Aylin Fidan Korcum

High TRAIL death receptor 4 and decoy receptor 2 expression correlates with significant cell death in pancreatic ductal adenocarcinoma patients.

Objectives: The importance of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL receptor expression in pancreatic carcinoma development is not known. To reveal the putative connection of TRAIL and TRAIL receptor expression profile to this process, we analyzed and compared the expression profile of TRAIL and its receptors in pancreatic tissues of both noncancer patients and patients with pancreatic ductal adenocarcinoma (PDAC). Methods: Thirty-one noncancer patients and 34 PDAC patients were included in the study. TRAIL and TRAIL receptor expression profiles were determined by immunohistochemistry. Annexin V binding revealed the apoptotic index in pancreas. Lastly, the tumor grade, tumor stage, tumor diameter, perineural invasion, and number of lymph node metastasis were used for comparison purposes. Results: TRAIL decoy receptor 2 (DcR2) and death receptor 4 expression were up-regulated in PDAC patients compared with noncancer patients, and the ductal cells of PDAC patients displayed significant levels of apoptosis. In addition, acinar cells from PDAC patients had higher DcR2 expression but lower death receptor 4 expression. Increased DcR2 expression was also observed in Langerhans islets of PDAC patients. Conclusions: Differential alteration of TRAIL and TRAIL receptor expression profiles in PDAC patients suggest that the TRAIL/TRAIL receptor system may play a pivotal role during pancreatic carcinoma development.

High levels of endogenous tumor necrosis factor-related apoptosis-inducing ligand expression correlate with increased cell death in human pancreas.

Objectives: Type 1 diabetes (T1D) has been characterized by the T cell-mediated destruction of pancreatic &bgr; cells. Although various members of the tumor necrosis factor (TNF) family, such as Fas ligand or TNF, have recently been implicated in the development of T1D, the lack of TNF-related apoptosis-inducing ligand (TRAIL) expression or function facilitates the onset of T1D. Thus, the goal of the present study was to investigate the expression profiles of TRAIL and its receptors in human pancreas. Methods: Pancreata of 31 patients were analyzed by immunohistochemistry using antibodies developed against TRAIL and its receptors. Apoptosis was confirmed by Annexin V-fluorescein isothiocyanate binding and terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick end labeling assays. Results: Acinar cells displayed high levels of TRAIL and death receptor 4, but only low levels of death receptor 5. In contrast, only TRAIL and TRAIL decoy receptors (DcR1, DcR2) were detected in ductal cells. Similarly, Langerhans islets expressed only TRAIL and TRAIL decoy receptor. High levels of TRAIL expression in pancreas correlated with increased number of apoptotic cells. Conclusions: Although the expression of TRAIL decoy receptors might be necessary for defense from TRAIL-induced apoptosis, high levels of TRAIL may provide protection for Langerhans islets from the immunological attack of cytotoxic T cells.

Stage I small cell carcinoma of the endometrium: survival and management options

Small cell carcinoma (SCC) of the endometrium is a rare but aggressive disease with early systemic involvement. Patient survival is short. To date, no effective treatment protocol has been established. Surgery, radiotherapy, and chemotherapy have been used either alone or in combination. The case of a patient with stage IB endometrial SCC is presented with an overview based on all reported cases of SCC of the endometrium and its treatment with particular reference to stage I cases.

Effect of complementary and alternative medicine during radiotherapy on radiation toxicity

Goal of workTo examine the frequency and types of complementary and alternative medicine use in patients undergoing radiotherapy and to analyze the effects these therapies have on the toxicities of radiotherapy.Materials and methodsA total of 210 consecutive cancer patients undergoing radiation therapy were included. After radiation therapy, each patient completed a standard questionnaire, and the association between radiation toxicity and complementary and alternative medicine use was analyzed.Main resultsAmong the study population, 44.3% of patients reported using at least one form of complementary and alternative medicine during radiotherapy. The most commonly chosen complementary and alternative medicine was stinging nettle. Complementary and alternative medicine use decreased lower gastrointestinal (F = 3.26, P = .009) and genitourinary toxicities (F = 2.38, P = .043), while it increased laryngeal toxicity (F = 2.63, P = .028). A significant correlation between the type of complementary and alternative medicine used and the degree of these toxicities was not demonstrated.ConclusionsUse of complementary and alternative medicine among cancer patients during radiation therapy may affect the degree of radiation toxicity. Further randomized controlled clinical trials are needed to determine the benefits and risks of complementary and alternative medicine use during radiation therapy.

