Endocervical Cytology: Inter- and Intra-Observer Variability in Conventional Pap Smears.

INTRODUCTION: Although the cytological diagnostic criteria for cervical squamous and glandular lesions are established by the Bethesda System for Reporting Cervical Cytology, the reproducibility of the diagnosis of these lesions has been shown to be variable in previous studies. At best, occasional good kappa (κ) values were reached both inter- and intra-observerly. Generally, consensus on high-grade lesions has been better compared to milder changes. METHODS: Altogether, 167 conventional Pap smears from 50 patients with histologically confirmed endocervical adenocarcinomas (EAC) and adenocarcinomas in situ (AIS) and from 28 patients with histologically proven high-grade intraepithelial lesions were analyzed by four cytopathologists. Twenty of the smears were later re-evaluated by the same cytopathologists. κ-values between cytopathologists in the categories of squamous versus glandular, negative for intraepithelial lesion or malignancy (NILM), atypical, and preneoplastic/neoplastic were calculated. The diagnostic Pap smears of EAC and AIS with best and worst consensus between observers were then morphologically analyzed. RESULTS: The reproducibility ranged from poor to substantial. The overall κ-values between the four cytopathologists were 0.412, 0.314, 0.272, and 0.082, respectively, in the categories of preneoplastic/neoplastic, squamous versus glandular, NILM, and atypical. Overall intra-observer κ-values were correspondingly 0.491, 0.616, 0.345, and 0.241. In the diagnostic smears of AIS and EAC, the nuclear size >2 times the normal and nuclear pleomorphism were the commonest features associated with good diagnostic consensus and the lack of nuclear enlargement and degenerative changes were associated with poor consensus. CONCLUSIONS: The reproducibility of preneoplasia/neoplasia diagnoses was better than that of atypia and NILM both in the inter- and intra-observer part in this study. In the smears from AIS and EAC patients, general neoplasia-associated features were more common in samples with good agreement by the four cytopathologists of the neoplastic nature and the endocervical origin of the lesion.

Point-of-Care Digital Cytology With Artificial Intelligence for Cervical Cancer Screening in a Resource-Limited Setting.

Importance: Cervical cancer is highly preventable but remains a common and deadly cancer in areas without screening programs. The creation of a diagnostic system to digitize Papanicolaou test samples and analyze them using a cloud-based deep learning system (DLS) may provide needed cervical cancer screening to resource-limited areas. Objective: To determine whether artificial intelligence-supported digital microscopy diagnostics can be implemented in a resource-limited setting and used for analysis of Papanicolaou tests. Design, Setting, and Participants: In this diagnostic study, cervical smears from 740 HIV-positive women aged between 18 and 64 years were collected between September 1, 2018, and September 30, 2019. The smears were digitized with a portable slide scanner, uploaded to a cloud server using mobile networks, and used to train and validate a DLS for the detection of atypical cervical cells. This single-center study was conducted at a local health care center in rural Kenya. Exposures: Detection of squamous cell atypia in the digital samples by analysis with the DLS. Main Outcomes and Measures: The accuracy of the DLS in the detection of low- and high-grade squamous intraepithelial lesions in Papanicolaou test whole-slide images. Results: Papanicolaou test results from 740 HIV-positive women (mean [SD] age, 41.8 [10.3] years) were collected. The DLS was trained using 350 whole-slide images and validated on 361 whole-slide images (average size, 100 387 × 47 560 pixels). For detection of cervical cellular atypia, sensitivities were 95.7% (95% CI, 85.5%-99.5%) and 100% (95% CI, 82.4%-100%), and specificities were 84.7% (95% CI, 80.2%-88.5%) and 78.4% (95% CI, 73.6%-82.4%), compared with the pathologist assessment of digital and physical slides, respectively. Areas under the receiver operating characteristic curve were 0.94 and 0.96, respectively. Negative predictive values were high (99%-100%), and accuracy was high, particularly for the detection of high-grade lesions. Interrater agreement was substantial compared with the pathologist assessment of digital slides (κ = 0.72) and fair compared with the assessment of glass slides (κ = 0.36). No samples that were classified as high grade by manual sample analysis had false-negative assessments by the DLS. Conclusions and Relevance: In this study, digital microscopy with artificial intelligence was implemented at a rural clinic and used to detect atypical cervical smears with a high sensitivity compared with visual sample analysis.

