast cancer: a possible transient phenomenon of bisphosphonate (alendronate) treatment.

Breast cancer is the most common cancer and the second leading cause of cancer deaths among women in developed countries. Bone is a frequent site of metastatic disease with a stage-dependent incidence. Most women with breast cancer are at risk of osteoporosis due to their age or their breast cancer treatment. Scintigraphy enables imaging of the entire skeleton with high sensitivity but limited specificity. The false positive rate varies from 1.6% to as high as 22%, while the false negative rate varies from 0.96% to 13%. We observed a 70-year-old woman with a diagnosis of breast cancer and a false negative bone scan despite extensive bone metastases. She was under alendronate treatment for osteoporosis at the time. The false negative finding might be due to a transient phenomenon of alendronate, a bisphosphonate cleared from the plasma by uptake into bone and by renal excretion. 99mTc-MDP is eliminated via the same pathways, and therefore competition may occur between the two substances. Another possible explanation for the false negative bone scan could be that bone metastases, indicating hematogenous tumor spread, are detected earlier by CT scan or MRI than by bone scan. Breast cancer patients under bisphosphonate treatment for osteoporosis must be carefully evaluated for bone metastasis during radionuclide studies with 99mTc-MDP.

The development of pulmonary adenocarcinoma in a patient with Job's syndrome, a rare immunodeficiency condition.

The hyperimmunoglobulin E (HIE) (Job's) syndrome often has it onset in childhood and is characterized by markedly elevated serum IgE levels, chronic dermatitis and recurrent pyogenic infections. Lymphoid malignancies have most commonly been associated with this syndrome while the first case in the literature of carcinoma associated with HIE syndrome was a squamous cell carcinoma of the vulva, described by Clark et al. in 1998. We observed a male patient with Job's syndrome diagnosed at age three who presented with bone pain and a metastatic epithelial tumor of the bone revealed by biopsy. Diagnostic procedures aimed at detecting the primary site showed multiple mediastinal lymph nodes with lung and liver metastases on computed tomography scans and an extradural spinal metastasis at the upper thoracic level on magnetic resonance imaging. Although the patient refused a bronchoscopic procedure, a diagnosis of pulmonary adenocarcinoma was established on the basis of sputum cytology and the clinical aspects of tumor extent. Intravenous corticosteroids and palliative radiotherapy were given for the spinal metastasis. Palliative chemotherapy could not be started because of the patient's poor performance status as well as nosocomial fungal pneumonia and pseudomonal urogenital infection with bacteremia. Despite the antifungal and broad-spectrum antimicrobial treatments, the patient died of pseudomonal sepsis.

Rapid tumor lysis syndrome in a patient with metastatic colon cancer as a complication of treatment with 5-fluorouracil/leucoverin and irinotecan.

Tumor lysis syndrome is a potentially fatal complication of anti-cancer therapy that is usually seen in patients with bulky, rapidly proliferating, treatment-sensitive tumors such as hematological malignancies, but it rarely occurs in a variety of solid tumors such as colorectal carcinoma. Combination chemotherapy with infusional 5-fluorouracil/leucoverin and irinotecan has been recently accepted as the first treatment option for metastatic colorectal cancer. We present a case of tumor lysis syndrome in a patient with metastatic colon carcinoma that occurred 72 hrs after the initial course of a combination chemotherapy with irinotecan and 5-fluorouracil/leucoverin. Despite the immediate treatment with aggressive hydration by a sodium bicarbonate infusion, followed by forced diuresis and uricolytic therapy, he died of a sudden cardiac arrest complicated by acute renal failure. Our case indicates that administration of 5-fluorouracil/leucoverin and irinotecan for bulky tumors of colorectal origin with a rapid doubling time may induce an acute tumor lysis syndrome, which necessitates frequent laboratory monitoring and a close follow-up of the patient as well as prompt initiation of appropriate therapeutic measures.

Paclitaxel-carboplatin induced radiation recall colitis.

