Correlations between CD34 Immunolabelled Blood Vessels and CD34 mRNA Expression in Colorectal Cancer.

PURPOSE: This study aims to determine the correlation between microvessel density of CD34 immunolabelled blood vessels and CD34 mRNA gene expression in colorectal cancer tissue. MATERIAL/METHODS: Standard immunohistochemistry and gene expression was perform on samples collected from 76 patients with colorectal cancer in order to determinate the number of CD34 immunolabelled blood vessels and the relative quantity of CD34 mRNA. RESULTS: For the study group, the mean CD34 immunolabelled microvascular density (MVD) was of 307/mm2, and the mean CD34 gene expression value for colon cancer was 2.303. The low p value (<0.001) of the Spearman correlation test showed a significant direct correlation between CD34 MVD and CD34 gene expression for the entire study group. CONCLUSIONS: CD34 gene`s expression can be looked at as a prognostic factor in colorectal cancer.

A phase 2a randomized controlled study to evaluate the pharmacokinetic, safety, tolerability and clinical effect of topically applied Umeclidinium in subjects with primary axillary hyperhidrosis.

BACKGROUND: Hyperhidrosis is a common medical condition which can have a significant impact on quality of life. Umeclidinium (UMEC) is a long-acting muscarinic antagonist (LAMA) developed as a dermal formulation. OBJECTIVES: This 2-week, double-blind, randomized, vehicle-controlled study evaluated systemic exposure, safety and tolerability of topically administered UMEC in subjects with primary axillary hyperhidrosis. Clinical effect was a secondary objective, measured by gravimetry and the hyperhidrosis disease severity scale (HDSS). Vehicle was included to evaluate safety. METHODS: Twenty-three subjects were randomized to either 1.85% UMEC (N = 18) or vehicle (N = 5) once daily. RESULTS: Measurable plasma concentrations were observed in 78% of subjects after the treatment. Nine subjects (50%) on UMEC and two subjects (40%) on vehicle reported AEs, most commonly application site reactions. At Day 15, seven subjects (41%) in UMEC and two subjects (40%) in vehicle had at least a 50% reduction in sweat production. Eight subjects (47%) in UMEC and one subject (20%) in vehicle had at least a two-point reduction in HDSS. No comparisons of treatment arms were planned prospectively. CONCLUSIONS: The measurable exposure, acceptable safety and preliminary clinical activity observed in this proof-of-concept study suggest the potential clinical utility of topical UMEC in subjects with axillary hyperhidrosis.

Squamous Esophageal Carcinoma Synchronous to Pericolic Malignant Conjunctive Tumor.

Esophageal carcinoma represents a great diagnostic and therapeutic challenge due to the anatomical situation and physiopathology of the disease. The medical challenge can be even greater since esophageal carcinoma can evolve concomitant to another malignant tumor with different localization. This paper's aim is to present a case of squamous esophageal cancer associated to another primitive malignant tumor-malignant pericolic conjunctive tumor, this kind of association being singular in medical literature from our knowledge. Upon emergency presentation the patient was sketching a sub-occlusive syndrome with mild anemia and inflammatory syndrome, somehow suggesting a possible right colon cancer. However, discreet upper digestive pole symptomatology that, on first sight, seemed secondary, made the consultant to perform a superior digestive endoscopy that raised a strong suspicion of early stage esophageal carcinoma. Further exploration was not completed because occlusive complication occurred and the patient needed emergency surgery. On laparotomy a stenotic right colic angle tumor was discovered that later proved to be extra-mucosal, with conjunctive origin. Our paper focuses on highlighting the crucial importance of the imagistic explorations in the primary diagnosis of esophageal carcinoma, in the correct staging (lymphatic extension, loco-regional or distant metastases) and also for malignant tumors with another localization that can radically modify the therapeutic strategy.

A Novel Method for Studying the Pharmacokinetics of [(14) C]Umeclidinium After Application to the Axilla or Palm of Healthy Male Subjects.

Umeclidinium (UMEC), a long-acting muscarinic antagonist approved for chronic obstructive pulmonary disease (COPD), was investigated for primary hyperhidrosis as topical therapy. This study evaluated the pharmacokinetics, safety, and tolerability of a single dose of [(14) C]UMEC applied to either unoccluded axilla (UA), occluded axilla (OA), or occluded palm (OP) of healthy males. After 8 h the formulation was removed. [(14) C]UMEC plasma concentrations (Cp) were quantified by accelerator mass spectrometry. Occlusion increased systemic exposure by 3.8-fold. Due to UMEC absorption-limited pharmacokinetics, Cp data from the OA were combined with intravenous data from a phase I study. The data were described by a two-compartment population model with sequential zero and first-order absorption and linear elimination. Simulated systemic exposure following q.d. doses to axilla was similar to the exposure from the inhaled therapy, suggesting that systemic safety following dermal administration can be bridged to the inhaled program, and offering the potential for a reduced number of studies and/or subjects.