Overexpression of HSP27 and HSP70 is associated with decreased survival among patients with esophageal adenocarcinoma.

BACKGROUND: Overexpression of heat shock proteins (HSPs) is associated with several malignancies and contributes to the development, progression, and metastasis of cancer, in addition to the inhibition of cellular death. In recent years, there has been active research into using HSP inhibitors in several malignancies. Due to the poor prognosis of esophageal adenocarcinoma (EAC), it would be valuable to find new biomarkers for the development of cancer treatments. AIM: To evaluate the expressions of HSP27 and HSP70 and their effect on survival in EAC. METHODS: Immunohistochemical analyses and evaluations of HSP27 and HSP70 expression were performed on all available samples from 93 patients diagnosed with EAC between 1990 and 2007 at two university hospitals. Fifteen cases with Barrett's metaplasia and 5 control cases from the same patient population were included in the analysis. HSP expression was quantitatively assessed and classified as high or low. Kaplan-Meier analyses and Cox regression models adjusting for age and sex as well as tumor site, stage, and grade were used to evaluate the effect on survival. RESULTS: Tumor stage and surgical treatment were the main prognostic factors. High HSP27 expression in cancer cases was a strong negative predictive factor, with a mean survival of 23 mo compared to the 49 mo in cases with a low expression (P = 0.018). The results were similar for HSP70, with a poorer survival of 17 mo in cases with high HSP70 expression, in contrast to 40 mo (P = 0.006) in cases with a low expression. A Cox regression survival analysis was performed, adjusting for possible confounding factors, and higher HSP27 and HSP70 expressions remained an independent negative prognostic factor. The HSPs' correlation with survival was not affected by cancer treatments. When the analysis was adjusted for all factors, the odds ratios for HSP27 and HSP70 were 3.3 (CI: 1.6-6.6, P = 0.001) and 2.2 (CI: 1.2-3.9, P = 0.02), respectively. CONCLUSION: HSP27 and HSP70 overexpression is associated with poor survival in EAC, which is, to the best of our knowledge, reported for the first time.

Cell Block in Cytological Diagnostics: Review of Preparatory Techniques.

OBJECTIVE: The cell block (CB) technique refers to the processing of sediments, blood clots, or grossly visible tissue fragments from cytological specimens into paraffin blocks that can be cut and stained by the same methods used for histopathology. The technique brings additional tissue architectural information. CB can be used for ancillary techniques such as immunocytochemistry and molecular techniques. STUDY DESIGN: We reviewed the literature on the various preparatory techniques of CBs. RESULTS: There is a wide range of preparatory techniques for CBs and no golden standard for CBs exists: tens of methods are used in various institutions. The majority of the methods are modified in house techniques with a few commercially available kits. The techniques most commonly used are the plasma/thrombin method, the agar method, and commercially available Histogel- and Cellient CB-methods. Dissatisfaction with the cellular yield of the CBs is common. CONCLUSIONS: In the CBs, the cytological material is preserved for future use, which is a tremendous advantage in the era of targeted therapy and biobanking. The CB is thus central to the future of cytology: more can be done with less material and with less invasiveness to the patient.

Reduction mammaplasty in patients with history of breast cancer: The incidence of occult cancer and high-risk lesions.

