Francesco Legge

Increased Cyclooxygenase-2 Expression Is Associated With Chemotherapy Resistance and Poor Survival in Cervical Cancer Patients

PURPOSE To investigate the expression of cyclooxygenase (COX-2) and its association with clinicopathologic parameters and clinical outcome in patients with cervical cancer. PATIENTS AND METHODS The study included 84 patients with stage IB to IVA cervical cancer. Patients with early-stage cases (n = 21) underwent radical surgery, whereas patients with locally advanced cervical cancer (LACC) (n = 63) were first administered neoadjuvant cisplatin-based treatment and subjected to surgery in case of response. Immunohistochemical analysis was performed on paraffin-embedded sections with rabbit antiserum against COX-2. RESULTS COX-2--integrated density values in the overall population ranged from 1.2 to 82.3, with mean plus minus SE values of 27.4 plus minus 2.4. According to the chosen cutoff value, 36 (42.9%) of 84 patients were scored as COX-2 positive. COX-2 levels were shown to be highly associated with tumor susceptibility to neoadjuvant treatment. COX-2 showed a progressive increase from mean plus minus SE values of 19.9 plus minus 8.0 in complete responders through 31.5 plus minus 3.5 in partial responses to 44.8 plus minus 3.9 in patients who were not responsive (P =.0054). When logistic regression was applied, only advanced stage and COX-2 positivity retained independent roles in predicting a poor chance of response to treatment. COX-2--positive patients had a shorter overall survival (OS) rate than COX-2--negative patients. In patients with LACC, the 2-year OS rate was 38% in COX-2--positive versus 85% in COX-2--negative patients (P =.0001). In the multivariate analysis, only advanced stage and COX-2 positivity retained independent negative prognostic roles for OS. CONCLUSION The assessment of COX-2 status could provide additional information to identify patients with cervical cancer with a poor chance of response to neoadjuvant treatment and unfavorable prognosis.

Cyclooxygenase-2 expression in endometrial carcinoma: correlation with clinicopathologic parameters and clinical outcome.

Cyclooxygenase‐2 (COX‐2) is overexpressed in endometrial hyperplasia and carcinoma, but no data have been reported until now about the expression of COX‐2 and its possible clinical significance in endometrial carcinoma. We investigated by immunohistochemistry the expression of COX‐2 in a single institutional series of primary untreated endometrial carcinoma patients. The relationship between COX‐2 expression and microsatellite instability (MI) status was also analyzed.

Carboplatin Plus Paclitaxel Versus Carboplatin Plus Pegylated Liposomal Doxorubicin As First-Line Treatment for Patients With Ovarian Cancer: The MITO-2 Randomized Phase III Trial

PURPOSE Carboplatin/paclitaxel is the standard first-line chemotherapy for patients with advanced ovarian cancer. Multicentre Italian Trials in Ovarian Cancer-2 (MITO-2), an academic multicenter phase III trial, tested whether carboplatin/pegylated liposomal doxorubicin (PLD) was more effective than standard chemotherapy. PATIENTS AND METHODS Chemotherapy-naive patients with stage IC to IV ovarian cancer (age ≤ 75 years; Eastern Cooperative Oncology Group performance status ≤ 2) were randomly assigned to carboplatin area under the curve (AUC) 5 plus paclitaxel 175 mg/m(2) or to carboplatin AUC 5 plus PLD 30 mg/m(2), every 3 weeks for six cycles. Primary end point was progression-free survival (PFS). With 632 events in 820 enrolled patients, the study would have 80% power to detect a 0.80 hazard ratio (HR) of PFS. RESULTS Eight hundred twenty patients were randomly assigned. Disease stages III and IV were prevalent. Occurrence of PFS events substantially slowed before obtaining the planned number. Therefore, in concert with the Independent Data Monitoring Committee, final analysis was performed with 556 events, after a median follow-up of 40 months. Median PFS times were 19.0 and 16.8 months with carboplatin/PLD and carboplatin/paclitaxel, respectively (HR, 0.95; 95% CI, 0.81 to 1.13; P = .58). Median overall survival times were 61.6 and 53.2 months with carboplatin/PLD and carboplatin/paclitaxel, respectively (HR, 0.89; 95% CI, 0.72 to 1.12; P = .32). Carboplatin/PLD produced a similar response rate but different toxicity (less neurotoxicity and alopecia but more hematologic adverse effects). There was no relevant difference in global quality of life after three and six cycles. CONCLUSION Carboplatin/PLD was not superior to carboplatin/paclitaxel, which remains the standard first-line chemotherapy for advanced ovarian cancer. However, given the observed CIs and the different toxicity, carboplatin/PLD could be considered an alternative to standard therapy.

