Primary tumor resection for initially staged IV breast cancer: An emphasis on programmed death-ligand 1 expression, promoter methylation status, and survival.

Conventional therapy modalities for advanced breast cancer are problematic, whereas checkpoint blockade immunotherapy has been considered as a promising approach. This study aims to determine programmed death-ligand 1 (PD-L1) expression and methylation status of PD-L1 promoter in primary tumor tissue and metastatic foci of patients with stage IV breast cancer.Clinicopathological data and survival rates of 57 breast cancer patients, who were initially staged IV, and operated for intact tumors, were retrospectively analyzed. Immunohistochemical analysis of PD-L1 using 57 primary tumors, 33 paired metastatic lymph nodes, and 14 paired distant metastases was performed. Additionally, the methylation rate of the PD-L1 gene promoter region was determined with real-time polymerase chain reaction (PCR) analysis in 38 samples.Overall PD-L1 expression in primary tumors was 23.1% (12/52). PD-L1 positivity was reduced in lymph nodes by 15.2% (5/33) and in distant metastases by 21.4% (3/14). PD-L1 expression diverged between primary and metastatic foci in a subset of cases (18.2% for lymph node and 33.3% for distant metastasis). In general, the PD-L1 promoter was not methylated, and mean methylation rates were low (min. 0%-max. 21%). We observed no correlation between PD-L1 expression, promoter methylation, and survival.Neither the expression nor the methylation status of PD-L1 in patients, who were presented with stage IV breast cancer and operated for an intact primary tumor, had a statistically significant relation with survival. Discordance in PD-L1 expression between primary tumor and metastasis should be considered during pathological and clinical management of patients who would undergo checkpoint blockade therapy.

Liposome-mediated intraperitoneal interleukin 10 gene transfer increases survival in cecal litigation and puncture model of sepsis.

Interleukin 10 (IL-10) has been considered to alleviate the inflammatory cytokine response in various models of sepsis. Although being regarded as a key immunomodulator molecule to be beneficial for the treatment of sepsis, recombinant IL-10 treatment is limited by efficacy and tolerability. We tested a novel approach and conducted i.p. liposomal IL-10 gene transfer 24 h before the cecal ligation and puncture in mice and observed 75% mortality at the end of the 7th day. The mortality was 100% in the group where the gene transfer was not performed. The transgene expression is observed mainly in the endothelium in all vital organs. The results demonstrate the advantageous role of de novo IL-10 synthesis in early stages of sepsis and suggest the beneficial impact of gene transfer approach to recombinant protein infusions.

Human telomerase reverse transcriptase mRNA is highly expressed in normal breast tissues and down-regulated in ductal carcinoma in situ.

Telomerase is a ribonuclear protein that maintains telomere length in eukaryotic cells. Activation of the human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, has been implicated in cellular immortalization and may play a critical role in carcinogenesis. Prior studies in DCIS have been small, and used polymerase chain reaction (PCR)-based methods on heterogeneous tissue extracts. In this study, we used in situ hybridization to determine the cell type and topographic expression pattern of hTERT mRNA in a large series of cased in normal breast ductal-lobular units and ductal carcinoma in situ (DCIS). A total of 120 breast samples were evaluated. High level of hTERT mRNA expression was observed in both normal breast ductal-lobular units and DCIS, which showed a very heterogeneous expression pattern. Overall, hTERT mRNA expression was significantly higher in normal cells compared to DCIS (p=0.000). These results suggest that hTERT not only plays an important role in breast cancer progression but it is also involved in regulating the cellular function of normal breast ductal-lobular units. This finding challenges the conventional view that hTERT mRNA expression is repressed in somatic cells but activated in neoplastic cells. Our results also suggest that telomerase reverse transcriptase mRNA expression may play an important role in the homeostasis of normal breast epithelial cells and neoplastic cells do not necessarily have increased level of expression of hTERT.

In situ human telomerase reverse transcriptase expression pattern in normal and neoplastic ovarian tissues.

Telomerase is a ribonuclear protein reverse transcriptase that maintains telomere length in eukaryotic cells. Activation of telomerase has been implicated in human cellular immortalization and carcinogenesis. Telomerase activity in ovarian neoplasm has been studied using polymerase chain reaction (PCR)-based methods and shown to be correlated with malignancy. However, we believe those results must be interpreted with caution because such studies used a heterogeneous mix of cells, including normal cell type known to express telomerase when activated. The present study used in situ hybridization that allows determination of the type of cells expressing telomerase, as well as the intensity of that expression, in ovarian neoplasms. A total of 75 specimens were studied. Epithelial telomerase reverse transcriptase mRNA expression was detected in 28 of 31 epithelial ovarian carcinomas, 1 of 1 malignant granulosa cell tumor, 7 of 9 serous borderline ovarian tumors, 11 of 11 mucinous borderline ovarian tumors, 4 of 5 serous cystadenofibromas, 2 of 4 serous cystadenomas, 8 of 8 mucinous cystadenomas, and 0 of 6 normal ovaries except the corpus luteum. Telomerase expression is heterogeneously found in both benign and malignant epithelial tissues. We conclude that human telomerase reverse transcriptase mRNA expression does not seem to be a reliable marker for clinical use in differentiating between benign and malignant tumors.