INTRODUCTION: Contralateral reduction mammaplasty is regularly included in the treatment of breast cancer patients. We analyzed the incidence of occult breast cancer and high-risk lesions in reduction mammaplasty specimens of women with previous breast cancer. We also analyzed if timing of reduction mammaplasty in relation to oncological treatment influenced the incidence of abnormal findings, and compared if patients with abnormal contralateral histopathology differed from the study population in terms of demographics. MATERIALS AND METHODS: The study consisted of 329 breast cancer patients, who underwent symmetrizing reduction mammaplasty between 1/2007 and 12/2011. The data was retrospectively analyzed for demographics, operative and histopathology reports, oncological treatment, and postoperative follow-up. RESULTS: Reduction mammaplasty specimens revealed abnormal findings in 68 (21.5%) patients. High-risk lesions (ADH, ALH, and LCIS) were revealed in 37 (11.7%), and cancer in six (1.9%) patients. Abnormal histopathology correlated with higher age (p = 0.0053), heavier specimen (p = 0.0491), and with no previous breast surgery (p < 0.001). Abnormal histopathological findings were more frequent in patients with reduction mammaplasty performed prior to oncological treatment (p < 0.001), and in patients with immediate reconstruction (p = 0.0064). CONCLUSION: The incidences of malignant and high-risk lesions are doubled compared to patients without prior breast cancer. Patients with abnormal histopathology cannot be preoperatively identified based on demographics. If reduction mammaplasty is performed before oncological treatment, the incidence of abnormal findings is higher. In the light of our results, contralateral reduction mammaplasty with histopathological evaluation in breast cancer patients offers a sophisticated tool to catch those patients whose contralateral breast needs increased attention.

Breast Cancer Detection by Preoperative Imaging in Reduction Mammaplasty Patients: A Single Center Study of 918 Patients.

BACKGROUND: The role of preoperative imaging and the usability of different imaging modalities is highly variable and controversial in reduction mammaplasty patients. Our study describes the imaging process in a single center in regard to modality selection, age and timing, and of the association between imaging and histopathological findings in reduction mammaplasty specimens. METHODS: Nine hundred eighteen women, who underwent reduction mammaplasty during 1.1.2007-31.12.2011, were retrospectively reviewed for demographics, preoperative imaging, further preoperative examinations, and pathology reports. RESULTS: Preoperative imaging had been conducted for 89.2% (n = 819) of the patients. In 49 (6.0%) patients, suspicious preoperative imaging led to further examinations revealing 2 high-risk lesions (atypical ductal hyperplasia (ADH), lobular carcinoma in situ (LCIS)), and 2 cancers preoperatively. Postoperatively abnormal histopathology specimens were revealed in 88 (10.4%) patients. The incidence of high-risk lesions was 5.5% (n = 47), and the incidence of cancer was 1.2% (n = 10). Preoperative imaging was normal (BI-RADS 1 and BI-RADS 2) in 80.8% of these patients. The sensitivity of the preoperative imaging for cancer detection was 20.0%, and the specificity was 100.0%. CONCLUSIONS: Preoperative imaging and further examinations do not sufficiently detect malignant or cancer risk-increasing findings. Therefore, histopathological analysis of reduction mammaplasty specimens seems mandatory.

Should we routinely analyze reduction mammaplasty specimens?

BACKGROUND: Reduction mammaplasty is one of the most common plastic surgery procedures. Preoperative imaging and histopathology protocols vary among countries and institutions. We aimed to analyze the incidence of occult breast cancer and high-risk lesions in reduction mammaplasty specimens. We also analyzed whether patients with abnormal histopathology differed from the study population in terms of demographics. PATIENTS AND METHODS: In total, 918 women who underwent reduction mammaplasty from January 2007 to December 2011 were retrospectively reviewed for demographics, preoperative imaging, further preoperative examinations, pathology reports, and postoperative follow-up. RESULTS: Abnormal histopathological findings were revealed in 88 (10%) patients with a mean age of 49.5 ± 10.2 years. The incidence of breast cancer was 1.2%, and the incidence of high-risk lesions (atypical ductal and lobular hyperplasia and lobular carcinoma in situ) was 5.5%. Age and specimen weights were significantly higher in patients with abnormal histopathology. Eighty-one percent of patients with abnormal histopathology had normal preoperative imaging revealing two high-risk and two cancer findings. Two patients developed breast cancer in the same breast in which the high-risk lesion was originally detected. CONCLUSION: Women with abnormal histopathology cannot be sufficiently detected preoperatively. Therefore, histopathological analysis of reduction mammaplasty specimens seems mandatory. Reduction mammaplasty combined with subsequent histopathological examination offers a sufficient chance of detecting cancer and risk-increasing lesions that merits the cost of histopathology.