Radiotherapy-induced decreases in substance P levels may potentiate melanoma growth.

Substance P, a member of the tachykinin family, is expressed in primary invasive malignant melanomas, metastatic melanomas, melanomas in situ, atypical naevi, and spindle and epithelioid cell naevi. The role of substance P in cancer development and progression is not clear. Radiotherapy, which is used extensively in the treatment of malignancies, alters substance P levels. It is, however, not known whether radiotherapy affects substance P levels in melanomas or in the tumor microenvironment. Given the fact that melanomas express substance P, possible radiation-induced changes in substance P content may underlie their radio-resistance. Hence, the aim of the present study was to determine the effects of radiotherapy on the growth of B16F10 melanomas as well as on the tumor and systemic expression of substance P. In vivo exposure of tumor-bearing C5BL/6 mice to ionizing radiation (45 Gy administered in three fractions) arrested tumor growth for three weeks and induced 3-fold increases in survival, as well as decreasing substance P levels in primary tumors and the surrounding skin. Although radiotherapy was applied locally (1 x 1 cm) at the mid-flank region of the animal, it also induced systemic changes in the levels of substance P. Specifically, radiotherapy decreased substance P levels in skin distant from the radiation field as well as in the lungs and adrenals. In order to understand the significance of this effect, B16F10 cells and cells made from metastatic lesions (B16LNAD cells) were treated with substance P. Substance P inhibited the growth of B16F10 and B16LNAD cells and further potentiated the inhibitory effects of radiotherapy. These findings demonstrate for the first time that substance P inhibits melanoma growth, and that radiotherapy-induced decreases in substance P levels may underlie the radio-resistance of melanomas.

Activation of neuroimmune pathways increases therapeutic effects of radiotherapy on poorly differentiated breast carcinoma

Recent studies document the importance of neuronal dysfunction in cancer development and metastasis. We reported previously that both depletion of neuropeptides in capsaicin-sensitive sensory nerve endings and vagotomy increases metastasis of triple negative breast carcinoma. Of the sensory neuropeptides, Substance P (SP) is distributed widely for regulation of immune functions. We therefore examined the affects of continuous exposure to low doses of SP on brain metastatic cells of the mouse breast carcinoma (4TBM) in the presence of radiotherapy (RT) thought to increase antigenicity of cancer cells. 4TBM cells have a cancer stem cell phenotype and induce extensive visceral metastasis after orthotopic inoculation into the mammary pad. Results demonstrated that SP treatment decreases the number of tumor-infiltrating myeloid-derived suppressor cells as well as the TNF-α response to LPS challenge. SP also increased CD4+Cd25(bright) cells in draining lymph nodes of tumor-bearing animals and IFN-γ secretion from leukocyte culture prepared from lymph nodes and spleens of tumor-bearing animals. SP also prevented tumor-induced degeneration of sensory nerve endings and altered release of angiogenic factors from cancer-associated fibroblasts (CAF) and tumor explants. In accordance with these observed immunological effects, combination treatment of continuous SP with a single dose of RT induced complete tumor regression and significantly reduced or prevented metastasis in 50% of the animals while suppressing primary tumor growth and metastasis in the remaining mice. These original findings demonstrate that SP through neuroimmune modulation can prevent formation of immune suppression in the tumor microenvironment, enhance cytotoxic immunity in the presence of RT and prevent metastatic growth.

Thalidomide combined with irradiation alters the activity of two proteases.

