Biomedical subjects

Alfredo Santinelli

Publications and source records attributed to Alfredo Santinelli.

17 recordsLinked to original sources

PubMed2006

Posaconazole prophylaxis in experimental systemic zygomycosis.

Three isolates of zygomycetes belonging to two different genera (Rhizopus oryzae and Absidia corymbifera) were used to produce a systemic infection in neutropenic mice. On days -2 and -1 and at 2 h prior to infection, the mice received either posaconazole (POS) at doses ranging from 20 to 80 mg/kg of body weight/day or amphotericin B (AMB) at 1 mg/kg/day. Antifungal drug efficacy was assessed by determination of the prolongation of survival, determination of the percentage of infected organs (brain, lung, spleen, and kidney), and histological examination for the number of infection foci and their sizes in brain and kidney tissues. AMB significantly prolonged the survival of mice infected with all isolates. POS significantly prolonged the survival of mice infected with zygomycetes. Cultured organs from mice infected with R. oryzae were all positive, while treated mice challenged with A. corymbifera generally showed lower percentages of infected organs compared with the percentages for the controls. Zygomycete isolates established an active infection (the presence of hyphae) in the brains and the kidneys of all controls. In mice challenged with R. oryzae, both antifungal drugs were effective at reducing the number and the size of infection foci in the kidneys. Only AMB reduced the numbers, but not the sizes, of infection foci in the brain. Finally, both drugs significantly reduced the numbers and the sizes of infection foci in both tissues of mice infected with A. corymbifera. Our data suggest that prophylaxis with POS has some potential to prevent zygomycosis.

Absidia↗

PubMed2006

HER2 expression and gene amplification in pT2a Gleason score 6 prostate cancer incidentally detected in cystoprostatectomies: comparison with clinically detected androgen-dependent and androgen-independent cancer.

Previous studies have demonstrated HER2 protein overexpression and/or gene amplification in a subset of patients with clinically significant prostate cancer (PCa), especially in the androgen-independent phase of the disease. There are no studies on incidentally detected PCa. The aim of the study was to analyze HER2 expression and gene amplification in PCa incidentally detected in cystoprostatectomies. High-grade prostatic intraepithelial neoplasia (HGPIN) was also investigated. Comparison was made with clinically detected PCa, both untreated and hormonally treated, and with androgen-independent PCa. Nineteen cystoprostatectomy (CyP) and 44 radical prostatectomy specimens (25 untreated and 19 hormonally treated) with pT2a Gleason score 6 cancer and HGPIN were used in this study. It also included 9 specimens of transurethral resection of the prostate with hormone-independent cancer and 8 cases of normal prostate tissue from CyP specimens without PCa and prostatic intraepithelial neoplasia. HER2 protein and Ki-67 were investigated immunohistochemically. Patients with immunohistochemical scores of 2+ and 3+ were considered to have HER2 overexpression (HercepTest method). Dual-color fluorescence in situ hybridization analysis was performed using the CEP-17/HER dual probe combination. High-grade prostatic intraepithelial neoplasia showed HER2 overexpression in 26% of the CyP cases and in 40% and 83% of the untreated and treated cases, respectively. Prostate cancer showed HER2 overexpression in 16% of cases in the CyP group and in 36% and 47.5% in the untreated and treated groups, respectively. HER2 overexpression was present in 78% of androgen-independent cancers. HER2 gene amplification was seen in a small proportion of nuclei and some of the cases. In HGPIN, it ranged from 1.1% (in 5 cases) in the CyP group to 2.1% (in 10 cases) and 1.9% (in 6 cases) in the untreated and treated groups, respectively. In PCa, the proportion of nuclei with gene amplification was 0.7% (in 3 cases) in the CyP group, 2.6% (in 10 cases) and 2.5% (in 12 cases) in the untreated and treated groups, respectively, and 9% (in 6 cases) in the androgen-independent PCa. Ki-67 expression in HGPIN and PCa in CyP specimens was lower than in the radical prostatectomies and cases of transurethral resection of the prostate. Our findings in the current HER2-related study indicate that incidentally detected cancer has features of less aggressiveness than clinically detected cancer. This may contribute to a better understanding of the results obtained in screening programs where insignificant cancers are detected along with clinically significant cancers.