Screening primary sclerosing cholangitis and biliary dysplasia with endoscopic retrograde cholangiography and brush cytology: risk factors for biliary neoplasia.

BACKGROUND AND STUDY AIMS: Primary sclerosing cholangitis (PSC) is associated with increased risk of biliary dysplasia and cholangiocarcinoma (CCA). The aim of this study was to evaluate the role of early endoscopic retrograde cholangiography (ERC) with systematic brush cytology to identify risk factors associated with biliary neoplasia. PATIENTS AND METHODS: Patients who were referred for their first ERC for suspicion of PSC between January 2006 and October 2011 were included in the study. Brush cytology specimens were scored as benign, suspicious, or malignant. End points were CCA, biliary dysplasia, benign histology, or benign disease course for ≥ 2 years. RESULTS: PSC was diagnosed in 261 patients (125 men, 136 women), most of whom were asymptomatic (n = 211). Cholangiographic changes were mild in 57.1 %. Men presented with advanced disease more often than women. Brush cytology was benign in 243, suspicious in 16, and malignant in 2 patients. Follow-up completed in 249 patients indicated a benign disease course in 232 patients. Seven patients were diagnosed with CCA and eight had biliary dysplasia in the explanted liver. Thus, 15 patients had biliary neoplasia, and suspicious or malignant brush cytology had been detected in 8 of them at initial brushing. Advanced extrahepatic cholangiographic changes with elevated aminotransferases at diagnosis seemed to be associated with increased risk of biliary neoplasia. CONCLUSIONS: Even in mostly asymptomatic patients with PSC, 42.9 % had advanced disease and 6.9 % presented with suspicious or malignant brush cytology at first ERC. Advanced extrahepatic ERC changes with elevated aminotransferases at diagnosis might be risk factors for biliary neoplasia.

CIP2A expression and prognostic role in patients with esophageal adenocarcinoma.

CIP2A is overexpressed in many cancers, including esophageal squamous cell carcinoma. The regulation of c-MYC and CIP2A expression is characterized by a positive feedback mechanism facilitating the expression of both of them and accelerating cancer cell proliferation in gastric cancer. Increased CIP2A expression is a predictor of poor survival in some cancers. The incidence of positive CIP2A immunostaining and its association with c-MYC and its predictive value in esophageal adenocarcinoma are unknown. All esophageal adenocarcinoma patients from 1990 to 2007 with sufficient material for analysis of CIP2A and c-MYC in two university hospitals were included in the study. In addition, biopsies from Barrett's epithelium from the cancer patients and control tissue from normal esophageal mucosa adjacent to the tumor were included. CIP2A was moderately or strongly positive in 77.9 %, and c-MYC in 93.8 % of the cancer specimens. These frequencies were statistically different from the expression in normal esophageal epithelium. In addition, there was a positive correlation between CIP2A and c-MYC expression (p = 0.018). According to adjusted Cox regression survival analysis, CIP2A and c-MYC had no effect on survival. However, among patients with stage IVA-IVB cancer, there was a trend toward poor prognosis in CIP2A-positive patients. The expression of CIP2A and c-MYC was associated with each other, and their overexpression was found in most cases of esophageal adenocarcinoma. However, CIP2A and c-MYC had no effect on survival.

Long-term results of ablation with antireflux surgery for Barrett's esophagus: a clinical and molecular biologic study.