Pharmacometrics: Focus on the Patient.

Pharmacometrics, whether using simple or complex models, has contributed to rational and efficient drug development,(1-3) with the main focus on early drug development.(4) This article describes why opportunities more directly focused on the patient abound in late stage development, illustrating the concept with three innovative examples which focus on benefits to patients, enabling drugs that are truly efficacious to reach the market faster in diseases with high unmet medical needs, while maintaining adequate safety.

Evaluation of Angiogenesis in Colorectal Cancer.

PURPOSE: Angiogenesis is an important step in the process of cancer growth. The purpose of this study was to determine the neoangiogenesis with CD31, CD34 and CD105, and tried to observe the differences between these three antibodies. MATERIAL/METHODS: The blood vessels stained with CD31, CD 34 and CD105 were counted, and we reported their number per square millimeter to obtain microvascular density (MVD). For angiogenesis quantification we determined the neoformation blood vessels with CD105. The CD31 and CD34 were used as control markers, in order to observe the difference between neoformation blood vessels and mature vessels. RESULTS: Comparing the average effective vessels marked with the 3 markers, Student t test showed that the mean number of blood vessels market with CD 34 is higher than blood vessels market with CD31 and CD 105. The value of the Student t test was highly significant in all three cases (p<0.001). By calculating the Pearson correlation coefficient for the relationship CD31-CD105 we obtained a value r = 0.440, which corresponds to p = 0.0013 < 0.05, indicating a statistically significant direct correlation between the two factors. CONCLUSIONS: An important number of vessels (around 40%) that can be found in tumor area are neoformation vessels, this concept being an important assessment for the choice of the correct and effective treatment in colorectal adenocarcinoma.

Correlations Between Intratumoral Microvessel Density and Histopathological Type or Neoadjuvant Radiotherapy for Rectal Carcinoma.

PURPOSE: This study aims to evaluate intratumoral microvessel density in rectal carcinoma cases with different histopathological type (adenocarcinoma and mucinous carcinoma) and different preoperatory neoadjuvant radiotherapy status (irradiated / non-irradiated) ,thus analyzing any possible statistical correlation between these parameters. MATERIAL AND METHODS: Our prospective study consists in standard immunohistochemistry procedures using CD34, CD31 and CD105 antibodies, which were performed on 25 samples of rectal carcinoma, in order to determine intratumoral microvessel density. RESULTS: The 25 case study group was divided either by histopathological type or by prior radiotherapeutical treatment as follows: 9 cases of mucinous carcinoma versus 16 cases of adenocarcinoma and 13 cases of rectal cancer that have not received neoadjuvant radiotherapy versus 12 cases of rectal cancer with preoperatory radiotherapy. CONCLUSIONS: The number of intratumoral microvessels is higher in non-irradiated rectal tumors and in adenocarcinomas, this remark being statistical significant (with only one exception - CD34 staining in non-irradiated versus irradiated tumors) for all types of vessels (new-grown and mature). This result is due to the benefic effect of neoadjuvant radiotherapy on decreasing angiogenic activity, thus having an important prognostic value for rectal cancer.

Autophagy and Neovascularization in Colorectal Cancer.

PURPOSE: This study aims to determinate the microvessel density at the base of the tumor, as well in tumor's mass, in order to determinate the number of neovascularization vessels (marked with CD105) in comparison with presence or absence of autophagy puncta. MATERIAL/METHODS: Standard immunohistochemistry was performed on 38 samples of colorectal adenocarcinoma, in order to determinate the presence of autophagy and neovascularization blood vessels with the help of LC3, CD34, CD31 and CD105 antibodies. RESULTS: The autophagy process was observed in the cancerous cells and was noted as present in both regions of interest from the tumor. The mean number of blood vessels market with CD105 is higher in tumor mass then at its base, p value of the Student t test being highly significant (p<0.0001). CONCLUSIONS: The presence of autophagy puncta was notice in every case, both in the mass of the tumor and at its base. Microvascular density of new-grown blood vessels is higher in the mass of the tumor compared with the base of the tumor.

Population pharmacokinetics of azithromycin in whole blood, peripheral blood mononuclear cells, and polymorphonuclear cells in healthy adults.

