Umut Demirci

Imatinib mesylate-induced acute liver failure in a patient with gastrointestinal stromal tumors

Imatinib mesylate is a drug that has been approved for treatment of chronic myeloid leukemia, Philadelphia-positive acute lymphoblastic leukemia, and advanced gastrointestinal stromal tumors. Several cases of hepatotoxicity, including fatal liver failure, have been reported with the long-term use of imatinib mesylate. Generally hepatotoxicity resolves after discontinuation of imatinib. Despite discontinuation of imatinib, hepatotoxicity can be progressive. Steroid may be useful in these patients and should be started early. We report a 53-year-old woman with advanced gastrointestinal stromal tumors who developed hepatotoxicity while receiving imatinib and subsequently acute liver failure. Ten weeks after commencing imatinib treatment, hepatotoxicity was determined. Imatinib was immediately ceased. Subsequently, a week later hepatic encephalopathy, jaundice, and coagulopathy occurred. Prednisolone was commenced. Liver biopsy was performed five weeks after the determining of hepatotoxicity. Biopsy showed sinusoidal congestion, necrosis of hepatocytes, inflammation, and hepatocyte drop out around the hepatic venule consistent with drug toxicity. Her liver function tests normalized with a nine-week prednisolone treatment. The patient was discharged. Her liver enzymes remained in normal range following visits. In cases of imatinib-induced acute hepatitis, the administration of prednisolone may be useful in the resolution of the acute episode and allow the reintroduction of a drug without risking recurrence of hepatitis.

Efficiency and Side Effects of Sorafenib Therapy for Advanced Hepatocellular Carcinoma: A Retrospective Study by the Anatolian Society of Medical Oncology

BACKGROUND Inoperable and metastatic hepatocellular carcinoma (HCC) is associated with a poor prognosis and low chemotherapeutic efficiency. Sorafenib is an oral multi-kinase inhibitor exerting its effects via the RAF/ MEK/ERK pathway, vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor beta (PDGFR-β) tyrosine kinases. Randomized studies have shown a significant contribution of sorafenib to life expectancy and quality of life of cancer patients. The aim of the present study is to evaluate the efficacy and side effects of sorafenib therapy in Turkey. MATERIALS AND METHODS Data for 103 patients (82 males, 21 females) receiving sorafenib therapy in 13 centers from February 2008 to December 2012 were evaluated. Median age was 61 years and median ECOG performance status was 1 (range: 0-2). 60 patients (58%) had hepatitis B, 15 patients (15%) had hepatitis C infection and 12 patients (12%) had a history of alcohol consumption. All of the patients had Child scores meeting the utilization permit of the drug in our country (Child A). RESULTS A total of 571 cycles of sorafenib therapy were administered with a median of four per patient. Among the evaluable cases, there was partial response in 15 (15%), stable disease in 52 (50%), and progressive disease in 36 (35%). Median progression-free survival was 18 weeks and median overall survival was 48 weeks. The dose was reduced only in 6 patients and discontinued in 2 patients due to grade 3-4 toxicity, 18 patients (17%) suffering hand-foot syndrome, 7 (7%) diarrhea, and 2 (2%) vomiting. CONCLUSIONS This retrospective study demonstrated better efficacy of sorafenib therapy in patients with advanced HCC compared to the literature while progression-free survival and overall survival findings were comparable. The side effect rates indicate that the drug was tolerated well. In conclusion, among the available treatment options, sorafenib is an efficient and tolerable agent in patients with inoperable or metastatic HCC.

Efficacy and Safety of Concomitant Chemoradiotherapy with Cisplatin and Docetaxel in Patients with Locally Advanced Squamous Cell Head and Neck Cancers