Lymphocyte populations in human lymph nodes. Alterations in CD4+ CD25+ T regulatory cell phenotype and T‐cell receptor Vβ repertoire

Here we provide a description of lymphocyte populations in human lymph nodes (LN) with a special emphasis on the CD4+ lymphocyte population constitutively expressing CD25 at a high level and endowed with immunoregulatory properties [T regulatory (Treg) cells]. Lymph nodes were analysed by multicolour flow cytometry in parallel with correspondent peripheral blood (PB). Immunomagnetically purified Treg cells were tested for anergy and suppressive activity in a CD3/T‐cell receptor (TCR)‐driven proliferation assay. Compared to PB, there was a reduced T/B lymphocyte ratio in LN. Both LN and PB contained a similar proportion of CD4+ lymphocytes but, conversely, CD8+ lymphocytes were less represented in PB, with a consequent increase in the ratio of CD4+/CD8+ natural killer cells were < 2% (PB range 6–22%). No significant differences existed in the frequency of the other lymphocyte subpopulations examined (naïve‐type CD4+ and CD8+ lymphocytes, activated B and CD4+ lymphocytes, and effector‐type CD8+ lymphocytes). LN and PB contained similar percentages of CD4+ lymphocytes constitutively expressing intermediate or high levels of CD25. CD4+ CD25++ cells constitutively coexpressed high levels of CD152 and were therefore identified as Treg cells. Treg cells in LN and PB differed in terms of CD45RB, HLA‐DR, CD45RO, and CD62L expression. Also the TCRVβ repertoire diverged between Treg cells from LN and PB. Similar to Treg cells from PB, Treg cells from LN were anergic and efficiently inhibited other CD4+ and CD8+ lymphocyte proliferation. This study extends the information on the diversities in lymphocyte composition between human LN and PB, and reports for the first time a description of the phenotypic and functional characteristics of Treg cells in human LN, highlighting the importance of the LN microenvironment in shaping the surface phenotype of Treg cells.

Prognostic role of the ratio between cyclooxygenase-2 in tumor and stroma compartments in cervical cancer.

Purpose: The aim of this study was to analyze the clinical role of cyclooxygenase (COX)-2 in a large series of 175 cervical cancer patients. Experimental Design: Immunohistochemistry was performed on paraffin-embedded sections by using rabbit antiserum against COX-2. The tumor:stroma (T/S) ratio of COX-2 expression was used to define the overall COX-2 content in the tumor. Results: The T/S COX-2 ratio values ranged from 0.03 to 48.2 (mean ± SE, 3.7 ± 0.5). A total of 95 of 175 patients (54.3%) were scored as having a high (>1) T/S COX-2 ratio. In locally advanced cervical cancer patients who underwent neoadjuvant treatment, the percentage of cases showing a high T/S COX-2 ratio was greater in patients who did not respond to treatment (26 of 29 patients, 89.7%) than in patients with a partial (32 of 50 patients, 64.0%) or complete (19 of 44 patients, 43.2%) response (P = 0.0003). When logistic regression was applied, International Federation of Gynecologists and Obstetricians (FIGO) stage (χ2 = 11.3; P = 0.0008) and T/S COX-2 ratio (χ2 = 5.3; P = 0.021) retained an independent role in predicting a poor chance of response. Cases with a high T/S COX-2 ratio had a shorter overall survival (OS) [2-year OS, 61%(95% confidence interval 750–83)] than cases with a low T/S COX-2 ratio (2-year OS, 90%; 95% confidence interval, 81–99; P = 0.0001). In multivariate analysis, the status of T/S COX-2 IDV ratio, together with advanced stage, retained an independent negative prognostic role for OS. Conclusions: The assessment of COX-2 status in both tumor and stroma compartment could provide valuable information to identify cervical cancer patients endowed with a very poor chance of response to neoadjuvant treatment and unfavorable prognosis.