Adult↗

PubMed2006

Biliary tract cancers: molecular profiling as a tool for treatment decisions. A literature review.

Biliary tract cancer is a quite rare disease; despite recent significant advances in imaging modalities, most of the patients have advanced disease at presentation thus making radical surgery not feasible. Many different chemotherapeutic regimens have been investigated in small uncontrolled studies, with generally disappointing results. We extensively reviewed the literature on this topic trying to give an explanation to chemoresistance in this setting of patients and considering the molecular profiling as a tool for treatment decision. This review is divided in two parts, in the first one we illustrated chemotherapy results and possible mechanisms of resistance. In the second part we analysed the new molecular targets developing an hypothesis about the future therapeutics perspectives.

Antineoplastic Agents↗

PubMed2006

Mismatch repair system (MMR) status correlates with response and survival in non-small cell lung cancer (NSCLC) patients.

Pre-clinical data suggested a relationship between inactivation of hMLH1 and hMSH2 and resistance to drugs like cisplatin and carboplatin, but not oxaliplatin. We then hypothesised that NSCLC showing loss of expression of the mismatch repair system (MMR), could be refractory to cisplatin-based, but not to oxaliplatin-based chemotherapy. Immunohistochemical expression of hMLH1 and hMSH2 was analysed on tumour samples from 93 advanced NSCLC, receiving chemotherapy with either cisplatin or oxaliplatin in combination with gemcitabine. Patients showing loss of hMLH1 or hMSH2 expression in > or = 50% of tumour cells were deemed MMR-negative (Group A), whereas cases with a normal hMLH1 or hMSH2 expression in > 50% of the tumour cells were defined MMR-positive (Group B). No differences in the response and progression rate were found in the whole patients population and in the gemcitabine/cisplatin group for both hMLH1 and hMSH2. In the gemcitabine/oxaliplatin group response rate was 38% and 0% (p=0.04) for patients with or without loss of hMSH2 expression. Median survival according to MMR status in Groups A and B, respectively was: 17 months versus 9 months for hMLH1 (p=0.031) and 10 months versus 9 months for hMSH2 (p=0.8330). Both the difference in response rate and in median survival observed according to MMR status seem to confirm what has been suggested by preclinical studies.

Adaptor Proteins, Signal Transducing↗

PubMed2006

A phase I-II preoperative biomarker trial of fenretinide in ascitic ovarian cancer.

PURPOSE: To evaluate study feasibility, toxicity, drug concentrations, and activity of escalating doses of the synthetic retinoid fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] in ovarian cancer by measuring serum CA125 and cytomorphometric biomarkers in cancer cells collected from ascitic fluid before and after treatment. METHODS: Twenty-two naive patients with ascitic ovarian cancer were treated with escalating doses of 4-HPR at 0, 400, 600, and 800 mg/d for 1 to 4 weeks before surgery. Changes in the proportion of proliferating cells expressed by Ki67 and computer-assisted cytomorphometric variables (nuclear area, DNA index, and chromatin texture) were determined in ascitic cells. Drug levels were measured by high-performance liquid chromatography. RESULTS: Doses up to 800 mg/d were well tolerated, and no adverse reactions occurred. There was no effect of 4-HPR on changes in serum CA125, Ki67 expression, which were assessed in 75% of subjects, and cytomorphometric variables, which were assessed in 80% of subjects. Plasma retinol levels were significantly lower in affected women than healthy donors. 4-HPR plasma concentrations increased slightly with increasing doses and attained a 1.4 micromol/L concentration with 800 mg/d. Drug levels in malignant ascitic cells and tumor tissue were higher than in plasma but were 50 and 5 times lower, respectively, than in carcinoma cells treated in vitro with 1 micromol/L 4-HPR. CONCLUSIONS: Cell biomarkers can be measured in ascitic cells to assess drug activity. Under our experimental conditions, 4-HPR did not show activity in advanced ovarian cancer cells. However, clinical evidence supports further investigation of fenretinide for ovarian cancer prevention.

Adult↗

PubMed2005

Nonapical and cytoplasmic expression of interleukin-8, CXCR1, and CXCR2 correlates with cell proliferation and microvessel density in prostate cancer.

