Corrado Terranova

Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition

Significance Some cancers, termed carcinosarcomas (CSs), have mixed cell types, with either epithelial or mesenchymal features. Sequencing the genomes of uterine and ovarian CSs demonstrated that these different cell types derive from a common precursor cell that has many mutations typical of epithelial cancers. In addition, we find that these tumors have a significant burden of point mutations and amplification of histone genes, suggesting a potential role of these mutations in sarcomatous transformation. Consistent with this finding, expression of specific histone gene mutations in uterine carcinoma cells changed gene expression toward a mesenchymal state. These findings have potential implications for the treatment of these cancers. Carcinosarcomas (CSs) of the uterus and ovary are highly aggressive neoplasms containing both carcinomatous and sarcomatous elements. We analyzed the mutational landscape of 68 uterine and ovarian CSs by whole-exome sequencing. We also performed multiregion whole-exome sequencing comprising two carcinoma and sarcoma samples from six tumors to resolve their evolutionary histories. The results demonstrated that carcinomatous and sarcomatous elements derive from a common precursor having mutations typical of carcinomas. In addition to mutations in cancer genes previously identified in uterine and ovarian carcinomas such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4, and BCOR, we found an excess of mutations in genes encoding histone H2A and H2B, as well as significant amplification of the segment of chromosome 6p harboring the histone gene cluster containing these genes. We also found frequent deletions of the genes TP53 and MBD3 (a member with CHD4 of the nucleosome remodeling deacetylase complex) and frequent amplification of chromosome segments containing the genes PIK3CA, TERT, and MYC. Stable transgenic expression of H2A and H2B in a uterine serous carcinoma cell line demonstrated that mutant, but not wild-type, histones increased expression of markers of epithelial–mesenchymal transition (EMT) as well as tumor migratory and invasive properties, suggesting a role in sarcomatous transformation. Comparison of the phylogenetic relationships of carcinomatous and sarcomatous elements of the same tumors demonstrated separate lineages leading to these two components. These findings define the genetic landscape of CSs and suggest therapeutic targets for these highly aggressive neoplasms.

A comparison of three different entry techniques in gynecological laparoscopic surgery: a randomized prospective trial

OBJECTIVEnLaparoscopic entry techniques vary and still remain debated. We conducted a randomized control trial to compare three entry techniques.nnnSTUDY DESIGNnWomen aged 18-70 years, nominated for laparoscopic surgery at University of Rome Campus Bio-Medico, were randomized into three different groups: Veress needle (VER), Direct trocar insertion (DIR) and Open technique (OP). For each group, minor complications (extra-peritoneal insufflation, trocar site bleeding, omental injury and surgical site infection), failed entry and time of entry of the main trocar were evaluated. Major complications were also considered. Between-group comparisons were performed using chi-square test. Significance P value was <0.05.nnnRESULTSnA series of 595 consecutive procedures were included: 193 in the VER group, 187 in the DIR group and 215 in the OP group. Minor complications occurred in 36 cases: extraperitoneal insufflation (n=6) in the VER group only, site bleeding (n=2 in the VER group, n=2 in the DIR group and n=1 in the OP group), site infection (n=5 in the VER and n=6 in OP group), and omental injury (n=6 in the VER group and n=3 in the DIR group). Failed entry occurred in 4 cases of the VER group and 1 case of the DIR group. Mean time of entry was 212.4, 71.4 and 161.7s for the VER, DIR and OP groups respectively. Among major complications, one bowel injury resulted following the Veress technique.nnnCONCLUSIONSnIn our series, DIR and OP entry presented a lower risk of minor complications compared with VER. In addition, time of entry was shorter in DIR than with OP entry.

Dual HER2/PIK3CA Targeting Overcomes Single-Agent Acquired Resistance in HER2-Amplified Uterine Serous Carcinoma Cell Lines In Vitro and In Vivo

HER2/neu gene amplification and PIK3CA driver mutations are common in uterine serous carcinoma (USC) and may represent ideal therapeutic targets against this aggressive variant of endometrial cancer. We examined the sensitivity to neratinib, taselisib, and the combination of the two compounds in in vitro and in vivo experiments using PIK3CA-mutated and PIK3CA wild-type HER2/neu–amplified USC cell lines. Cell viability and cell-cycle distribution were assessed using flow-cytometry assays. Downstream signaling was assessed by immunoblotting. Preclinical efficacy of single versus dual inhibition was evaluated in vivo using two USC xenografts. We found both single-agent neratinib and taselisib to be active but only transiently effective in controlling the in vivo growth of USC xenografts harboring HER2/neu gene amplification with or without oncogenic PIK3CA mutations. In contrast, the combination of the two inhibitors caused a stronger and long-lasting growth inhibition in both USC xenografts when compared with single-agent therapy. Combined targeting of HER2 and PIK3CA was associated with a significant and dose-dependent increase in the percentage of cells in the G0–G1 phase of the cell cycle and a dose-dependent decline in the phosphorylation of S6. Importantly, dual inhibition therapy initiated after tumor progression in single-agent–treated mice was still remarkably effective at inducing tumor regression in both large PIK3CA and pan-ErbB inhibitor–resistant USC xenografts. Dual HER2/PIK3CA blockade may represent a novel therapeutic option for USC patients harboring tumors with HER2/neu gene amplification and mutated or wild-type PIK3CA resistant to chemotherapy. Mol Cancer Ther; 14(11); 2519–26. ©2015 AACR.