Azithromycin's extensive distribution to proinflammatory cells, including peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs), may be important to its antimicrobial and anti-inflammatory properties. The need to simultaneously predict azithromycin concentrations in whole blood ("blood"), PBMCs, and PMNs motivated this investigation. A single-dose study in 20 healthy adults was conducted, and nonlinear mixed effects modeling was used to simultaneously describe azithromycin concentrations in blood, PBMCs, and PMNs (simultaneous PK model). Data were well described by a four-compartment mamillary model. Apparent central clearance and volume of distribution estimates were 67.3 l/hour and 336 l (interindividual variability of 114 and 122%, respectively). Bootstrapping and visual predictive checks showed adequate model performance. Azithromycin concentrations in blood, PBMCs, and PMNs from external studies of healthy adults and cystic fibrosis patients were within the 5th and 95th percentiles of model simulations. This novel empirical model can be used to predict azithromycin concentrations in blood, PBMCs, and PMNs with different dosing regimens.

Problems of diagnosis and treatment caused by ingested foreign bodies.

An ingested foreign body often passes the gastrointestinal tract without any complications. Foreign bodies, such as fish bones, chicken bones and toothpicks, have been known to cause perforation of the gastrointestinal tract. We present 4 cases: the first 2 of a 27-year-old male and a 48-years-old female respectively, with acute abdomen, diffuse purulent peritonitis, with ileum perforation, both caused by accidentally ingesting a wire, 1 case of a 64-year-old male with sigmoid perforation, caused by accidentally ingesting a toothpick and 1 case of a 52-year-old female presented with left buttock painful swelling for 1 week associated with fever,physical examination revealed an ischiorectal abscess.During incision and drainage a 3 cm chicken bone was found inside the abscess cavity. Evolution was favorable in all 4 cases.

Development of a population pharmacokinetic model to describe azithromycin whole-blood and plasma concentrations over time in healthy subjects.

Azithromycin (AZI), a broad-spectrum antibiotic, accumulates in polymorphonuclear cells and peripheral blood mononuclear cells. The distribution of AZI in proinflammatory cells may be important to the anti-inflammatory properties. Previous studies have described plasma AZI pharmacokinetics. The objective of this study was to describe the pharmacokinetics of AZI in whole blood (concentration in whole blood [Cb]) and plasma (concentration in plasma [Cp]) of healthy subjects. In this study, 12 subjects received AZI (500 mg once a day for 3 days). AZI Cb and Cp were quantified in serial samples collected up to 3 weeks after the last dose and analyzed using noncompartmental and compartmental methods. After the last dose, Cb was greater than Cp. Importantly, Cb, but not Cp, was quantifiable in all but one subject at 3 weeks. The blood area under the curve during a 24-h dosing interval (AUC24) was ∼2-fold greater than the plasma AUC24, but simulations suggested that Cb was not at steady state by day 3. Upon exploration of numerous models, an empirical 3-compartment model adequately described Cp and Cb, but Cp was somewhat underestimated. Intercompartmental clearance (CL; likely representing cells) was lower than apparent oral CL (18 versus 118 liters/h). Plasma, peripheral, and cell compartmental volumes were 439 liters, 2,980 liters, and 3,084 liters, respectively. Interindividual variability in CL was low (26.2%), while the volume of distribution variability was high (107%). This is the first report to describe AZI Cb in healthy subjects, the distribution parameters between Cp and Cb, and AZI retention in blood for up to 3 weeks following 3 daily doses. The model can be used to predict Cb from Cp for AZI under various dosing regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01026064.).

Pancreatic true cysts--diagnosis and treatment difficulties.

Pancreatic true cysts represent a rare, heterogeneous group of pancreatic tumors; therapeutic strategy is based on patient's general status, cyst topography, and especially the estimated risk of malignancy. This paper aim is to present 7 cases of pancreatic true cysts, operated on a six years period (January 2004-January 2010) in our surgical clinic: 2 men and 5 women, aged between 24-61 years old; cyst diameter varies between 3.5-15 cm, tumor location being pancreatic head in two cases and the distal pancreas in 5 cases. Surgical treatment consisted in cyst enucleation (two cases), splenopancreatectomy (three cases), duodenopancreatectomy (one case), and subtotal splenopancreatectomy (one case). Histology was represented by serous cystadenoma (one case), mucinous cystadenoma (2 cases), intraductal papillary mucinous cystadenoma (one case), and papillary cystadenocarcinoma (3 cases).Postoperative results were good in all cases, with 3 postoperative pancreatic external fistulas, resolved conservatory; no case of post-pancreatectomy diabetes mellitus was registered. In conclusion, surgical removal of the pancreatic cystic tumors is necessary, especially due to the risk of malignancy, at least in the absence of rigorous histological proofs of benignancy. Postoperative results are favorable in terms of postoperative morbidity and mortality.

