Cathepsin D in primary squamous laryngeal tumors: correlation with clinico-pathological parameters and receptor status.

Using an immunoradiometric assay, Cathepsin D (Cath D) levels were measured in the cytosol of 23 normal and 39 neoplastic human laryngeal tissues. Scattered Cath D levels (from 2.2 to 17.8 pM/mg protein; median = 7.6) were found in normal mucosa specimens. Cath D concentrations range from 2.0 to 29.3 pM/mg protein (median = 8.5) in laryngeal tumors. When a comparison between Cath D levels in normal and neoplastic tissue specimens from the same patient was done, Cath D levels were significantly higher in laryngeal cancers than in their normal counterparts (P = 0.03). No correlation with clinico-pathological parameters and steroid hormone and epidermal growth factor receptor status was found. Further studies should investigate whether the production of Cath D by laryngeal tumors could have a clinical relevance for this neoplasia.     

Glutathione S-transferase activity in epithelial ovarian cancer: Association with response to chemotherapy and disease outcome

Background: Conflicting data have been reported about the associationbetween glutathione S-transferase (GST), a family of proteins implicated indetoxification of cytotoxic drugs in human ovarian in vitro models, andresponse to chemotherapy and prognosis in ovarian cancer patients. The aim ofthis study was to analyze the possible clinical role of GST activity in alarge series of primary ovarian cancer patients.Patients and methods: The study included a large series of primaryuntreated ovarian cancer patients who underwent cytoreductive surgery andchemotherapy and who were followed up in a single institution. GST activitylevels were assessed in tumor extracts by using a biochemical assay. A cut-offof 250 units of enzymatic activity was chosen according to the receiveroperating characteristics (ROC) curve.Results: GST activity levels were distributed in an asymmetrical manner(median: 266 units; range: 4–918 units) and did not seem to beassociated with stage, histopathological grading, ascites, or residual tumorafter surgery. Higher GST activity levels were found in patients who respondedto chemotherapy (median: 298 units, range: 50–691) than in those whoresponded only partially (median: 227 units, range: 19–747) or not atall to chemotherapy (median: 246 units, range: 4–811) (H = 7.02, P =0.029). Moreover, the percentage of cases with >250 units was significantlyhigher among complete responders (66%) than partial responders(37%) or non-responders (48%) (² = 7.32;P = 0.025). When multivariate analysis, including clinico-pathologicalparameters and GST activity status as predictors of response to chemotherapy,was carried out, residual tumor, stage and GST status retained independentpredictive value. Patients with high GST activity had more favourableprognosis than those with low GST activity. The median PFS was 42 months forpatients with high GST activity compared to 17 months for those with low GSTactivity (P = 0.037). The median overall survival was 72 months forhigh-GST-activity and42 months for low-GST-activity patients (P = 0.043). Substantially similarresults were obtained in the subgroup of stage II–III–IV ovariancancer patients. Multivariate analysis including the clinico-pathologicalparameters and GST activity status was performed in stage III–IV ovariancancer patients: Stage IV disease, residual tumor >2 cm, the presence ofascites and low GST activity status retained independent negative prognosticroles.Conclusion: A direct association between high GST activity and a betterclinical outcome in terms of response to chemotherapy and survival has beenobserved in a large series of primary untreated ovarian cancer patients. Theseresults, which are contrary to the expectations raised by in vitro studies,emphasize the need for caution when translating in vitro-generated hypothesesto the clinical setting.     

Quercetin potentiates the effect of adriamycin in a multidrug-resistant MCF-7 human breast-cancer cell line: P-glycoprotein as a possible target

This study demonstrates that the flavonoid quercetin (Q), a plant-derived compound with low toxicity in vivo, greatly potentiates the growth-inhibitory activity of Adriamycin (ADR) on MCF-7 ADR-resistant human breast cancer cells. The effect of Q was dose-dependent at concentrations ranging between 1 and 10 M. Since ADR resistance in these cells is associated with the expression of high levels of P-glycoprotein (Pgp), we evaluated the effect of Q and related flavonoids of Pgp activity in cytofluorographic efflux experiments with the fluorescent dye rhodamine 123 (Rh 123). Our results indicate that Q and 3-OMe Q (3,4,7-trimethoxyquercetin) but not the 3-rhamnosylglucoside of Q (rutin) inhibit the Pgp pump-efflux activity in a dose-related manner. Moreover, 10 M Q reduces the expression of the immunoreactive Pgp in MCF-7 ADR-resistant cells as evaluated by cytofluorimetric assay. In conclusion, these findings provide a further biological basis for the potential therapeutic application of Q as an anticancer drug either alone or in combination with ADR in multidrug-resistant breast tumor cells.This work was partially supported by grants from MURST (60% and 40%) and CNR (Special Projects: A.C.R.O. 94.01098.PF 39); R. DeVincenzo and G. Ferrandina are recipients of fellowships from the Italian Association for Cancer Research (AIRC); M. Cianfriglia was partly supported by the AIDS research project (contract 720/P)     