BACKGROUND Chemoradiation (CRT) using cisplatin-based regimens has become the standard of care in the treatment of squamous cell head and neck cancers (SCHNC). The impact of taxanes as radiosensitizing agents with concurrent CRT regimens is unknown. We therefore retrospectively evaluated the efficacy and tolerability of a weekly cisplatin+docetaxel combination with CRT in locally advanced SCHNC. METHODS Sixty-six patients with locally advanced SCHNC (39.4% stage IV, 53% stage III, and 7.6% stage II) were assessed retrospectively. Total radiation dose to the PTV of gross disease (primary and/or node) was 70 Gy/ 35 fractions, 5 fractions per week. Minimum doses of 60 Gy and 50 Gy were administered to PTVs of elective high risk and low risk disease, respectively. Chemotherapy (CT) consisted of weekly cisplatin (20 mg/m2) +docetaxel (20 mg/m2) concurrently with RT. RESULTS The median age of the patients was 58 years (range, 32-77). Objective response rate was 83.3%. The 2-year progression-free survival (PFS) and overall survival (OS) were 75.7% and 78.3%, respectively. The most common grade 3 and 4 toxicities were mucositis (36.4%), nausea and vomiting (12.1%), neutropenia (4.5%). CONCLUSION Weekly cisplatin and docetaxel concurrent with RT for locally advanced SCHNC was found tolerable with high efficacy.

Discordances in HER2 status between primary gastric cancer and corresponding metastatic sites

OBJECTIVE Determination of human epidermal growth factor receptor-2 status in advanced gastric cancer is important in clinical decision making. In the trastuzumab for GC trial, trastuzumab-based therapy demonstrated a significant overall survival benefit in patients with human epidermal growth factor receptor-2-positive advanced gastric cancer. Human epidermal growth factor receptor-2 discordance in gastric cancer primary and its metastases has been long debated. The aim of the study was to evaluate the rate of human epidermal growth factor receptor-2 discordance and its effect on treatment decisions in advanced gastric cancer. METHODS A total of 74 patients with advanced gastric cancer were included in the study. Both immunohistochemical staining and dual-color silver in situ hybridization were performed in all patients to evaluate the human epidermal growth factor receptor-2 status of the primary lesion and paired metastasis. RESULTS The assessment of human epidermal growth factor receptor-2 status with the immunohistochemical staining method and dual-color silver in situ hybridization revealed a discordance rate of 9.5 and 16.2%, respectively. However, this discordance was clinically meaningful in only one patient leading to a change in treatment decision. While this patient had a human epidermal growth factor receptor-2-negative status in primary tumor (immunohistochemical = 0, dual-color silver in situ hybridization = negative), the human epidermal growth factor receptor-2 status was positive for liver metastasis (immunohistochemical = 2+, dual-color silver in situ hybridization = positive). Trastuzumab was added to the chemotherapy regimen. CONCLUSIONS In this study, we found a higher rate of human epidermal growth factor receptor-2 discordance between primary gastric tumor and metastatic lesions compared with the rates reported in previous studies. Detection of a human epidermal growth factor receptor-2-positive metastasis with a human epidermal growth factor receptor-2-negative primary tumor suggests that investigation of human epidermal growth factor receptor-2 is also required for the metastatic lesion and that trastuzumab could be administered in the case of a positive result.

Prognostic factors for lymph node negative stage I and IIA non-small cell lung cancer: multicenter experiences.

BACKGROUND Surgery is the only curative treatment for operable non-small lung cancer (NSCLC) and the importance of adjuvant chemotherapy for stage IB patients is unclear. Herein, we evaluated prognostic factors for survival and factors related with adjuvant treatment decisions for stage I and IIA NSCLC patients without lymph node metastasis. MATERIALS AND METHODS We retrospectively analyzed 302 patients who had undergone curative surgery for prognostic factors regarding survival and clinicopathological factors related to adjuvant chemotherapy. RESULTS Nearly 90% of the patients underwent lobectomy or pneumonectomy with mediastinal lymph node resection. For the others, wedge resection were performed. The patients were diagnosed as stage IA in 35%, IB in 49% and IIA in 17%. Histopathological type (p=0.02), tumor diameter (p=0.01) and stage (p<0.001) were found to be related to adjuvant chemotherapy decisions, while operation type, lypmhovascular invasion (LVI), grade and the presence of recurrence were important factors in predicting overall survival (OS), and operation type, tumor size greater than 4 cm, T stage, LVI, and visceral pleural invasion were related with disease free survival (DFS). Multivariate analysis showed operation type (p<0.001, hazard ratio (HR):1.91) and the presence of recurrence (p<0.001, HR:0.007) were independent prognostic factors for OS, as well visceral pleural invasion (p=0.01, HR:0.57) and LVI (p=0.004, HR:0.57) for DFS. CONCLUSIONS Although adjuvant chemotherapy is standard for early stage lymph node positive NSCLC, it has less clear importance in stage I and IIA patients without lymph node metastasis.