Carcinoid tumour of the appendix: problems of diagnosis and treatment.

Carcinoids (neuroendocrine tumours) are considered the most common primary appendiceal neoplasm. Primary appendiceal tumours are uncommon. Routine histopathological examination of appendicectomy specimens is justified given the not infrequent incidental finding of appendiceal tumours. In cases of appendicitis in the elderly, the index of suspicion for epithelial tumours of the appendix should be raised. Moreover, once the diagnosis of an adenomatous lesion is made, colonoscopic examination of the entire large bowel is mandatory given the frequency of synchronous colorectal neoplasia in our population. In our study, we review 3 cases of carcinoid tumor of the appendix and describe their presentation, treatment and outcome. They are often diagnosed incidentally after histopathological examination of the vermiform appendix submitted in the course of the management of another clinical diagnosis. Appendectomy is appropriate for lesions < 1 cm but for lesions over 2 cm in diameter there is a significant increase in metastatic spread and thus right hemicolectomy is required in such cases. Appendiceal carcinoid tumours are found in 0,3 - 0,9 per cent of patients undergoing appendicectomy. Controversy exists over the management following appendicectomy, especially with regard to the role of right hemicolectomy in patients with tumours smaller than 2 cm in diameter.

[Postoperative enteral feeding in digestive anastomosis with proximal oesophageal partner]. / Nutritia enterala postoperatorie în anastomozele digestive ce au ca partener proximal esofagul.

This paper aim is to discuss the advantages of enteral postoperative feeding on patients submitted to surgery finalized through an eso-digestive anastomosis; in these cases enteral feeding is often delayed 5-8 days after the surgery, and in case of an anastomotic dehiscence may be even impossible. Also, the paper promotes duodenostomy as an important enteral feeding way, and discusses the indications and contraindications of different enteral nutrition pathways in such cases. There were studied 230 cases, 149 cases submitted to cancer surgery and 81 cases with benign condition surgery followed by an eso-digestive anastomosis, in which the following enteral nutrition pathways was practiced: nasogastric or naso-esojejunal feeding tube (55 cases); Witzel jejunostomy (28 cases); gastrostomy (79 cases); duodenostomy (68 cases). Postoperative morbidity induced exclusively by the enteral nutrition pathway was encountered in 36% of patients. On patients with an eso-gastric cervical anastomosis or esogastric thoracic anastomosis we used jejunostomy as enteral feeding path and a gastric tube passed by pyloric canal for gastric decompression. In cases of esophageal reconstruction for benign esophageal strictures gastrostomy remains the best feeding method. Duodenostomy was practiced as a feeding pathway in cases of total gastrectomy with esojejunal anastomosis, with closure of the duodenal stump.

[Soft tissue sarcoma--problems of diagnosis and treatment]. / Sarcoamele de parti moi--probleme de diagnostic si tratament.

Soft tissue sarcomas are a rare group of cancers compromising 1% of all malignancies and there has been a slight increase in incidence. We present 3 cases of soft tissue sarcomas (the tumors were located to the right axilary region, perianal and dorsale face of the left leg) hospitalized in 2nd Surgical Clinic of Emergency Hospital of Craiova and we discuss the difficulties of diagnosis and treatment. The classification and characterization of soft-tissue sarcomas have evolved as the information supplied by histologic analysis has been supplemented with that provided by immunohistochemical analysis. Surgical resection involving wide margins, with or without radiotherapy, offers the best chance of cure in the absence of metastatic disease. There is little evidence that local recurrence increases the likelihood of metastatic spread, although debate on this point continues. Except for rhabdomyosarcomas and Ewing's sarcomas, the use of adjuvant chemotherapy generally does little to influence the natural history of the disease. In conclusion surgical treatment is mainstay of treatment for soft-tissue sarcomas and is usefull the prompt diagnosis for decrease the risk of local recurrence and metastatic disease.

Synchronous squamous esophageal carcinoma and urothelial renal cancer.

Synchronous development of a second primary cancer in patients with esophageal squamous cell carcinoma was reported in 2.73%-11% of the cases. Although the synchronous association between esophageal and renal cancer is very rare, an increasingly number of cases is reported in medical literature. This study's aim is to report a case of synchronous esophageal squamous cell carcinoma and an urothelial carcinoma of the right kidney. Patient G.D. was admitted in our clinic with esophageal cancer diagnosis; during the preoperative work-up protocol, an asymptomatic right renal mass was discovered. A nephroureteroscopy with biopsy was performed and the urothelial renal cancer diagnosis was established. The patient is proposed for seriate surgery: nephroureterectomy on the first stage, then esophagectomy with gastric reconstruction was performed. Postoperative evolution was unfavourable, patient being finally discharged, on his request, with severely altered status.

