Regulatory T Cells in Patients with Idiopathic Thrombocytopenic Purpura.

OBJECTIVE: Immune thrombocytopenic purpura (ITP) is an immune-mediated bleeding disorder in which platelets are opsonized by autoantibodies and destroyed by an Fc receptor-mediated phagocytosis by the reticuloendothelial system within the spleen. Autoimmune processes are also considered in the pathogenesis of this disorder. CD4+CD25+FoxP3+ regulatory T (Treg) cells and CD8+CD28- Treg cells have roles in autoimmune diseases. We investigated these regulatory cells in ITP patients. MATERIALS AND METHODS: We included 22 ITP patients and 16 age-matched healthy subjects. CD4+CD25+FoxP3+ Treg cells and CD8+CD28- cells were investigated by three-color flow cytometry. The ratios of these cell populations to total lymphocytes were calculated. Statistical analysis was carried out with the Mann-Whitney U test. RESULTS: CD4+CD25+ Treg cells were 9.69±3.70% and 12.99±5.58% in patients with ITP and controls, respectively. CD4+CD25highFoxP3+ cells were 27.72±19.74% and 27.55±23.98% in ITP patients and controls, respectively. The percentages of both of these cell types were not statistically significant when compared to the control group. CONCLUSION: We did not find any differences in ratios of CD4+CD25+FoxP3+ Treg cells or CD8+CD28- T cells in lymphocytes between patients and healthy subjects. We conclude that these circulatory cells are not different in ITP, but further studies are needed to explore the putative roles of these regulatory cells.

Long term survival with the combination of interferon and chemotherapy in metastatic melanoma.

The prognosis of metastatic melanoma is poor. Pre-targeted treatment era, the combination of interferon-α (IF-α) plus chemotherapy had been used and have generally short response duration. Herein, we present a metastatic melanoma case that achieved long-term durable complete response (CR) IF-α plus chemotherapy and IF-α maintenance therapy and had lower Regulatory T (Treg) cells. A fifty-year old woman was admitted to the hospital with metastatic melanoma. Lactate dehydrogenase (LDH) level was 660U/L. The percentage of CD4+CD25+ Treg cells was 2.4% in CD4+ lymphocytes. The IF-α plus chemotherapy and IF-α maintenance were administered. After six courses of chemotherapy, CR was achieved. Vitiligo and hypothyroidism occurred. The patient has remained in CR for approximately 7 years until second pleural metastases were detected and death. The patient has positive prognostic factors such as induction of autoimmunity, small tumor volume, mild elevated LDH level, and lower Treg cell percentage. She survived long term with CR after IF-α treatment with concurrent chemotherapy and maintenance. IF-α plus chemotherapy may be a treatment option for metastatic melanoma in selected cases who cannot reach new targeted drugs.

Broca's aphasia due to cerebral venous sinus thrombosis following chemotherapy for small cell lung cancer: A case report and review of literature.

Cancer is associated with an increased risk of cerebrovascular incidents and treatment with chemotherapy enhances that risk further. Brocha's aphasia is a stroke-related syndrome, the presentation of which has been rarely reported during cisplatin-based chemotherapy. The current study presents the case of a 27-year-old male with advanced-stage small cell lung cancer. The patient developed Broca's aphasia following cisplatin-based chemotherapy.

Long-term Survival after Lapatinib Rechallenge in Isolated Brain Metastasis of HER2-positive Breast Cancer.

Lapatinib is an effective drug in HER2-positive breast cancer. We present a case with successful treatment of lapatinib in brain metastasis of HER2+ breast cancer. Forty-eight years old woman was admitted our clinic with early breast cancer. In third years after adjuvant chemotherapy and trastuzumab, isolated and multiple brain metastasis were detected. After whole brain RT, lapatinib (with capecitabine for 10 months and with letrozole for 3 months) has been used. Volumetric reduction of lesions was achieved and symptoms disappeared. When lapatinib discontinued, brain metastasis relapses. Lapatinib plus capecitabine reinduction has been started. Totally, longer survival than 45 months was achieved after first brain metastasis detection. Because both combinations of lapatinib with capecitabine and letrozole were effective and reinduction treatment was successful, presented case has strongly supported activity of lapatinib treatment in brain metastasis of HER2+ breast cancer.

Malignant melanoma and papillary thyroid carcinoma that were diagnosed concurrently and treated simultaneously: A case report.