Definition of a dynamic laparoscopic model for the prediction of incomplete cytoreduction in advanced epithelial ovarian cancer: Proof of a concept

OBJECTIVE To develop an updated laparoscopy-based model to predict incomplete cytoreduction (RT>0) in advanced epithelial ovarian cancer (AEOC), after the introduction of upper abdominal surgery (UAS). PATIENTS AND METHODS The presence of omental cake, peritoneal extensive carcinomatosis, diaphragmatic confluent carcinomatosis, bowel infiltration, stomach and/or spleen and/or lesser omentum infiltration, and superficial liver metastases was evaluated by staging laparoscopy (S-LPS) in a consecutive series of 234 women with newly diagnosed AEOC, receiving laparotomic PDS after S-LPS. Parameters showing a specificity≥75%, PPV≥50%, and NPV≥50% received 1 point score, with an additional one point in the presence of an accuracy of ≥60% in predicting incomplete cytoreduction. The overall discriminating performance of the LPS-PI was finally estimated by ROC curve analysis. RESULTS No-gross residual disease at PDS was achieved in 135 cases (57.5%). Among them, UAS was required in 72 cases (53.3%) for a total of 112 procedures, and around 25% of these patients received bowel resection, excluding recto-sigmoid resection. We observed a very high overall agreement between S-LPS and laparotomic findings, which ranged from 74.7% for omental cake to 94.8% for stomach infiltration. At a LPS-PIV≥10 the chance of achieving complete PDS was 0, and the risk of unnecessary laparotomy was 33.2%. Discriminating performance of LPS-PI was very high (AUC=0.885). CONCLUSIONS S-LPS is confirmed as an accurate tool in the prediction of complete PDS in women with AEOC. The updated LPS-PI showed improved discriminating performance, with a lower rate of inappropriate laparotomic explorations at the established cut-off value of 10.

Phase II study of the combination carboplatin plus celecoxib in heavily pre-treated recurrent ovarian cancer patients

BackgroundCyclooxygenase-2 overexpression is associated with poor outcome and resistance to platinum-based chemotherapy in ovarian cancer. We evaluated the antitumor activity and safety of the combination carboplatin plus the COX-2 inhibitor celecoxib in recurrent heavily-treated OC patients.MethodsPatients were administered oral celecoxib (400 mg/day) in combination with intravenous carboplatin (AUC5, q28). A Simons two-stage design was employed.Results45 patients were enrolled: 23 (51.1%) presented platinum-resistance, and 27 (60%) had received at least 3 prior regimens for recurrence. The response rate was 28.9% with 3 complete and 10 partial responses (median duration of response = 6 months). Only one (0.4%) G4 non-febrile neutropenia was observed; G3 neutropenia, anemia, or thrombocytopenia, were observed in 2.5%, 1.7%, and 1.7% of the cycles, respectively. G3-4 vomiting was reported in only 1.7%, and 0.4% of the cycles were associated with G3 dyspepsia or diarrhea or constipation. Only one patient experienced G3 hypertension associated to G2 hypersensitivity reaction. No differences in baseline versus post-treatment Quality of Life scores were observed. Median progression free survival and overall survival were 5 and 13 months, respectively.ConclusionsCelecoxib combined with carboplatin showed promising activity and it is well tolerated in heavily-treated recurrent ovarian cancer patients.Trial registration numberNCT01124435 (ClinicalTrials.gov Identifier) and 935/03 (study ID numbers).