Intracystic papillary carcinoma of the breast: one of the youngest patient in the literature

A 29-year-old premenouposal women presented with bloody nipple discharge and mass in her left breast. Ultrasonography showed periareolar two solid and two cyctic masses in the ductal tract. Excisional biopsy was performed. Macroscopically, the size of the cyctic lesion was 1 9 1 cm in diameter and pathological examination showed intracystic papillary carcinoma (IPC) and intraductal carcinoma where IPC was in continuity in the 8 mm area. After excisional biopsy, left mastectomy and sentinel lymph node dissection (SLND) were performed. On pathological examination 0.5 cm residuel IPC was determined (Fig. 1). Immunohistochemical staining showed estrogen and progesteron receptor were positive Her2/neu was 2?, confirmed by the fluorosein in situ hybridization (FISH). There was no metastasis in sentinel lymph nodes. According to the TNM classification, the postoperative stage was T2N0M0 as stage IIA. After mastectomy we planned adjuvant endocrine therapy in this case. IPC is a non-invasive papillary carcinoma variant and accounts for 0.5–1% of all breast cancer. Although IPC was reported non-invasive carcinoma, generally associated with ductal carcinoma in situ (DCIS) around the main tumor or invasive carcinoma [1–4]. Papillary carcinomas were classified as invasive and non-invasive forms. The non-invasive form was divided into the diffuse form and the localized form. We present a case of IPC accompanying intraductal carcinoma. IPC generally occurs in older women, around 60–70 years as against other breast carcinomas [5, 6]. Although IPC commonly diagnosed in older women, our case is very young woman who is one of the youngest women in the literature. Our review of the literature, more than 1200 women and 50 men that affected IPC. The median age of these patients was 69 (range 27–99 years). There are no clear guidelines on how to treat the tumor [7]. Generally, IPC shows no invasive growth outside of the cyst and is treated similarly to DCIS [8, 9]. Several studies have shown IPC’s prognosis is excellent and recurrence rates low [3–5, 10–13]. In the present case, we performed mastectomy and SLN biopsy after excisional biopsy that confirmed histological diagnosis of cystic papillary carcinoma. After surgery she has been using adjuvant endocrine therapy. Surgical excision is the form the basis of treatment of IPC. Breast-conserving surgery and mastectomy have been used in the treatment. All interventions were not show differences than the other and all procedurs with a good prognosis [4, 7, 13]. The surgical management of IPC appears to parallel that of invasive ductal carcinoma, with a lower rate of breast conservation in older studies [4]. In addition to surgical excision, several studies have reported on the use of adjuvant radiation and/ or endocrine therapy in the management of IPC [4, 7, 13]. There is no consensus as to the role of axillary staging procedures for IPC [14]. Although many authors have suggested that IPC, be treated similar to DCIS it has been reported that, like IPC, DCIS with microinvasion has an 8– 14% incidence of axillary lymph node involvement. Therefore, sentinel lymph node biopsy has been recomended for these patients [15–17]. In conclusion, IPC is the most common appear in older women, however can also determined in younger women M. Baykara U. Coskun (&) U. Demirci R. Yildiz M. Benekli S. Buyukberber Department of Medical Oncology SD, Gazi University Medical School, Besevler, Ankara 06500, Turkey e-mail: ugurcos@hotmail.com

Synchronous testicular liposarcoma and prostate adenocarcinoma: a case report

Prostate adenocarcinoma is the most common malignancy and the second leading cause of cancer related deaths in men. Testicular liposarcomas are uncommon soft tissue neoplasms. We report coexistence of prostate cancer and testicular liposarcoma in a 69 year-old-man because while orchiectomy endications are decreasing day by day, these second malignancies should not be missed.