Preoperative local staging of endometrial cancer: the challenge of imaging techniques and serum biomarkers

ObjectiveThe aim of this study is to prospectively evaluate and compare the accuracy of high-frequency TVS and of two type of MRI (dynamic contrast-enhanced MRI or diffusion-weighted MRI), in association with HE4 in preoperative endometrial cancer (EC) staging.Study designStarting from January 2012 to February 2015, all patients with EC at prior endometrial biopsy, referred to the Division of Gynaecologic Oncology of the University Campus Bio-Medico of Rome, were prospectively included in the study. All of them underwent complete surgical staging hysterectomy and bilateral oophorectomy, pelvic and lumboaortic lymphadenectomy, according to 2011 NCCN guidelines. The day before surgery, patients underwent to transvaginal ultrasonography (TVS), HE4 serum dosage, and using a computer-based random procedure, to dynamic contrast-enhanced MRI (Group A) or to diffusion-weighted MRI (Group B), to assess myometrial invasion and cervical involvement.ResultsStarting from January 2012 to February 2015, a total of 79 patients were considered for the analysis and randomly divided into Group A (nxa0=xa038) and Group B (nxa0=xa041). Regarding myometrial invasion, MRI and TVS resulted comparable in terms of preoperative detection. Concerning the cervical infiltration, the association between TVS and HE4 is characterized by a better preoperative diagnostic validity (TVSxa0+xa0HE4 96.3 vs. 91xa0% for MRI and 85xa0% for the TVS).ConclusionOur results, even the low number of enrolled patients, are promising and may lead to a greater efficiency and lower health care costs in identifying those women who require radical surgery and pelvic lymphadenectomy and should be addressed, in specialized centers.

A randomized controlled trial comparing four versus six courses of adjuvant platinum-based chemotherapy in locally advanced cervical cancer patients previously treated with neo-adjuvant chemotherapy plus radical surgery

OBJECTIVES. The aim of this study was to compare 4 versus 6 courses of adjuvant chemotherapy after neoadjuvant chemotherapy plus radical surgery in terms of overall survival (OS), disease-free survival (DFS), recurrence rate and toxicity profile. METHODS. We randomly assigned 200 patients with IB2-IIB cervical cancer to receive 4 (Group A) or 6 (Group B) courses of cisplatin 100 mg/mq and paclitaxel 175 mg/mq every 21 days. RESULTS. At 4-years follow-up, the comparison of recurrence rate (p = 1; RR = 1.005; 95% CI = 0.87 to 1.161), OS (p = 0.906) and DFS (p = 0.825) did not show statistically significant differences between the two groups. Data analysis showed statistically significant differences between the two groups in term of episodes of leukopenia (p = 0.0072; RR = 1.513; 95% CI = 1.127-2.03), anemia (p = 0.048; RR = 1.188; CI = 1.012-1.395) and febrile neutropenia (p = 0.042; RR = 1.119; 95% CI = 1.014-1.235), in favor of Group A. As regards non-hematological toxicities, there were no statistically significant differences in terms of gastrointestinal symptoms (p = 0.49; RR = 1.046; CI = 0.948-1.153. On the contrary, there was a statistically significant difference regarding neurological symptoms (p=0.014; RR=1.208; CI=1.046-1.395), that were less frequent in Group A (13%) than in Group B (28%). CONCLUSIONS. Adjuvant treatment with 4 or 6 courses of platinum-based chemotherapy showed similar results in terms of OS and DSF, with a favorable toxicity profile in favor of the first regimen.