Malignant melanoma can be successfully treated when it is identified in its early stages, but the disease is associated with a poor prognosis when it is detected in an advanced stage. Papillary thyroid carcinoma is a thyroid cancer that has a good prognosis. The present study reports a rare case of malignant melanoma and papillary thyroid carcinoma that were diagnosed concurrently and treated simultaneously. The present patient was a 37-year-old male, in whom examination of a skin biopsy that was obtained from a lesion in the right retroauricular region revealed the lesion to be consistent with malignant melanoma. The patient underwent radical neck dissection upon the detection of malignant melanoma metastasis to the sentinel lymph node. Metastases of papillary thyroid carcinoma were detected in four out of 38 lymph nodes. The patient was then diagnosed with papillary thyroid carcinoma and underwent total thyroidectomy. The patient was administered with high-dose followed by moderate-dose interferon-α therapy for the treatment of malignant melanoma. The patient also received concurrent radioactive iodine therapy for the treatment of papillary thyroid carcinoma, at the same time as the interferon therapy. The two primary tumors of the patient were treated successfully. During therapy, no serious side-effects were observed, with the exception of fever caused by high-dose interferon therapy. Malignant melanoma and papillary thyroid carcinoma may occur concurrently, although this is rarely observed. The present study reports a rare case that demonstrates that the two tumors can be successfully treated simultaneously.

Mean platelet volume as a prognostic marker in metastatic colorectal cancer patients treated with bevacizumab-combined chemotherapy.

BACKGROUND: Recent studies have revealed a prognostic impact of the MPV (mean platelet volume)/platelet count ratio in terms of survival in advanced non-small cell lung cancer. However, there has been no direct analysis of the survival impact of MPV in patients with mCRC. The aim of the study is to evaluate the pretreatment MPV of patients with metastatic and non-metastatic colorectal cancer (non-mCRC) and also the prognostic significance of pretreatment MPV to progression in mCRC patients treated with bevacizumab-combined chemotherapy. MATERIALS AND METHODS: Fifty-three metastatic and ninety-five non-metastatic colorectal cancer patients were included into the study. Data on sex, age, lymph node status, MPV, platelet and platecrit (PCT) levels were obtained retrospectively from the patient medical records. RESULTS: The MPV was significantly higher in the patients with mCRC compared to those with non-mCRC (7.895±1.060 versus 7.322±1.136, p=0.013). The benefit of bevacizumab on PFS was significantly greater among the patients with low MPV than those with high MPV. The hazard ratio (HR) of disease progression was 0.41 (95%CI, 0.174-0.986; p=0.04). In conclusion, despite the retrospective design and small sample size, MPV can be considered a prognostic factor for mCRC patients treated with bevacizumab-combined chemotherapy.

HLA-G in testicular germ cell tumors.

BACKGROUND: HLA-G is a non-classical major histocompatibility complex class I molecule. HLA-G expression has been found in various types of solid and hematological malignancies. It is also expressed in normal testicular and epididymal tissue. However, expression of HLA-G in testicular germ cell tumors has not been extensively studied. The aim of this study was to investigate whether HLA-G protein is present in different components of testicular germ cell tumors. PATIENTS AND METHODS: 34 testicular cancer patients, for whom tumor tissue was available, were included in the study. Immunohistochemical staining was performed on tissue sections from formalin-fixed, paraffin-embedded tissue samples. RESULTS: 7 (20.6%) patients had positive HLA-G staining in at least 1 component of the tumor sample. In 3 of 7 patients with intratubular germ cell neoplasia, staining with HLA-G was seen in this component. All of the choriocarcinoma components were strongly positive, and about 40% of teratoma components had immunopositivity. The components of seminoma and embryonal carcinoma, and most yolk sac tumors were negative. HLA-G immuno-positivity was not associated with tumor size, retroperitoneal lymph node involvement, distant metastasis, or relapse/refractory status. CONCLUSION: This study demonstrated that testicular choriocarcinoma and some teratomas express HLA-G, but not seminoma, embryonal carcinoma, and yolk sac tumors.

MicroRNA-21 as an indicator of aggressive phenotype in breast cancer.

OBJECTIVE: The recently discovered microRNAs (miRNAs) are non-protein-coding, endogenous small RNAs. The aim of this study was to investigate the relationship between microRNA-21 (miR-21) and the clinicopathological features of breast cancer. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded (FFPE) tissue samples were collected from 15 patients who had undergone surgery for primary breast cancer. The miR-21 expression levels in normal and cancer tissues were analyzed using real-time quantitative reverse transcriptase polymerase chain reaction (real-time qRT-PCR). The correlations between the miR-21 expression level and the stage of disease, the tumor size, lymph node involvement, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, and disease-free survival (DFS) were investigated. RESULTS: The miR-21 expression levels were significantly higher in patients with stage III disease, patients with more than 3 axillary lymph node metastases and HER2-positive patients than in patients with stage I-II disease, patients with 1-3 axillary lymph node metastases and HER2-negative patients (p = 0.005, p = 0.037, and p = 0.014, respectively). Patients with high miR-21 expression level had a significantly shorter DFS than patients with low miR-21 expression level (median DFS: 18 and 56 months, respectively; p = 0.004). CONCLUSION: These results show that miR-21 is an indicator of an aggressive breast cancer phenotype and that it may be a new therapeutic target in the treatment of breast cancer in the future.