BACKGROUND: The initial results from ablation therapy for metaplastic/dysplastic Barrett's esophagus (BE) are promising, but the results of extended follow-up evaluation are seldom reported. METHODS: Neodymium:yttrium-aluminum-garnet laser ablation and successful antireflux surgery for 18 patients with metaplastic BE primarily resulted in the total histologic eradication of BE in 15 patients (83%). After antireflux surgery, the healing of gastroesophageal reflux disease (GERD) was objectively verified in all the patients. At late follow-up evaluation, endoscopy, conventional histology, molecular oxidative stress analyses in comparison with normal control conditions (8-hydroxydeoxyguanosine [8-OHdG], superoxide dismutase [SOD], glutathione [GSH], myeloperoxydase [MP]), and immunohistochemistry (p53, and Cdx2, caudal-related homeobox gene 2, marking intestinal differentiation) of the neosquamous epithelium were performed. RESULTS: At the end of the follow-up period (range, 3-15 years; mean, 8 years), intestinal metaplasia without dysplasia was detected histologically in eight patients (44%). Six patients had macroscopic BE (mean length, 3.5 cm; range 1-10 cm). The neosquamous epithelium was histologically normal, with no underlying columnar tissue. The fundoplication was endoscopically normal in 14 patients (82%). The 8-OHdG level was higher in the neosquamous epithelium than in the control conditions in the distal esophagus (4.3 vs. 0.52; P = 0.0002) and the proximal esophagus (1.8 vs. 0.95; P = 0.006). Likewise, SOD activity was higher in the neosquamous epithelium (0.38 vs. 0.12; P = 0.0005), whereas MP activity and GSH levels remained normal. Three patients showed slight nuclear p53 expression (typical in normal inflammatory reactions), whereas Cdx2 positivity was confined to one case with recurrent intestinal metaplasia. CONCLUSIONS: The neosquamous mucosa, generated by the ablation of BE and the treatment of GERD with fundoplication, was stable during long-term follow-up evaluation in two-thirds of the patients with initial eradication. It had normal p53 expression and no Cdx2 protein expression. The oxidative stress of the neosquamous esophagus remained high, although the clinical significance of this is unclear.

Biliary dysplasia in patients with primary sclerosing cholangitis: additional value of DNA ploidity.

BACKGROUND: Detection of biliary dysplasia in PSC is essential for proper timing of liver transplantation to prevent the development of cholangiocancer, which is considered a contraindication for liver transplantation in most centres. In patients with PSC, differential diagnosis of benign, premalignant and malignant biliary strictures is difficult. AIMS: This prospective study aimed to evaluate the role of DNA analysis in combination with brush cytology, scored ERCP findings, and tumour markers to detect hepatobiliary dysplasia and malignancy. MATERIAL AND METHODS: Brush samples for cytology and for evaluation of DNA content analysed with flow cytometry came from 102 consecutive PSC patients referred for ERCP. Symptoms, serum Ca19-9 and CEA were determined at the time of index biliary examination. ERCP findings were scored for intra- and extrahepatic changes. The end-points were liver transplantation or diagnosis of malignancy or dysplasia. RESULTS: Most of the patients were asymptomatic at the time of ERCP: 73% had no symptoms, and 12% had only mild symptoms. An aneuploid DNA content was evident in 20 (20%) patients, and cells suspected for malignancy in 22 (21%). Seven patients had both aneuploidity and cytology (7%) suspicious for malignancy. An end-point, diagnosis of malignancy or liver transplantation was achieved in 42 patients. Combining DNA ploidity and cytology in patients at the end-point, sensitivity was 72%, specificity 82%, positive predictive value 86% and negative predictive value 67%. DISCUSSION AND CONCLUSION: In this mostly asymptomatic PSC-patient population, 33% demonstrated abnormal brush cytology or aneuploidity. Determining DNA ploidy and brush cytology during ERCP offers a useful tool for identifying those PSC patients who are at high risk of developing cholangiocancer.

[Reporting of thyroid fine needle samples is changing in Finland--the Bethesda system in thyroid cytology]. / Bethesda-järjestelmä kilpirauhasen sytologiassa.