Some chemotherapeutic agents can "recall" the irradiated volumes by skin or pulmonary reactions in cancer patients who previously received radiation therapy. We report a recall colitis following the administration of paclitaxel-containing regimen in a patient who had been irradiated for a carcinoma of the uterine cervix. A 63-year-old woman underwent a Wertheim operation because of uterine cervix carcinoma. After 8 years of follow-up, a local recurrence was observed and she received curative external radiotherapy (45 Gy) to the pelvis. No significant adverse events were observed during the radiotherapy. Approximately one year later, she was hospitalized because of metastatic disease with multiple pulmonary nodules, and a chemotherapy regimen consisting of paclitaxel and carboplatin was administered. The day after the administration of chemotherapy the patient had diarrhea and rectal bleeding. Histological examination of the biopsy taken from rectal hyperemic lesions showed a radiation colitis. The symptoms reappeared after the administration of each course of chemotherapy and continued until the death of the patient despite the interruption of the chemotherapy. In conclusion, the probability of recall phenomena should be kept in mind in patients who received previously with pelvic radiotherapy and treated later with cytotoxic chemotherapy.

A patient with nonfunctional pancreatic neuroendocrine tumor and incidental metachronous colon carcinoma detected by positron emission tomography: case report.

Pancreatic neuroendocrine tumors constitute about 2% of all gastrointestinal neoplasms. Approximately half of the pancreatic euroendocrine tumors are nonfunctional. Due to lack of specific symptoms, most patients with nonfunctional pancreatic neuroendocrine tumors present with locally advanced or metastatic disease. Second primary malignancies are seen very rarely in these patients. Colon carcinoma ranks third in frequency among primary sites of cancer in both men and women in western countries. Presence of a metachronous colon adenocarcinoma in a patient with nonfunctional pancreatic neuroendocrine tumor has not been reported before. We present a patient who had an asymptomatic mass in the head of the pancreas, detected by ultrasonography in 1996. The patient did not consent to operation. In 2002, after the diagnosis of an unresectable, nonfunctional pancreatic neuroendocrine tumor, interferon alpha- 2b and octreotide were started. A year after biological treatment, he refused further treatment. In 2004, during the evaluation of dissemination of the asymptomatic disease, positron emission tomography revealed a high uptake by the descending colon despite the failure of other imaging methods. After surgery for operable colon carcinoma, the patient received chemotherapy and biological therapy for both tumors. Since 2005, he has been doing well without any further treatment thus far. In conclusion, computerized tomography/magnetic resonance imaging and octreotide scintigraphy may be insufficient to show disseminated disease and asymptomatic second primary malignancies. Therefore, positron emission tomography is a valuable promising option for the evaluation of gastroenteropancreatic neuroendocrine tumors and concomitant or metachronous malignancies. Lifelong follow-up by a multidisciplinary oncology team is needed so that a long-term survival can be achieved with integrated multimodal systemic treatment approaches.

Cardiotoxicity of de Gramont's regimen: incidence, clinical characteristics and long-term follow-up.

BACKGROUND: The incidence of 5-fluorouracil (5-FU)-related cardiotoxicity seems to be dosage and schedule dependent. It was reported as 1.6-3% with earlier bolus regimens whereas this increased up to 7.6-18% with prolonged (4-5 days) infusion regimens. Knowledge of the cardiotoxicity incidence in patients treated with the widely used de Gramont's regimen (2 days infusional 5-FU) and the long-term follow-up of affected patients is still limited. METHODS: We investigated the incidence and clinical characteristics of the cardiotoxicity of de Gramont's regimen and long-term follow-up of the affected patients. RESULTS: Nine of a total of 231 patients receiving de Gramont's regimen experienced cardiac events, revealing an overall incidence of 3.9%. Four (2.5%) cases were receiving de Gramont's regimen only. Cardiac manifestations were acute coronary syndrome (n = 6), congestive heart failure (n = 2) and atrial fibrillation (n = 1). Cardiotoxicity occurred in the first cycle in eight patients, and in the second cycle in one. The median onset day was day 2. Cardiac symptoms occurred mostly at night time (seven patients) and the onset was a few hours after the bolus part of the regimen in four out of seven patients. After the cardiotoxicity, treatments were continued safely without 5-FU. CONCLUSIONS: de Gramont's regimen has a lower incidence of cardiotoxicity compared with more prolonged 5-FU-based infusion regimens. Nevertheless, patients should still be carefully monitored especially in the first cycles and at night time.