PURPOSE: We characterized interleukin-8 (IL-8) and IL-8 receptor expression (CXCR1 and CXCR2) in prostate cancer to address their significance to this disease. EXPERIMENTAL DESIGN: Immunohistochemistry was conducted on 40 cases of human prostate biopsy containing histologically normal and neoplastic tissue, excised from patients with locally confined or invasive androgen-dependent prostate cancer, and 10 cases of transurethral resection of the prostate material from patients with androgen-independent disease. RESULTS: Weak to moderate IL-8 expression was strictly localized to the apical membrane of normal prostate epithelium. In contrast, membranous expression of IL-8, CXCR1, and CXCR2 was nonapical in cancer cells of Gleason pattern 3 and 4, whereas circumferential expression was present in Gleason pattern 5 and androgen-independent prostate cancer. Each of IL-8, CXCR1, and CXCR2 were also increasingly localized to the cytoplasm of cancer cells in correlation with advancing stage of disease. Cytoplasmic expression (but not apical membrane expression) of IL-8 in Gleason pattern 3 and 4 cancer correlated with Ki-67 expression (R = 0.79; P < 0.001), cyclin D1 expression (R = 0.79; P < 0.001), and microvessel density (R = 0.81; P < 0.001). In vitro studies on androgen-independent PC3 cells confirmed the mitogenic activity of IL-8, increasing the rate of cell proliferation through activation of both CXCR1 and CXCR2 receptors. CONCLUSIONS: We propose that the concurrent increase in IL-8 and IL-8 receptor expression in human prostate cancer induces autocrine signaling that may be functionally significant in initiating and promoting the progression of prostate cancer by underpinning cell proliferation and angiogenesis.

Aged↗

PubMed2005

Incidentally detected prostate cancer in cystoprostatectomies: pathological and morphometric comparison with clinically detected cancer in totally embedded specimens.

There are limited data regarding the pathological features of incidentally detected prostate cancer. Examination of cystoprostatectomy specimens obtained during bladder cancer treatment affords a unique opportunity to examine incidentally detected prostate cancer and determine its relationship with clinically detected prostate cancer obtained during radical prostatectomy. We compared the pathological findings of incidentally detected prostate cancer in 132 consecutive cystoprostatectomy specimens from patients treated for bladder cancer with a consecutive series of 228 radical prostatectomy specimens from patients treated for prostate cancer. All specimens were totally embedded and whole-mounted. Karyometry was evaluated in select subsets of patients from the study groups. Incidentally detected cancer was found in 42% of cystoprostatectomy specimens, and the cancers were of lower Gleason score and lower pathological stage with fewer positive surgical margins than in clinically detected cancers in age-matched radical prostatectomies. High-grade prostatic intraepithelial neoplasia (PIN) was present in 82% of radical prostatectomy specimens, in 70% of cystoprostatectomies with incidentally detected prostate cancer, and in 54% of cystoprostatectomies without prostate cancer. Mean nuclear and nucleolar area was lower in incidentally detected cancer and PIN when compared with clinically detected cancer and PIN, respectively, similar to the results with proliferative indices. We conclude that incidentally detected cancer is less aggressive than clinically detected cancer.

Humans↗

PubMed2005

Efficacy of caspofungin against Aspergillus terreus.

We investigated the in vitro and in vivo activities of caspofungin against Aspergillus terreus. The drug increased survival and reduced tissue fungal burden in neutropenic mice. Therefore, our data support the role of caspofungin in treating systemic infections due to this emerging pathogen.

Animals↗

PubMed2004

Immunohistochemical evaluation of urokinase plasminogen activator receptor in noninvasive and early invasive urothelial papillary neoplasia.