Nesfatin-1 in advanced lung cancer patients with weight loss.

The cachexia occurs frequently in lung cancer patients. Among appetite regulatory peptides, alteration of expressions of leptin and ghrelin is demonstrated in cachectic cancer patients, but nesfatin-1 has not been yet studied in cancer. We investigated serum nesfatin-1 level in advanced lung cancer patients. Forty-one lung cancer patients and 24 healthy subjects were included to the study. Nesfatin-1 serum levels were analyzed by ELISA kit. Serum nesfatin-1 levels were lower in lung cancer patients than in healthy subjects (0.52±0.19ng/ml vs 0.75±0.23ng/ml; p<0.001). In lung cancer patients with weight loss, nesfatin-1 levels were decreased compared to the patients without weight loss (0.44±0.16ng/ml vs 0.63±0.18ng/ml; p<0.001). Whereas, there were no any difference between patients without weight loss and control subjects (0.63±0.18ng/ml vs 0.75±0.23ng/ml; p:0.129) or between SCLC and NSCLC patients (0.53±0.18ng/ml vs 0.52±0.20ng/ml; p:0.458). No significant correlation was found between serum nesfatin-1 values and BMI. In conclusion, loss of fat mass may decrease serum nesfatin-1 level in lung cancer patients with weight loss. The future studies which explore biological significance of low serum nesfatin-1 level in cancer are needed.

Immunoregulatory function of HLA-G in gastric cancer.

BACKGROUND: Human leukocyte antigen (HLA)-G-positive gastric cancers are associated with poor survival, but links with tumor escape mechanisms remain to be determined. MATERIALS AND METHODS: We used immunohistochemistry to investigate HLA-G expression, tumor infiltrating CD8+ T lymphocytes, and Treg cells in 52 gastric cancer patients. RESULTS: There were 29 cancer-related deaths during the follow-up period. Kaplan-Meier analysis indicated that patients with HLA-G-positive (n=16) primary tumors had a significantly poorer prognosis than patients with HLA-G-negative tumors (n=36, p=0.008). The median survival time was 14 months and 47 months, respectively. Patients with high numbers of Tregs and low numbers of CD8+T lymphocytes in the primary tumor had a poorer prognosis than those with low numbers of Tregs and high numbers of CD8+T lymphocytes (p=0.034, p=0.043). Multivariate Cox proportional hazard regression analysis showed that HLA-G expression (hazard ratio: 2.662; 95% confidence interval: 1.242-5.723; p=0.012) and stage (hazard ratio: 2.012;95% confidence interval: 1.112-3.715; p=0.041) were independent unfavorable factors for patient survival. CONCLUSIONS: We found a significant positive correlation between HLA-G expression and the number of tumor infiltrating Tregs (p=0.01) and a negative correlation with the number of CD8+T lymphocytes (p=0.041). HLA-G may protect gastric cancer cells from cytolysis by inducing Foxp3+Treg lymphocytes and suppressing CD8+T lymphocytes.

Clinicopathological features and survival of young Turkish patients with testicular germ cell tumors.

BACKGROUND: Testicular germ cell tumors (TGCTs) are a relatively common malignancy in young men. The aim of this study was to investigate the clinicopathological features and survival of young Turkish patients with TGCT. MATERIALS AND METHODS: In this retrospective study, the clinical and pathological characteristics of young Turkish patients with TGCT who were monitored by the Department of Medical Oncology of a military hospital between 2008 and 2013 were investigated. Overall survival data were analyzed. RESULTS: Ninety-six patients were included in the study. The mean age was 26.4 years. Among the patients, 17.7% had seminoma and 43.8% had mixed non-seminomatous germ cell tumors. Some 46.9% were Stage I, 30.2% were Stage II, and 22.9 were Stage III. Of the patients, 83.3% received chemotherapy, 25% underwent retroperitoneal lymph node dissection (RPLND), 3.1% received radiotherapy, and 12.5% were followed-up without treatment. In addition, 18.8% of the patients were administered salvage chemotherapy due to relapse or progression. The 5-year overall survival rate was 90.2% for all patients. The 2-year overall survival rate was 100% for Stage I patients, 94% for Stage II patients, and 70.2% for Stage III patients. The difference between the survival curves of stages was statistically significant (p=0.029). CONCLUSIONS: In young Turkish patients with TGCT, good results were obtained with appropriate treatment, most receiving chemotherapy. The prognosis of the disease was good even in the advanced stage.