[Esophago-digestive anastomosis dehiscence]. / Dehiscenta anastomozelor esofagodigestive.

This paper aim is to discuss the main etiopathogenic aspects responsible for eso-digestive anastomotic leakage, as well as prophylactic and therapeutic measures of this postoperative complication. There were studied 173 consecutive eso-digestive anastomosis: 103 anastomosis performed for malignancy and 70 anastomosis for benign conditions. Surgical operations followed by an eso-digestive anastomosis were: esophageal reconstruction for benign esophageal caustic strictures (n=67); total gastrectomy (n=55); total esophagectomy (n=13); total esophagectomy plus total gastrectomy (one case); eso-gastrectomies (n=34); upper gastric pole resection (n=2); distal esophageal resection (n=1). Eso-digestive anastomosis topography were cervical (n=81), intrathoracic (n=37) and abdominal (n=57). There were 30 eso-gastrostomies, 81 eso-jejunostomies, and 62 eso-colostomies. There were recorded 24 eso-digestive anastomotic dehiscences (13.8%): 14 in the cervical region (17.2% out of 81 cervical anastomosis); 5 intrathoracic leakages (14.2% out of 35 anastomosis); 5 intraabdominal anastomotic dehiscences (8.7% out of 57 intraabdominal anastomosis). Four patients died as an anastomotic leakage consequence: two patients died after cervical eso-gastrostomy dehiscences, one patient died after an intrathoracic eso-jejunostomy leakage, and one patient died after intraabdominal eso-gastrostomy leakage. In conclusion, we analyze postoperative results, emphasizing the role of discovering and removal of predisposing factors which may lead to an eso-digestive anastomotic leakage.

An inhibitor-resistant mutant of Hck protects CML cells against the antiproliferative and apoptotic effects of the broad-spectrum Src family kinase inhibitor A-419259.

Chronic myelogenous leukemia (CML) is driven by Bcr-Abl, a constitutively active protein-tyrosine kinase that stimulates proliferation and survival of myeloid progenitors. Global inhibition of myeloid Src family kinase (SFK) activity with the broad-spectrum pyrrolo-pyrimidine inhibitor, A-419259, blocks proliferation and induces apoptosis in CML cell lines, suggesting that transformation by Bcr-Abl requires SFK activity. However, the contribution of Hck and other individual SFKs to Bcr-Abl signaling is less clear. Here, we developed an A-419259-resistant mutant of Hck by replacing the gatekeeper residue (Thr-338; c-Src numbering) in the inhibitor-binding site with a bulkier methionine residue (Hck-T338M). This substitution reduced Hck sensitivity to A-419259 by more than 30-fold without significantly affecting kinase activity in vitro. Expression of Hck-T338M protected K-562 CML cells and Bcr-Abl-transformed TF-1 myeloid cells from the apoptotic and antiproliferative effects of A-419259. These effects correlated with persistence of Hck-T338M kinase activity in the presence of the compound, and were accompanied by sustained Erk and Stat5 activation. In contrast, control cells expressing equivalent levels of wild-type Hck retained sensitivity to the inhibitor. We also show for the first time that A-419259 induces cell-cycle arrest and apoptosis in primary CD34(+) CML cells with equal potency to imatinib. These data suggest that Hck has a nonredundant function as a key downstream signaling partner for Bcr-Abl and may represent a potential drug target in CML.

[A rare cause of peritoneal fistula]. / Fistula abdominala de cauza neobisnuita.

The abdominal pregnancy is an extremely rare variety of the ectopic pregnancy. The symptoms are atypical, which causes a delay in putting the diagnosis, which is established most of the times when complications appear, which are always severe, and endanger the patients lives. This paper presents a rare complication of the abdominal pregnancy, at about 6 months old, stopped in evolution, complicated by an abscess, generalised peritonitis and peritoneal fistula. The diagnosis and treatment of the abdominal ectopic pregnancy are discussed.

[Gastric volvulus--complication of a large paraesophageal hiatal hernia]. / Volvulusul gastric--complicatie posibila in herniile hiatale paraesofagiene mari.

The authors present the case of a patient with a large paraesophageal hiatal hernia complicated with organo-axial gastric volvulus. We discuss problems of diagnosis and therapeutical options.