Hepatotoxicity associated with lapatinib in an experimental rat model

BACKGROUND The current study is the first to evaluate the biochemical and histopathological features of hepatic toxicity of lapatinib. METHODS Twenty Wistar albino rats were allocated into three groups: experimental toxicity was induced with lapatinib (10mg/kg) administered for 28 days (Group 1), 42 days (Group 2) orally in a single dose by gavage. Control group received only sterile water. Rats in Group 1 and Group 2 were sacrificed after the collection of blood and tissue samples on the 28th and 42nd days, respectively. RESULTS Subjects in Group 1 and Group 2 had significantly higher levels of alanin aminotransferase (ALT), albumin, triglyceride and very low density lipoprotein (VLDL) when compared with the control group. None of the subjects in the two experimental groups showed normal histology. There were parenchymal acinar transformation zones, sinusoidal dilatation, hydropic degeneration of hepatocytes, vacuolisation of hepatocytes around the portal areas, and mild inflammation with dominance of mononuclear cells besides neutrophil and eosinophil leucocytes in portal areas, especially pronounced in Group 2. CONCLUSION This study demonstrated that lapatinib brings about deterioration of lipid profile and triggers hepatic toxicity mainly as sinusoidal injury with elevation in transaminase levels, especially ALT.

Lymphoproliferative disorders in multiple primary cancers.

BACKGROUND Cancer survivors are at increased risk of second cancers. Lymphoproliferative disorders (LPD) are common neoplasms that are primary or subsequent cancers in cases of multiple primary cancer. We here analyzed metachronous or synchronous LPD in multiple primary cancers. METHODS Between 2001 and 2010, LPD were assessed retrospectively in 242 multiple primary cancers patients. RESULTS Forty nine (20.2%) patients with LPD were detected. Six patients had two LPD where one patient had three LPD. The median age of patients was 60.5 years (range: 28-81). LPD were diagnosed in 29 patients as primary cancer, in 23 patients as second cancer, and in three patients as third cancer in multiple primary cancers. Primary tumor median age was 56 (range: 20-79). Diffuse large B cell lymphoma (n=16), breast cancer (n=9), and lung cancer (n=6) were detected as subsequent cancers. Alklylating agents were used in 19 patients (43.2%) and 20 patients (45.5%) had received radiotherapy for primary cancer treatment. The median follow-up was 70 months (range: 7-284). Second malignancies were detected after a median of 51 months (range: 7-278), and third malignancies with a median of 18 months (range: 6-72). CONCLUSIONS In this study, although breast and lung cancer were the most frequent detected solid cancers in LPD survivors, diffuse large B cell lymphoma was the most frequent detected LPD in multiple primary cancers.

Low-dose docetaxel/cisplatin - leucovorin and 46 hour infusional fluorouracil in metastatic gastric carcinoma.

BACKGROUND Phase II and III trials of docetaxel, cisplatin and fluorouracil (DCF) have shown superior efficacy versus cisplatin and fluorouracil alone but with high rates of hematologic toxicity in metastatic gastric cancer cases. To reduce toxicity while maintaining the efficacy of DCF, we investigated low dose docetaxel (D), cispatin (C) - leucovorin and fluorouracil (De Gramont regimen). PATIENT AND METHODS Chemotherapy-naive patients with metastatic gastric cancer (MGC) received D 60 mg/m2 on day 1 and cisplatin 30 mg/m2 on day 1-2 and the De Gramont regimen (Folinic acid 400 mg/m2 on day 1 and 5-FU 2400 mg/m2/46 h continuous infusion) every 3 weeks. The primary endpoint was response rate. RESULTS One hundred twenty patients with a median age of 52.5 years (range, 32-78) received a median of 6 cycles (range, 2-12 cycles). Of the 120 evaluable patients, 4 showed complete remission and 36 achieved a partial response. The overall response rate was 56.6%. Twenty eight patients (23.3%) showed stable disease and 52 (43.3%) progression. The median time to progression was 7 months (95%CI 6-7.9). The median overall survival was 15 months (95%CI 13.7-16.2). The most frequent hematological toxicity was leucopenia, which occurred at grade 3/4 intensity in 24 patients (20%). CONCLUSIONS Low-dose DC- De Gramont regimen is active in MGC with a tolerable toxicity profile.