Mean platelet volume increase after tamoxifen, but not after anastrazole in adjuvant therapy of breast cancer.

AIM: To investigate differences of platelet indices in breast cancer patients after tamoxifen (tmx) and anastrazole adjuvant treatment. METHODS: In this retrospective study, 46 postmenopausal women (20 with tmx and 26 with anastrazole) with breast cancer who received adjuvant hormone therapy were enrolled. The biochemical and complete blood count (CBC) parameters were documented before hormone treatment start and after 1 year. RESULTS: The lymphocyte count was higher after tmx use, but not anastrazole. Total white blood cells were increased both after 1-year tmx and anastrazole using. Mean platelet volume (MPV) increased after tmx use (8.2 +/- 0.94-8.97 +/- 0.97; P: 0.041), while it was not different after anastrazole use (7.96 +/- 1.08-7.89 +/- 0.99; P: 0.585). Other platelet parameters did not alter with tmx or anastrazole treatment. CONCLUSION: We found increased MPV after tmx treatment, but did not after anastrazole treatment. The advanced studies which explore biological significance of high MPV in breast cancer patients used endocrine therapy, should be established.

CD8+CD28- cells and CD4+CD25+ regulatory T cells in the peripheral blood of advanced stage lung cancer patients.

AIM: To evaluate the CD8+CD28- and CD4+CD25+ regulatory T (Treg) cells in addition to other some lymphocyte subgroups in peripheral blood of advanced stage lung cancer patients. METHODS: The study group (n = 28) comprised chemotherapy and radiotherapy naïve patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The control group (n = 22) consisted of age- and sex-matched healthy volunteers. Flow cytometry was used to count T cells, natural killer (NK) cells and CD4+CD25 Treg cells, and for CD8+ T cell subgroup analysis. Flow cytometry was performed and annexin V binding was used for apoptotic cell evaluation. RESULTS: In patient group, the percentage of CD8+CD28- cells among lymphocytes was elevated, and there was also an increase in the CD28-/CD28+ cell ratio among CD8 lymphocyte population. The distribution of CD8 cells was different in lung cancer patients when compared with the control group. The absolute count of CD4+CD25(bright) cells and the percentages of these cells among total lymphocytes were higher in the patient group. The Annexin V(+) cell percentages among CD8+CD28- and CD8+CD28+ lymphocytes were higher in the patient group than in the control group. No differences were found between the NSCLC and SCLC patients with respect to the hematological parameters and the distribution of lymphocyte subgroups. In NSCLC patients, the percentage of CD8+CD28- cells among the lymphocyte population was higher in patients with stage IV than those with stage III. CONCLUSION: These findings may reflect the possibility of tumor-induced immunosuppression and they should be complemented with further studies.

Hemicentral retinal artery occlusion in a breast cancer patient using anastrozole.

BACKGROUND: Anastrozole, an aromatase inhibitor, is commonly used in the adjuvant treatment of breast cancer. Anastrozole treatment is associated with a risk of thromboembolic events and retinal vascular side effects. Herein, we present a case of hemi-central retinal artery occlusion diagnosed in a breast cancer patient using anastrozole. CASE REPORT: A 53-year-old woman with a hypertensive and diabetic background was admitted to our hospital with breast cancer. Anastrozole treatment was started after surgery, adjuvant chemotherapy, and radiotherapy. Sudden painless loss of vision in the patient's right eye occurred within 13 months of Anastrozole treatment. A fluorescein angiogram revealed hemi-central retinal artery occlusion. CONCLUSION: To the best knowledge of the authors, this is the first report of hemi-central retinal artery occlusion in an anastrozole user.

Cerebrovascular accident after chemotherapy for testicular cancer.

Arterial thromboembolic events are not common after chemotherapy. We present a case of a cerebrovascular accident, which developed after chemotherapy in a patient with a germ cell tumor. A 34-year-old man with a testicular germ cell tumor who did not have any comorbid disease was admitted to hospital. After a radical inguinal orchiectomy, BEP (bleomycin, etoposide, and cisplatin) chemotherapy regimen was given. On the 10th day of the third cycle, aphasia and hemiplegia developed. Cerebrovascular accident was diagnosed. This event is a rare complication in a patient receiving BEP chemotherapy who did not have cardiovascular disease or thromboembolic risk factors.