A recommendation for the reporting of thyroid cytological specimens was made as the consensus of the expert meeting arranged by the U.S. National Cancer Institute (NCI). This Bethesda system will replace the former Papa classes also in thyroid cytology. The new Bethesda classification considers the representativeness of the thyroid specimen, and the classification is based on the correlation of the underlying histological change with the cytological report. In particular, follicular tumors and suspicion of them are separated from other tumors into their own group. The new system will bring about a significant improvement to the reports of thyroid cytological specimens.

Metastatic outgrowth encompasses COL-I, FN1, and POSTN up-regulation and assembly to fibrillar networks regulating cell adhesion, migration, and growth.

Although the outgrowth of micrometastases into macrometastases is the rate-limiting step in metastatic progression and the main determinant of cancer fatality, the molecular mechanisms involved have been little studied. Here, we compared the gene expression profiles of melanoma lymph node micro- and macrometastases and unexpectedly found no common up-regulation of any single growth factor/cytokine, except for the cytokine-like SPP1. Importantly, metastatic outgrowth was found to be consistently associated with activation of the transforming growth factor-beta signaling pathway (confirmed by phospho-SMAD2 staining) and concerted up-regulation of POSTN, FN1, COL-I, and VCAN genes-all inducible by transforming growth factor-beta. The encoded extracellular matrix proteins were found to together form intricate fibrillar networks around tumor cell nests in melanoma and breast cancer metastases from various organs. Functional analyses suggested that these newly synthesized protein networks regulate adhesion, migration, and growth of tumor cells, fibroblasts, and endothelial cells. POSTN acted as an anti-adhesive molecule counteracting the adhesive functions of FN1 and COL-I. Further, cellular FN and POSTN were specifically overexpressed in the newly forming/formed tumor blood vessels. Transforming growth factor-beta receptors and the metastasis-related matrix proteins, POSTN and FN1, in particular, may thus provide attractive targets for development of new therapies against disseminated melanoma, breast cancer, and possibly other tumors, by affecting key processes of metastasis: tumor/stromal cell migration, growth, and angiogenesis.

Spontaneous recovery of myocardial function after ligation of Ameroid-stenosed coronary artery.

OBJECTIVES: We aimed to assess the spontaneous healing of myocardial function after occlusion of a chronically stenosed coronary vessel in a porcine model. DESIGN: Ischemia and infarction was produced by Ameroid constrictor placement and a subsequent ligation of the left circumflex artery. Cardiac MRI and 18FDG-PET were performed one and five weeks later. Ki67 staining was used to identify proliferating cells. RESULTS: Restoration of perfusion defect was detected by MRI (p=0.0065), reduced systolic function of the lateral segment spontaneously recovered (p=0.03). There was also a suggestive raise in impaired ejection fraction (p=0.06). Left ventricular early diastolic filling and peak filling rate were substantially improved (p=0.039 and p=0.0078). Scar size reduced (p=0.03). On the 18FDG-PET, deranged metabolism was alleviated (p=0.03). Cardiomyocytes with positive Ki-67 staining were located principally in the non-infarcted myocardium as compared to the infarction or border areas (p=0.037). CONCLUSIONS: We demonstrated spontaneous functional healing of ischemic and infarcted left ventricle, suggesting border zone perfusion recovery. Scar reduction was detected. Different pattern of myocyte proliferation between infarction and non-ischemic myocardium was seen.

Improved diastolic function after myoblast transplantation in a model of ischemia-infarction.

OBJECTIVES: The aim of this study was to evaluate the effect of myoblast transplantation on left ventricular function, perfusion, and scar formation after compromised coronary flow. DESIGN: A coronary vessel with Ameroid-induced stenosis was ligated and skeletal muscle was biopsied for isolation and cultivation of myoblasts. Two weeks after ligation, animals were randomly selected to receive intramyocardial injections of 2 x 10(6) myoblasts or vehicle. Fifteen animals survived the whole study period (n=9 and n=6, respectively). All animals underwent cardiac magnetic resonance imaging (MRI) and angiography pretreatment and four weeks posttreatment. RESULTS: Peak filling rate of the left ventricle improved in the myoblast group (p=0.0048), but not in the control group. Peak ejection rate and duration of diastole improved only in the myoblast group (p=0.049 and p=0.0039, respectively). Ejection fraction or local thickening did not change. Fibrosis and perfusion were similar in both groups, but more microvessels were present histologically in the myoblast group. CONCLUSIONS: In this preclinical study, autologous myoblast transplantation improved ischemic heart function via enhanced diastolic filling of the left ventricle.