Endotoxin challenge causes a proinflammatory state in obstructive jaundice.

The aim of this study was to investigate the relationship between the obstructive jaundice-induced cellular immune suppression and endotoxin challenge with respect to the levels of tumor necrosis factor (TNF), interleukin-10 (IL-10), and interleukin-2 (IL-2). Rats underwent either bile duct ligation or sham operation. At 21 days, all rats were challenged either with lipopolysaccharide (LPS) or saline. In the sham-operated group LPS injection significantly increased TNF levels at 90 min. The common bile duct ligated group showed a significant increase in TNF levels compared with all other groups, including the sham-operated, LPS-injected group, at 90 min. At 180 min following LPS challenge, TNF levels decreased, and there was no difference between any of the LPS-challenged groups at 180 min and any of the saline groups at either 90 or 180 min. In the sham-operated group, LPS injection significantly increased IL-10 levels at both 90 and 180 min. In the bile duct ligated group, LPS injection significantly increased IL-10 levels compared with saline injection at both 90 and 180 min. On the other hand, bile duct ligated animals had significantly less increase in IL-10 levels following LPS challenge at 90 min but not at 180 min. In common bile duct ligated rats, LPS challenge induced a significantly greater increase in IL-2 levels compared with all other groups. In conclusion, in the presence of obstructive jaundice, endotoxemia primes a more vigorous inflammatory response despite cellular immune depression.

Efficiency of ultrasound and ultrasound-guided fine needle aspiration cytology in preoperative assessment of axillary lymph node metastases in breast cancer.

PURPOSE: We performed this study to detect preoperative axillary metastases with ultrasound (US)-guided fine needle aspiration biopsy (FNAB), to eliminate the need for time-consuming and costly sentinel lymph node (SLN) scintigraphy and biopsy steps in the treatment of breast cancer patients, and in that of with suspicious US findings, and to evaluate the accuracy of preoperative US-guided FNAB for patients with suspicious lymph node metastases on US. METHODS: Patients with a suspicious breast lump or histopathologically proven breast cancer underwent breast-axillary US. Increase in lymph node size, cortical thickening, non-hilar cortical flow, and hilar changes were evaluated with gray scale-color Doppler US. FNAB was performed if US results were suspicious for malignancy. RESULTS: Thirty-eight axillary lymph nodes (ALN) underwent FNAB. ALN dissection, SLN scintigraphy, and biopsy steps were bypassed in 23 axillas with positive ALN FNAB (60.5%). The sensitivity of ALN FNAB was 88.46%; specificity and positive predictive value were 100%; and negative predictive value was 66.6% (inadequate cytology included; 76.7%, 100%, 100%, 53.3%, respectively). Asymmetrical cortical thickening, non-hilar cortical flow, and increase in hypoechogenity were only detected in metastatic nodes. Cortical thickening, and lymph node and breast mass size was higher in the metastatic group. CONCLUSION: By performing FNAB on suspicious lymph nodes, the routine, high-cost SLN scintigraphy and intraoperative gamma probe steps may be skipped, and axilla dissection can be performed directly. This leads to the elimination of the need for SLN investigation in more than half of the patients. The assessment of ALN metastases with preoperative US-guided FNAB is a cost-effective method with high specificity, that eliminates the need for costly and time-consuming SLN scintigraphy and biopsy steps, and helps in preoperative staging.

Interleukin-10 gene transfer: prevention of multiple organ injury in a murine cecal ligation and puncture model of sepsis.