Cyclooxygenase-2 (COX-2) expression in locally advanced cervical cancer patients undergoing chemoradiation plus surgery

PURPOSE To investigate whether cyclooxygenase-2 (COX-2) could be a marker of clinical outcome in cervical cancer patients undergoing concomitant chemoradiation plus surgery. METHODS AND MATERIALS The study included 33 locally advanced cervical cancer patients; all underwent neoadjuvant chemoradiation, and responsive patients underwent radical surgery. Immunohistochemistry was performed with rabbit antiserum against COX-2. RESULTS COX-2 integrated density values (IDVs) in the tumor component ranged from 1.4 to 72.3 (median 15.0); in stromal inflammatory cells, COX-2 IDVs ranged from 1.4 to 96.0 (median 16.0). A statistically significant inverse relation was found between the COX-2 IDVs of the tumor vs. the stromal inflammatory component (r = -0.52, p = 0.0017). When the ratio between COX-2 IDV in the tumor vs. the stromal compartment was <or=1, it was considered to indicate cervical tumor with COX-2 expression in the tumor component lower or equivalent to COX-2 expression in the stroma. According to the chosen cutoff value, 17 (51.5%) of 33 were scored as having a high (>1) tumor/stroma COX-2 IDV ratio. Patients with a high tumor/stroma COX-2 IDV ratio had a shorter disease-free survival than did those with a low tumor/stroma COX-2 IDV ratio (p = 0.030). Similarly, those with a high tumor/stroma COX-2 IDV ratio had a shorter overall survival (p = 0.033). CONCLUSION The assessment of COX-2 status in both the tumor and the stromal compartment could provide additional information in the prognostic characterization of cervical cancer patients administered concomitant chemoradiation plus surgery.

Neoadjuvant therapy changes the lymphocyte composition of tumor-draining lymph nodes in cervical carcinoma

The objective of the current study was to illustrate the influence of neoadjuvant therapy on the local immune response in patients with cervical carcinoma.

Laparoscopic Radical Hysterectomy After Concomitant Chemoradiation in Locally Advanced Cervical Cancer: A Prospective Phase II Study

OBJECTIVE To assess the feasibility of laparoscopic radical surgery in patients with locally advanced cervical cancer (LACC) who receive chemoradiation therapy (CT/RT). DESIGN Prospective phase II study (Canadian Task Force classification II-1). INTERVENTION Patients with LACC (FIGO stage IB2-III) were evaluated for accrual at the Gynecologic Oncology Unit of Catholic University, Rome/Campobasso. Neoadjuvant CT/RT included whole-pelvic irradiation (total dose, 45.0-50.4 Gy) combined with cisplatin and 5-fluorouracil. Objective response to treatment was evaluated according to Response Evaluation Criteria in Solid Tumors criteria. Laparoscopic radical hysterectomy (RH) plus pelvic and/or aortic lymphadenectomy was attempted within 6 to 8 weeks after CT/RT. The feasibility of laparoscopic RH, as well as the rate, pattern, and severity of early and late postoperative complications, were analyzed. RESULTS Between January 2010 and October 2013, a total of 58 patients were enrolled into the study. After CT/RT, 23 patients (39.6%) underwent type B2 RH, 31 (53.4%) underwent type C1 RH, and 4 (6.9%) underwent type C2 RH. Pelvic lymphadenectomy was performed in all cases. Laparoscopic RH was feasible in 55 of 58 cases (feasibility rate, 94.8%). No intraoperative complications were recorded. During the observation period (median, 22 months; range, 5-50 months), there were 28 complications, of which only 21.4% were grade 2 complications and 14.3% were grade 3 complications. As of January 2015, disease recurrence was documented in 4 cases (6.9%). CONCLUSION Total laparoscopic radical surgery is feasible in patients with LACC receiving preoperative CT/RT, providing perioperative outcomes comparable to those registered in early-stage disease.