OBJECTIVE: To investigate urokinase plasminogen activator receptor (uPAR) expression in urothelial papilloma and in noninvasive and early invasive papillary carcinoma. STUDY DESIGN: The study included 40 cases of papillary neoplasia of the urinary bladder subdivided into 10 cases of urothelial papilloma (UP); 10 of papillary carcinoma, grade 1; 10, grade 2 (G2); and 10, grade 3 (G3). Invasion of the subepithelial connective tissue was present in 5 cases of G2 and 7 cases of G3. According to the 2002 revision of the TNM system, these cases were defined as T1 and the others as Ta. uPAR expression was evaluated with an immunohistochemical technique in 5-microns-thick tissue sections. RESULTS: Difference in the distribution of positive cases in the 4 groups were statistically significant and greatest in G3. Statistically significant differences were also observed between Ta and T1 cases in terms of uPAR intensity. CONCLUSION: Detection of immunoreactivity for uPAR was associated with high grade UP carcinomas. These data indicate that uPAR is potentially an important prognostic factor in bladder carcinoma.

Biomarkers, Tumor↗

PubMed2004

Renal sarcoma associated with adult polycystic kidney disease. A case report and literature review.

The development of renal cell carcinoma in Adult Polycystic Kidney Disease (APKD) has been reported in the literature; one of the features of renal malignancy in APKD is the difficulty to make a diagnosis, and the majority of cases reported are incidental findings at surgery or autopsy. We report a rare case of renal sarcoma in a patient with APKD. Sarcoma associated with APKD does not seem to have particular biological characteristics when compared with primary renal sarcoma; however the polycystic kidney represents an aggravating circumstance, because of the difficulty in making an early diagnosis of a disease with a poor prognosis.

Humans↗

PubMed2003

TP53 in urologic tumors.

TP53, a gene located on chromosome 17p13, encodes a nuclear protein (p53) involved in cell cycle regulation. This protein degrades in 20 minutes. However, the inactivated gene can produce a protein with a half-life 4-20 times longer than that of the wild type; it can be demonstrated by immunohistochemistry. Unfortunately, all the antibodies recognize both proteins, and the determination of a cutoff in the percentage of positive nuclei is required for the detection of cases with correlation of the TP53 mutation. In urologic tumors, p53 overexpression determination can be diagnostic help in low grade superficial bladder cancer, in cases of cystectomy and pN0, and in penile cancer without clinically involved lymph nodes. It does not seem useful in renal cell carcinoma or testicular germ cell tumors, and its utility is limited in prostate carcinoma.

Adenocarcinoma↗

PubMed2002

Prevalence of p53, bcl-2, and Ki-67 immunoreactivity and of apoptosis in normal oral epithelium and in premalignant and malignant lesions of the oral cavity.

PURPOSE: Loss of normal p53 is correlated to the progression of several preneoplastic lesions to neoplasms, and overexpression of bcl-2 determines an alteration of programmed cell death. There is an increased awareness of the importance of apoptosis in cancerogenesis, and a strong correlation of Ki-67 with high tumor grade has been reported. MATERIALS AND METHODS: The aim of our study was to investigate immunohistochemically the expression and relationship of p53, bcl-2, MIB-1, and the apoptotic index (AI) in normal oral epithelium, leukoplakia, dysplasia, and oral squamous cell carcinoma. RESULTS: A strong correlation was found between p53 overexpression and cell proliferation (MIB-1) and the AI. An inverse relationship was found between bcl-2 expression and MIB-1 and AI. A significant inverse relationship was found between p53 and bcl-2. A good positive correlation was present between AI and MIB-1 expression. CONCLUSIONS: Apoptosis could be important to help to understand oral carcinogenesis.

Apoptosis↗

PubMed2002

Vascular endothelial growth factor (VEGF) expression in healthy and inflamed human dental pulps.

Vascular endothelial growth factor (VEGF) is a glycoprotein that has the capability to increase vascular proliferation and permeability. VEGF has been found to be expressed in several different types of tumors, and it may contribute to the progression of malignant tumors. Immunostaining for VEGF and factor VIII was performed in normal healthy pulps and in irreversible pulpitis. In both cases the vessels were always positive for VEGF. Our immunohistochemical data show that the expression of VEGF was strongly positive in the inflammatory infiltrate in irreversible pulpitis. VEGF expression in the stromal cells in healthy pulps ranged from 20 to 100% (with a mean of 68.82), and in irreversible pulpitis ranged from 0 to 100% (with a mean of 62.35%); this difference was statistically significant (p = 0.05). This down-regulation in the stromal cells in irreversible pulpitis could be due to the presence, in a low compliance system such as the dental pulp, of inflammatory infiltrate. VEGF is probably a factor implicated in the etiology and progression of pulpitis. The microvessel density in healthy pulps was 90.00 +/- 27.5, while, in irreversible pulpitis, it was 56.68 +/- 21.15. This difference was statistically significant (p = 0.001). The decrease in microvessel density in irreversible pulpitis could be related to failing vascular function and blood flow decrease.