INTRODUCTION: The aim of this study was to determine the effect of immunoregulatory cytokine interleukin-10 (IL-10) gene therapy on multiple organ injury (MOI) induced by a cecal ligation and puncture (CLP) model of sepsis in mice. METHODS: Male Balb/c mice subjected to CLP were treated with either an hIL-10-carrying vector or an empty control vector. We assessed the degree of lung, liver, and kidney tissue destruction biochemically by measuring myeloperoxidase (MPO) and malondialdehyde (MDA) activity. Histologic assessments were based on neutrophil infiltration in lung and liver tissue. IL-10 protein expression was examined immunohistochemically, and ultrastructural changes in the liver were studied by transmission electron microscopy. We analyzed the expression of tumor necrosis factor-alpha (TNFalpha) mRNA by reverse transcription polymerase chain reaction 3, 8, and 24 hours after CLP in all organs. RESULTS: Organ damage was significantly reduced by hIL-10 gene transfer, which was associated at the tissue level with reduced MPO activity in the liver, lung, and kidney and decreased leukocyte sequestration and MDA formation in the lung. The liver MDA was not significantly higher in the hIL-10 gene therapy group than in the controls and seemed not to be affected by hIL-10 gene transfer. The reduced portal tract neutrophilic infiltration and preserved ultrastructure of the hepatocytes also showed that tissue function was not impaired. The lung and kidney TNFalpha mRNA expression was suppressed markedly in the hIL-10 gene therapy group, but liver TNFalpha mRNA expression varied over time. CONCLUSIONS: These findings showed that IL-10 gene therapy significantly attenuated sepsis-induced MOI.

Spontaneous recanalization of superior mesenteric artery occlusion following angioplasty and stenting of inferior mesenteric artery.

An 84-year-old woman with a history of hypertension and coronary artery disease was admitted with a progressively worsening diffuse abdominal pain. Computed tomography scan of the abdomen and angiography revealed occlusion of the origin and proximal portion of superior mesenteric artery. Aortography also showed severe origin stenosis of inferior mesenteric artery and that the distal part of the superior mesenteric artery was supplied by a prominent marginal artery of Drummond. Patient was effectively treated with percutaneous transluminal angioplasty and stenting of the inferior mesenteric artery. Follow-up imaging studies demonstrated patency of the stent and spontaneous recanalization of superior mesenteric artery occlusion.

Surgical treatment of chronic amebic colitis.

There are limited data concerning the surgical management of chronic amebic colitis (CAC) in the literature. We present our experience with 10 patients with CAC treated surgically. Patients' records were retrospectively analyzed for age, sex, duration of clinical manifestations, colonoscopic findings, the type of surgical operation, and the postoperative course. Total proctocolectomy and J-pouch construction was performed in two patients who had CAC with severe rectal involvement. Total colectomy and the Hartmann procedure was performed in eight patients with mild to moderate rectal involvement. This treatment was successful in preserving the rectum in four of the eight. Our results suggest that rectal preservation can be a reliable treatment option in patients with CAC who have mild to moderate rectal involvement. Total proctocolectomy and ileoanal anastomosis with pouch construction should be the treatment of choice for patients with CAC who have severe rectal involvement.

Amebic perforation of the colon: rare and frequently fatal complication.

Amebic colitis perforation is a rare clinical form of amebiasis characteristically associated with high morbidity and mortality. We here present our series of eight patients with amebic colitis perforation. These patients represent 5% of 150 patients hospitalized during the same period for chronic amebic colitis. Only 50% of our patients had a correct preoperative diagnosis, and signs of generalized peritonitis such as rebound tenderness or muscular rigidity were not as common as might have been expected. Our mortality rate was 50% despite aggressive surgical treatment. Every effort should be made to have an early diagnosis, which would lead to early treatment with antiamebic agents, earlier and more limited surgery, and improved survival of these patients.

Integrated breast diseases research and cancer registry in Turkey.

A system we call BDRS is implemented as an integrated disease specific system for breast diseases in order to obtain and use patient health data for clinical research, cancer registry and clinical care. It is an open, flexible and modular system that supports multi-institutional and multi-viewed utilization of health data. Three-tier web based architecture, and object oriented technologies have been employed to ensure its extendibility. Exchange and sharing of health data have been implemented with XML.

Telomerase in breast cancer: a critical evaluation.

Human chromosomes have highly specialized structures at their ends termed telomeres, repetitive, non-coding DNA sequences (5'-TTAGGG-3'), ranging in size from 5 to 20 kb in human cells. These highly specialized structures prevent chromosome ends from being recognized as double-strand DNA breaks, and they also provide protection from destabilizing agents. The mechanism for maintaining telomere integrity is controlled by telomerase, a ribonucleoprotein enzyme that specifically restores telomere sequences lost during replication by using an intrinsic RNA component as a template for polymerization. Telomerase has two core functional components required for its activity: the catalytic subunit of human telomerase reverse transcriptase (hTERT) and a telomerase RNA template (hTR). Telomerase is activated in the majority of immortal cell lines in culture and in most malignant tumors. This review outlines our current understanding of telomerase in breast cancer development and critically evaluates potential utilities in diagnosis, prognosis, and therapy.