HLA-G expression in B chronic lymphocytic leukemia: a new prognostic marker?

Chronic lymphocytic leukemia (CLL) is characterized by a malignant clonal population of lymphocytes, which are usually of the B cell lineage. Classical Rai and Binet staging of CLL is being superseded by new prognostic markers. The mutational status of the immunoglobulin variable region heavy-chain genes segregates the disease into more benign and more malignant versions, and has been confirmed as an important prognostic marker in prospective clinical trials. A search for surrogate markers for this assay has led to flow cytometric assays for CD38 and ZAP-70 expression. The human leukocyte antigen G (HLA-G) molecule exhibits limited tissue distribution and a low polymorphism that generate seven HLA-G isoforms. HLA-G exerts multiple immunoregulatory functions. Recent studies indicate an ectopic up-regulation in tumor cells that may favor their escape from anti-tumor immune responses. For this report we studied HLA-G in parallel with CD38 and ZAP-70 in B-cell chronic lymphocytic leukemia (B-CLL) patients. HLA-G expression was studied retrospectively in circulating B-CLL cells from 20 patients by flow cytometry using the anti-HLA-G specific monoclonal antibody MEM/G9. The proportion of leukemic cells expressing HLA-G varied from 1 to 34%. We detected a statistically significant correlation between HLA-G positive (>12%) expression and progression free survival (p=0.045), but no correlation with CD38 and ZAP-70. We also detected a statistically significant difference between Binet stage A; B and C (p=0.046) and a positive correlation between IL-10 and HLA-G (p=0.044). We conclude that positive HLA-G has an effect on progression - free survival, when compared with CD38 and ZAP-70.

Posttreatment with aminoguanidine attenuates renal ischemia/reperfusion injury in rats.

Acute renal failure secondary to ischemia/reperfusion (I/R) injury is associated with significant mortality and morbidity. Aminoguanidine (AG), an inducible nitric oxide synthase inhibitor with antioxidant properties, has been reported beneficial in renal I/R injury. The aim of the present study was to investigate the effect of AG on renal I/R injury and compare the effectiveness of different AG treatment modalities. Sprague-Dawley rats were randomly assigned to one of four groups. The control group (n = 6) received sham operation. The I/R group (n = 6), AG-I group (n = 8), and AG-II group (n = 8) received bilateral renal ischemia for 45 min followed by 24 hours of reperfusion. The AG-I group received AG (50 mg/kg) intraperitoneally four hours and 10 minutes before the induction of ischemia. The AG-II group received AG (50 mg/kg) intraperitoneally four hours and 10 minutes after the initiation of reperfusion. Serum urea and creatinine levels increased significantly in the I/R and AG-I groups compared to the control group. Kidney samples from rats in the I/R and AG-I groups revealed severe tubular damage at histopathological examination. Posttreatment with AG significantly reduced serum urea and creatinine levels and improved histopathological lesions compared with the I/R group. Although pretreatment with AG failed to protect kidneys against I/R injury in this experimental model, posttreatment with AG attenuated renal dysfunction and histopathological changes after I/R injury.

Results of combination therapy with amifostine, pentoxifylline, ciprofloxacin and dexamethasone in patients with myelodysplastic syndrome and acute myeloid leukemia.

Myelodysplastic syndrome (MDS) is a clonal disease of the bone marrow characterized by abnormal hematopoiesis and cytopenias. It has been shown that abnormal cytokine production together with apoptosis are major contributors to the cytopenias associated with the disorder. As the interaction of cytokines plays a role in the pathogenesis, suppression of the cytokine production by the administration of the combination of pentoxifylline, ciprofloxacin, and dexamethasone (PCD combination) has resulted in the correction of at least some aspects of the cytopenias in the majority of patients and in complete hematologic remission in a small percentage. The aminothiol prodrug amifostine, a compound to protect tissues from cytotoxic drugs and radiotherapy has been found to stimulate proliferation of normal hematopoiesis and suppress apoptosis in patients with MDS. In this study we report the results of combination therapy of amifostine and PCD in 12 patients with MDS and acute myeloid leukemia (AML). Amifostine was given in a dose of 200 mg/m(2), as an i.v. infusion administered in 10 min, three times a week; pentoxifylline 2400 mg/day, (3 x 800 mg) p.o.; ciprofloxacin, 1 g/day p.o.; dexamethasone 4.5 mg/day p.o. We achieved 66% response rate in our patients. In some cases responses were achieved in only thrombocytopenia or anemia whereas in others responses were achieved in multiple series. As a result it was found that amifostine + PCD combination may be beneficial in reversing cytopenias in the treatment of MDS and AML and is worth further study.