Adolescent↗

PubMed2002

Ki-67 expression in dentigerous cysts, unicystic ameloblastomas, and ameloblastomas arising from dental cysts.

This study investigated whether or not an ameloblastoma developing in the wall of a dentigerous cyst is a distinct lesion from the unicystic ameloblastoma. An immunohistochemical evaluation of Ki-67 in dentigerous cysts, unicystic ameloblastomas, and ameloblastomas arising in dentigerous cysts was done. The values of Ki-67 positivity were 3.14 for the dentigerous cyst, between 5.32 and 16.56 for unicystic ameloblastoma, and 11.77 for ameloblastoma arising in a dentigerous cyst. Statistically significant differences were found between the dentigerous cyst and the unicystic ameloblastoma and between the dentigerous cyst and the ameloblastoma arising from a dentigerous cyst. No statistically significant difference was present between unicystic ameloblastoma and ameloblastoma arising from dentigerous cyst. These immunohistochemical data confirm the hypothesis that an ameloblastoma arising from a dentigerous cyst has a similar biological behavior to the unicystic ameloblastoma and should be considered as merely a histologic variant.

Adult↗

PubMed2002

Evaluation of prognostic factors in radical prostatectomy specimens with cancer.

Prostate cancer (PCa) is a leading cause of morbidity and mortality in males accounting for approximately 30% of all new cases of cancer and approximately 14% of cancer deaths. Despite considerable advances achieved in the ability to detect and treat PCa, there have not been significant corresponding decreases in PCa-related morbidity and mortality. Proper examination of radical prostatectomy specimens by the pathologists is critical in determining the need for adjuvant treatment and prediction of patient outcome. The goal is to tailor the therapeutic approach to the clinical, morphological and molecular features of each patient.

Humans↗

PubMed2002

Immunohistochemical evaluation of HER-2/neu expression in infiltrating breast carcinoma: a study of reproducibility.

OBJECTIVE: To determine interobserver and intraobserver reproducibility in the assessment of the HercepTest- and TAB250-immunostained slides. STUDY DESIGN: Three independent expert pathologists (two with and one without training in HercepTest assessment) evaluated the HercepTest and TAB250-immunostained slides of 108 infiltrating breast carcinomas with a triple-blind method. The evaluation was repeated, with the same method and sequence of view, after 60 days. RESULTS: Expert pathologists, after adequate training in HercepTest evaluation, could reach excellent interobserver (K=.911, P<.001) and intraobserver reproducibility (K of .863-.926; P <.001 for all). The percentage of disagreement in intraobserver reproducibility ranged from 0.9% to 3.7%. Interobserver and intraobserver reproducibility in the evaluation of TAB250-immunostained slides was good (K = .658, P < .001) and from good to excellent (K of .600-.895, P < .001 for all), respectively. CONCLUSION: Optimization of the level of accuracy in HercepTest evaluation is mandatory because the decision to initiate therapy with Herceptin depends on the result. Moreover, considering that the percentage of disagreement in intraobserver reproducibility ranges from 0.9% to 3.7%, it is advisable that two expert pathologists evaluate all HercepTest slides with a double-blind method. If there are discordant results, they must be discussed by the same pathologists.

Antibodies, Monoclonal↗

PubMedDate not supplied

Image processing, diagnostic information extraction and quantitative assessment in pathology.

As we enter the information age we hold strong beliefs in the benefits of digital technology applied to pathology: numerical representation offers objectivity. Digital knowledge may indeed lead to significant information discovery, and, processing systems might be designed to allow a true evolution of capabilities. Questions arise whether the methodology underlying quantitative analysis provides the information that we need and whether it is appropriate for some of the problems encountered in diagnostic and prognostic histopathology. While one certainly would not dispute the value of statistical procedures, the clinical needs call for individual patient targeted prognosis.

Diagnostic Imaging↗