Quercetin inhibits the growth of a multidrug-resistant estrogen-receptor-negative MCF-7 human breast-cancer cell line expressing type II estrogen-binding sites

Summary It has been demonstrated that the flavonoid quercetin (3,3,4,5,7-pentahydroxyflavone; Q) inhibits the growth of several cancer cell lines. There is evidence suggesting that the antiproliferative activity of this substance is mediated by the so-called type II estrogen-binding, site (type II EBS). We looked for the presence of type II EBS and the effect of Q on the proliferation of an Adriamycinresistant estrogen-receptor-negative human breast-cancer cell line (MCF-7 ADRr). By whole-cell assay using estradiol labelled with 6,7-tritium ([³H]-E2) as a tracer, we demonstrated that MCF-7 ADRr cells contain type II EBSs. Competition analysis revealed that diethylstilbestrol (DES) and Q competed with similar potency for [³H]-Es binding to type II EBSs. The antiestrogen tamoxifen (TAM) competed for type II EBSs, albeit to a lesser extent than either DES or Q. Growth experiments demonstrated that Q and DES exerted a dose-dependent inhibition of cell proliferation in the range of concentrations between 10 nM and 10 m, whereas TAM was less effective. Q could also inhibit colony formation in a clonogenic assay. Our results indicate that multidrug-resistant estrogen-receptor-negative MCF-7 cells express, type II EBSs and are sensitive to the inhibitory effect of Q. This substance could be the parent compound of a novel class of anticancer agents.     

Effects of dexamethasone on the growth and epidermal growth factor receptor expression of the OVCA 433 ovarian cancer cells.

We studied the correlation between dexamethasone (Dex) induced growth effects and modulation of epidermal growth factor receptor (EGFR) expression in OVCA 433 ovarian cancer cells. These cells express specific high and low affinity 125I-EGF binding sites and are growth stimulated by EGF. Dex exhibits mitoinhibitory effects by recruiting OVCA 433 cells in the G0-G1 phase of the cycle, but increases the number of both the high and the low affinity EGFR in a dose dependent manner. The maximal EGFR expression increase occurs after 24 h of Dex treatment consistently with Northern blot studies. The mitogenic activity of EGF in OVCA 433 cells is not affected by the presence of Dex. Moreover Dex growth inhibition occurs in JA1 cells, an ovarian cancer cell line which expresses unfunctional EGFR and which is unresponsive to EGF. Our results indicate that the Dex induced growth effects occur independently of EGFR expression.     

Timing and Pattern of Recurrence in Ovarian Cancer Patients with High Tumor Dissemination Treated with Primary Debulking Surgery Versus Neoadjuvant Chemotherapy

Purpose

To compare the timing and pattern of recurrence in patients with advanced ovarian cancer (AOC) receiving primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS).

Methods

We retrospectively evaluated a consecutive series of 175 stage IIIC–IV epithelial ovarian cancer patients, with diffuse peritoneal carcinomatosis documented at initial surgical exploration. Forty patients received complete PDS, and the remaining 135 were treated with NACT followed by IDS with absent residual tumor after surgery.

Results

No differences were observed in the distribution of clinical pathological characteristics at the time of diagnosis between the two groups. The median follow-up was 31 months (range 9–150 months). We observed 20 (50.0 %) recurrences in the PDS group compared to 103 (76.3 %) in the IDS group (p = 0.001). Duration of primary platinum-free interval (PFI) was shorter in IDS compared to PDS group (13 vs. 21 months, respectively; p = 0.014). A significantly higher percentage of patients in the IDS group experienced platinum-resistant recurrences (35.9 vs. 5.0 %; p = 0.006) and carcinomatosis at the time of relapse (57.3 vs. 20.0 %; p = 0.0021). Finally, in women with platinum-sensitive recurrence, we observed a shorter secondary PFI in the IDS compared to PDS group (p = 0.006).

Conclusions

We documented a better behavior of recurrent disease in AOC patients with diffuse peritoneal carcinomatosis treated with complete PDS compared to women submitted to NACT followed by IDS with no residual tumor after surgery.     