The aim of the present study was to investigate the effects of thalidomide, a drug known for its anti‑angiogenic and antitumor properties, at its cytotoxic dose previously determined as 40 µg/ml (according to four cytotoxic test results). The effect of the drug alone and in combination with radiotherapy using Cobalt 60 (60Co) at 45 Gy on the enzymatic activity of substance‑P degrading A disintegrin and metalloproteinase (ADAM)10 and neprilysin (NEP) was investigated in the mouse breast cancer cell lines 4T1 and 4T1 heart metastases post‑capsaicin (4THMpc). Thalidomide (40 µg/ml) exerted differing effects on the activities of ADAM10 and NEP enzymes. In 4T1 cells, 40 µg/ml thalidomide alone did not alter ADAM10 enzyme activity. 60Co irradiation at 45 Gy alone caused a 42% inhibition in ADAM10 activity, however, the inhibition increased to 89% when combined therapy was used. By contrast, in the 4THMpc cell line, 40 µg/ml thalidomide alone induced a 66.6% increase in ADAM10 enzyme activity. Radiotherapy alone and thalidomide with 60Co combined therapy caused a 33.3 and 40% inhibition of ADAM10 activity, respectively. In 4T1 cells, thalidomide alone caused a 40.9% increase in NEP activity. Radiation therapy alone or in combination with the drug caused a 40.7% increase in NEP activity. In more aggressive 4THMpc cells, thalidomide alone caused a 26.6% increase in NEP activity. Radiotherapy alone and combined therapy caused a 33.3 and 37% increase in enzyme activity, respectively. To the best of our knowledge, the present study is the first to demonstrate that thalidomide alone or in combination with radiotherapy exhibits significant cytotoxic effects on 4T1 and 4THMpc mouse breast cancer cell lines indicating that this drug affects the enzymatic activity of ADAM10 and NEP in vitro.

The results of adjuvant radiotherapy in endometrial carcinoma

AIM To examine the clinical characteristics and treatment outcomes in patients with endometrial cancer receiving adjuvant radiotherapy. METHODS A total of 157 patients who received postoperative radiotherapy (RT) between 1999 and 2008 were evaluated, retrospectively. The mean age was 59 years (34-82). All patients received RT following surgery. Stage distribution was as follows: 92 patients (59%) stage I, 21 patients (13%) stage II, and 44 patients (28%) stage III. RESULTS Overall survival rate was 95% at 2 years and 84% at 5 years. By the end of follow up, 135 patients (86%) were disease-free, and 4 (2%) were alive with disease. Univariate and multivariate analyses identified stage, grade, and serosal involvement as significant predictors for overall survival. CONCLUSION The results of our study suggests that early stage, low-grade endometrial cancer with no serosal involvement is associated with a better survival and adjuvant radiotherapy is a well tolerated and effective therapeutic option.

Symptomatic Vertebral Hemangioma: Results of Radiotherapy

Objectives: To evaluate the efficacy of radiotherapy in treating vertebral hemangioma and review the literature. Methods: Radiotherapy was administered to 38 patients with medically refractory pain or to patients who had a hemangioma larger than one-third of the vertebral body. All patients received a total dose of 40 Gy in 20 fractions. The most frequently involved region was the lumbar spine [58 percent] followed by the thoracic region [21 percent]. Fourteen patients [37 percent] had multilevel involvement. Twenty-one patients also had several musculoskeletal disorders in the neighboring vertebrae. Results: A complete response was achieved in 22 patients [58 percent], partial response in 10 patients [26 percent], and no response in 6 patients [16 percent]. In patients with musculoskeletal disorders, complete, partial, and no response rates were 43 percent, 33 percent, and 24 percent, respectively. In patients with only a vertebral hemangioma, these same rates were 76.4 percent, 17.6 percent, and 6 percent, respectively; this difference was statistically significant [P = 0.03]. When sex, symptom duration, number of involved vertebrae, and location and size of the hemangioma were examined, there was no statistically significant relationship between these variables and the effect of radiotherapy on pain management. Conclusions: This large series involved 38 patients treated with a homogenous dose of radiation and fractionation schema. Radiotherapy is a relatively safe, effective, and tolerable treatment for symptomatic vertebral hemangiomas. Owing to the varying causes of pain for patients with musculoskeletal disorders with vertebral hemangioma, pain management may be an issue.

Breast and Tumor Bed

Radiotherapy (RT) following breast-conserving surgery is effective in improving local control and long-term survival. An additional boost to the tumor bed is also important to further decrease local recurrence after whole-breast irradiation. Precise delineation of RT target volumes and normal organs is critical for conformal RT. In this chapter, target volumes are defined and delineations of these volumes are also described according to the Radiation Therapy Oncology Group (RTOG) breast cancer atlas. Delineations are also shown in the treatment planning computed tomography (CT) scans from two patients who had undergone prior breast-conserving surgery.