CMV increases tubular apoptosis through the TNF-alpha-TNF-R1 pathway in a rat model of chronic renal allograft rejection.

INTRODUCTION: Destruction of transplanted kidneys through chronic allograft nephropathy [CAN], also known as chronic rejection, is the greatest obstacle in successful kidney transplantation. Causes behind CAN are many, from pre-transplant causes to infections. Viral infections, especially CMV, are a risk factor for chronic rejection. We have previously developed a rat kidney transplant model, in which CMV enhances the development of chronic rejection under triple drug treatment. In this model we have now further studied the routes of apoptosis in virus induced early CAN vs. the routes of apoptosis in a later developing non-infectious CAN. MATERIALS AND METHODS: Renal transplantations were performed in a strain combination of DA/BN under immunosuppression. One group of animals was infected with RCMV and the other was left uninfected. The grafts were harvested on days 3-40 after transplantation. Apoptotic cells were visualised by in situ terminal transferase mediated dUTP nick end labelling [TUNEL] from paraffin embedded, formalin fixed kidney grafts. Cytokines were labelled imunohistochemically from frozen sections, among them tumour necrosis factor alpha [TNF-alpha] and its receptor-protein 1 [TNF-R1] as well as CD 95 [FAS], caspase 3 and CD14. The results were semi-quantitatively scored from 0 to 3+ over various tissues structures separately. RESULTS: In the CMV infected grafts, we could demonstrate a more intense TUNEL reaction in tubular epithelium [2.0+/-1.0 vs. 0.8+/-0.5 at day 14, P<0.05] as well as an earlier increase in the expression TNF-alpha in the vascular endothelium [2.0+1.0 vs. 0.0+0.0 at days 3-5, P<0.05] than in the non-infected group. There was also an earlier increase in the tubular TNF-R1 expression [2.2+0.8 vs. 1.0+0.0 at days 5-7, P<0.05]. There was no difference in the expression of CD14, caspase 3 or FAS between the groups. CONCLUSIONS: CMV enhanced development of CAN was associated with tubular apoptosis and concomitant increase of TNF-alpha-TNF-R1, rather than the FAS-FAS-ligand activation.

Early treatment of acute rejections gives favorable long-term function after renal transplantation in small children.

AR is considered as a risk factor for CAN after kidney TX. We combined data on AR with long-term graft function and histopathology to assess whether early treatment of AR is beneficial for long-term graft outcome in small children. Seventy-seven children with a mean age of 4.7 yr were studied. Early AR were diagnosed with FNAB and treated with methylprednisolone already before clinical signs occurred. The children were grouped into three groups (clinical, subclinical, and no AR) and then followed prospectively up to seven yr after TX with measured GFR and core needle biopsies to assess histopathological findings with the CADI score. Early AR, whether clinical or subclinical, did not affect long-term graft survival (80% with AR vs. 83% without AR, at 10 yr). Late AR, more than one yr after TX, had an inferior graft survival 50% vs. 84% (p = 0.02). GFR declined and the CADI scores increased with time, but there were no significant differences between the three groups. Prompt and early treatment of post-operative AR gives favorable long-term graft function compared with children without AR. Late AR is a risk factor for inferior long-term graft function.

Ligation of ameroid-stenosed coronary artery leads to reproducible myocardial infarction--a pilot study in a porcine model.