Glassy cell carcinoma of the endometrium: a case report and review of the literature

Glassy cell carcinomas are composed of malignant cells showing a "ground glass" cytoplasm, distinct cell membranes, and large nuclei with prominent nucleoli. To our knowledge, only 12 cases of glassy cell endometrial carcinomas (EGCC) have been reported until now. A 63-year-old patient complaining of irregular vaginal bleeding underwent hysteroscopy-guided biopsy revealing a well-differentiated endometrial endometrioid adenocarcinoma. The patient underwent left salpingo-oophorectomy, total abdominal hysterectomy, and pelvic lymphadenectomy. The final diagnosis was FIGO stage IB poorly differentiated endometrial adenosquamous carcinoma with > 90% of glassy tumor cells. The patient is alive, with no evidence of disease for 69 months after diagnosis. We describe an additional case of EGCC and review the data of the literature, emphasizing the need to strictly define the criteria for the diagnosis and the potential usefulness of assessing biologic parameters for the prognostic characterization of this rare entity.     

Endometrial carcinoma recurring as carcinosarcoma: report of two cases

Endometrial carcinosarcoma is a rare, aggressive disease, accounting for approximately 3% of all uterine neoplasms. The emergence of sarcomatous elements is considered the evolution of subclones arising from high grade endometrial carcinomas. Here, we report two cases of primary endometrial carcinomas recurring as carcinosarcoma. Case 1. a 58-year-old postmenopausal woman diagnosed to have a poorly differentiated endometrial endometrioid adenocarcinoma (FIGO stage IB) developed an intra-abdominal recurrence of disease after 17 months from diagnosis. Histopathological analysis documented a biphasic neoplasia consisting of an epithelial (grade 3 endometrial endometrioid adenocarcinoma) and a sarcomatous component. Salvage chemotherapy with cisplatin, ifosfamide, epirubicin, and then with taxotere was attempted. The patient died after 2 months. Case 2. A 56-year-old woman with a diagnosis of grade 3 endometrial adenosquamous carcinoma of the endometrium (FIGO stage IIIA) experienced pelvic recurrence after five months from completion of chemotherapy. Definitive histology was malignant mixed mesodermal tumor with focal areas of chondrosarcomatous elements. The patient was triaged to exclusive concomitant chemoradiotherapy and salvage chemotherapy. The patient died after 3 months. We describe two cases of high grade endometrial carcinomas recurring as carcinosarcoma, thus providing evidence that the metaplastic sarcomatous evolution is a very rare event which can occur in patients with anaplastic endometrial cancer.     

Effects of beta non-selective and beta 1 selective adrenergic blocking agents on glucagon secretion from isolated perfused rat pancreas

To characterize beta-receptors which affect pancreatic A-cell activity, the effects of propranolol (beta non-selective blockade) and metoprolol (beta 1 selective blockade) were evaluated on epinephrine modulated insulin (IRI) and glucagon (IRG) release both in basal state and during metabolic stimulus (arginine 20 mM). The isolated perfused rat pancreas model with the exclusion of stomach and duodenum was used. Epinephrine infusion (at 10(-7) M) caused a prompt and sustained increase in basal IRG secretion and significantly potentiated glucagon release in response to metabolic stimulus. Insulin secretion was markedly suppressed by epinephrine both in basal conditions and during metabolic stimulus. Propranolol (at 10(-7) M) and metoprolol (at 10(-7) M) infusion clearly and similarly counteracted epinephrine stimulatory effects on IRG secretion but failed to elicit any significant effect on the epinephrine inhibited IRI release either in basal state or during the metabolic stimulus. These results suggest that, at least in the rat, the adrenergic stimulation of IRG release is mediated through a beta 1 receptor.     

Laparoscopic surgical management of localized recurrent ovarian cancer: a single-institution experience

Background

Optimally, secondary cytoreduction is acknowledged as a valid option in terms of oncologic outcome for patients with platinum-sensitive recurrent ovarian cancer. In cases of localized relapse, a laparoscopic approach has been attempted at various institutions, but studies on its role for this subset of patients still are limited. This report describes the authors’ experience using laparoscopic secondary cytoreduction for patients with localized recurrent ovarian cancer. The results from a retrospective analysis of a prospective case series are reported.

Methods

Between October 2011 and May 2013, 29 patients with localized recurrent ovarian cancer were selected for a laparoscopic cytoreduction. Two conversions to laparotomy occurred. The analyzed outcome variables included stage and site of disease, type of surgical procedure, operative time, blood loss, length of hospital stay, complications, and oncologic outcome.

Results

The median operating time was 188 min. The median estimated blood loss was 150 mL, and the median hospital stay was 4 days. Complete debulking was achieved for 96.2 % of the patients. No intraoperative complications occurred, and postoperative complications were noted in only one patient. The median disease-free survival time was 14 months.

Conclusions

For selected patients, laparoscopy is a feasible and safe approach to optimal cytoreduction for patients with localized recurrent ovarian cancer.