The effect of apoptotic activity, survivin, Ki-67, and P-glycoprotein expression on prognosis in pancreatic carcinoma.

OBJECTIVES: The pathogenetic mechanisms that regulate the aggressive behavior of pancreatic cancer still remain to be clarified. Alterations in the apoptotic pathway and proliferative activity of tumor cells as well as mechanisms contributing to the intrinsic drug resistance of pancreatic tumors have been investigated. Survivin is a recently described antiapoptotic protein, which, when overexpressed, is associated with worse prognosis in a majority of tumors. P-glycoprotein, a product of multidrug resistance gene-1 (MDR-1) was reported to be expressed in drug-resistant tumors. The purpose of this study was to investigate whether apoptosis, its regulation by survivin, tumor cell proliferation, and P-glycoprotein expression have a significant role on the biologic behavior of pancreatic adenocarcinoma. METHODS: Tumors of 45 patients with pancreatic adenocarcinoma were studied for the detection of survivin, P-glycoprotein, and Ki-67 expression by immunohistochemical method and apoptotic index by TUNEL method. Immunohistochemical staining was scored and Ki-67 and apoptotic indices were expressed as percentage of stained cells. RESULTS: Immunohistochemistry for survivin and P-glycoprotein revealed positive staining in 7 (15.4%) and 36 (79.5%) of the 45 tumors, respectively. The mean Ki-67 proliferative index was 43.75 +/- 25.30%. The mean apoptotic index evaluated with the TUNEL method was 37.12 +/- 34.55% for the whole group. We found no significant association between apoptotic index, expressions of survivin and P-glycoprotein, and clinicopathologic variables and survival. CONCLUSIONS: Apoptotic activity, survivin, and P-glycoprotein expression failed to predict the disease extent and biologic behavior in pancreatic adenocarcinoma in our cases.

Gastric cancer diagnosed in a patient with crescentic glomerulonephritis.

Malignant neoplasms are rarely associated with glomerular changes. The glomerular lesion seen most often in patients with malignancies is membranous glomerulonephritis. We report here a case of gastric cancer associated with rapidly progressive glomerulonephritis (RPGN). A 57-year-old man was admitted to our hospital with acute renal failure. Renal biopsy was performed, and the diagnosis was RPGN. Steroid treatment was instituted, but was complicated by hematemesis, and an early-stage gastric cancer was found after endoscopic examinations. Gastric biopsy revealed gastric adenocarcinoma. The patient's renal function improved with corticosteroid treatment and hemodialysis, and total gastrectomy was performed. The improvement in renal function persisted after the removal of the gastric cancer, and the RPGN and cancer have been in remission for 3 years.

Gemcitabine combined with infusional 5-fluorouracil and high-dose leucovorin for the treatment of advanced carcinoma of the pancreas.

BACKGROUND: 5-Fluorouracil (5-FU) and gemcitabine are the major active drugs in the treatment of pancreatic cancer. METHODS: Twenty-two patients with advanced pancreas cancer were treated with a new chemotherapy regimen consisting of infusional 5-FU and high-dose leucovorin with gemcitabine (GEMFUFOL). RESULTS: A total of 200 cycles of chemotherapy were administered. The response rate was 27.3%, all responses being partial. The median survival time and 1-year survival rate were, respectively, 13 months and 60.4%. The toxicity was very low and severe hematological toxicity was exceptional. CONCLUSION: The GEMFUFOL regimen can be an active regimen for the treatment of advanced pancreatic cancer and has a low toxicity.