OBJECTIVE: Myocardial gene and cellular therapies have revived the use of porcine ischemic heart models. Commonly applied ameroid-obstruction produces inconsistent coronary stenoses and myocardial lesions, whereas abrupt coronary occlusion causes arrhythmias and sudden death. To produce a constant myocardial lesion after adaptation to ischemia, we surgically modified the ameroid-model by ligation. As a pilot study for further cell therapy research, the spontaneous myocardial response is described. MATERIALS AND METHODS: Simultaneously with ameroid application, a loose loop of nonabsorbable thread was placed around the left circumflex artery (LCx) on 11 domestic piglets. Three weeks later, the loop was tightened. Coronary arteriograms with Rentrop collateral grading from 0 to 3, and 99mTc-single photon emission computerized tomography studies were performed 1 to 5 wk after ligation. At autopsy, the hearts were analyzed macroscopically, histologically, and with von Willebrandt factor-staining. RESULTS: LCx-banding was well-tolerated in nine animals, of which angiographic occlusion was gained in eight. Postmortem analysis revealed a 5 to 10 cm(2) transmural or subendocardial lateral myocardial infarction in all except one heart. One week after occlusion, LCx showed well-developed collateral filling (Rentrop-grade 2.7 +/- 0.4), which remained unchanged at 5 wk. On single photon emission computerized tomography-scans, lateral wall perfusion increased spontaneously between 1 and 5 wk (P = 0.02), and von Willebrandt factor revealed clusters of neovascularization at the borders of infarct areas. CONCLUSIONS: This new modification of ameroid model standardizes myocardial lesion, which might reduce animal number in preclinical studies, thus having ethical aspect. The remarked potential for spontaneous recovery in ischemic porcine myocardium should be considered in preclinical therapeutic studies.

Rapid progression of small cell carcinoma in a renal transplant recipient.

Immunosuppression is thought to be responsible for the increased incidence of tumor development after organ transplantation. Natural history of these tumors may be more aggressive than would be expected for a similar tumor in a patient without transplant. We describe the fulminant course of small cell carcinoma, likely of prostatic origin, in a kidney transplant patient. Small cell carcinoma (SCC) and especially SCC of the prostate is an aggressive and rare type of tumor. Due to its rarity, only case reports have been published. To our knowledge, this is the first case of SCC, likely of prostatic origin, in an organ transplant recipient (OTR). The case illustrates the aggressiveness of the disease as reflected by its fulminant progression, which may have been further accentuated by the immunosuppression.

The clinical value of parasternal sentinel node biopsy in breast cancer.

BACKGROUND: Lymphoscintigraphy (LS) with sentinel node (SN) biopsy is proposed to provide a feasible method to complete lymphatic staging in breast cancer. The aim of this study was to evaluate the clinical value of parasternal SN biopsy. METHODS: A total of 984 consecutive patients with clinical stage T1/2N0 invasive breast cancer who underwent LS and SN biopsy were included in the study. A prospectively collected database was used. An intratumoral injection of 50 to 145 MBq of (99m)Tc-labeled human albumin colloid (Nanocoll) was used for preoperative LS. RESULTS: LS showed the axillary SN in 844 (86%) cases and the parasternal SN in 138 (14%) cases. The median number of visualized parasternal SN was 2 (range, 1-6). Visualization of the parasternal SN was more common in patients with mediocentral tumors (81 of 399; 20%) and in patients with lateral tumors (56 of 585; 10%; P < .0001). Parasternal SNs were visualized more often, in 100 (17%) of 584 patients without axillary metastases compared with 38 (10%) of 400 patients with metastatic axillary nodes (P = .0006). Parasternal SNs were harvested successfully in 121 (88%) patients with visualization of those nodes. Parasternal SN metastases were detected in 18 patients, with a median of 1 metastasis (range, 1-4 metastases). Eight of these 18 patients were axillary node negative. CONCLUSIONS: Parasternal SN biopsy results in upstaging in 2% of all breast cancer patients who undergo SN biopsy. The clinical value of the procedure seems insignificant, although it may influence the adjuvant treatment regimen in some patients.