Surgical treatment of rectovaginal endometriosis with extensive vaginal infiltration: results of a systematic three-step vagino-laparoscopic approach

OBJECTIVEnRecto-vaginal endometriosis remains a surgical challenge. We propose a systematic surgical approach combining vaginal and laparoscopic steps for patients affected by deep endometriosis infiltrating the vaginal wall.nnnSTUDY DESIGNnThis is a prospective observational study, performed at Campus Bio-Medico of Rome, University Teaching Hospital. All consecutive patients, from 2008 to 2011, affected by symptomatic deep recto-vaginal endometriosis with full thickness vaginal wall involvement, underwent a systematic surgical approach, based on three consecutive surgical steps: vaginal route, laparoscopic approach and final vaginal excision. All patients included in the study were scheduled for two years follow-up with pelvic examination, transvaginal ultrasound and visual analog scale (VAS) evaluation of symptoms (dysmenorrhea, dyspareunia and chronic pelvic pain) at 3, 6, 12 and 24 months.nnnRESULTSnThirty-four patients were enrolled. No major complications were registered. Complications included superficial vascular lesions in two cases (5.9%), ureteral stenosis two weeks after surgery in one patient (2.9%), and bowel obstruction for paralytic ileus in one patient (2.9%). A de novo endometrioma was found at 12 months after surgery and a recurrent endometrioma was evident at 24 months. For all symptoms evaluated, there was a significant improvement within 3 months after surgery (p<0.05) and no statistically significant difference during follow-up (at 3, 6, 12 and 24 months).nnnCONCLUSIONnThe proposed systematic surgical approach consisting of three consecutive steps could simplify the approach to deep endometriosis while at the same time increasing the quality of endometriosis surgery, with important benefit for the women affected.

The Role of He4, a Novel Biomarker, in Predicting Optimal Cytoreduction After Neoadjuvant Chemotherapy in Advanced Ovarian Cancer

Objectives This study aimed to evaluate serum human epididymis protein 4 (HE4) changes during neoadjuvant chemotherapy (NACT) to establish HE4 predebulking surgery cutoff values and to demonstrate that CA125, HE4, and computed tomography (CT) taken together are better able to predict complete cytoreduction after NACT in advanced ovarian cancer patients. Methods From January 2006 to November 2015, patients affected by epithelial advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III–IV), considered not optimally resectable, were included in this prospective study. After 3 cycles of NACT, all patients underwent debulking surgery and were allocated, according to residual tumor (RT), into group A (RT = 0) and group B (RT > 0). Serum CA125, HE4, and CT images were recorded during NACT and compared singularly and with each other in term of accuracy, sensitivity, specificity, and positive and negative predictive value. Results A total of 94 and 20 patients were included in group A and group B, respectively. The HE4 values recorded before debulking surgery correlated with RT. The identified HE4 cutoff value of 226 pmol/L after NACT was able to classify patients at high or low risk of suboptimal surgery, with a sensitivity of 75% and a specificity of 85% (positive predictive value, 0.87; negative predictive value, 0.70). The combination of CA125, HE4, and CT imaging resulted in the best combination with a sensitivity of 96% and a specificity of 92% (positive predictive value, 0.96; negative predictive value, 0.94). Conclusions The novel biomarker HE4, in addition to CA125 and CT, is better able to predict the RT at debulking surgery and the prognosis of patients.

Suburethral sling in autoimmune patients: complications, quality of life, and success rate

Introduction and hypothesisSuburethral sling procedures are a mainstay for the surgical treatment of stress urinary incontinence (SUI). The interaction between the sling and the host is fundamental for the success of the procedure. Patients affected by autoimmune disease present with an overactive immune system; this should theoretically increase rejection risk.MethodsThe data from 19 autoimmune patients affected by SUI were retrospectively collected. Primary outcome consisted of evaluating whether tape-related complications may occur more frequently. Secondary outcome measures were assessment of objective and subjective cure of SUI. Changes from baseline were analyzed using the Mann–Whitney and Fisher tests.ResultsSuccess rate, evaluated at 12-month follow-up, was 89.5%. No tape erosion or urinary retention was observed; chronic pelvic pain and dyspareunia rates were 5.26% and 15.4%, respectively. One patient developed de novo urgency.ConclusionsAccording to our experience, the suburethral sling is a safe procedure with low complication rates comparable to those reported in the literature.

Liposome Encapsulated Doxorubicin Citrate (Ledc) as an AlternativeTherapeutic Option for Patients with Recurrent Ovarian Cancer Sufferingfrom Doxorubicin-Related Cutaneous Toxicity

Introduction: Pegylated liposomal doxorubicin (PLD) is considered to be the single-agent of first choice for patients with recurrent ovarian cancer following paclitaxel/carboplatin-based chemotherapy. However, this drug is associated with a local inflammatory tissue reaction, called palmoplantar erythrodysesthesia (PPE). A new liposomal formulation, known as Liposome Encapsulated Doxorubicin Citrate (LEDC), has been developed in the past decades to limit PPE. In this study we report our experience with LEDC in patients with recurrent ovarian cancer who discontinued doxil due to severe PPE. nMethods: The present retrospective study included 43 patients with recurrent ovarian cancer who were treated with LEDC administered at the dose of 50 mg/mq every 3 weeks until disease progression or unacceptable toxicity. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria Version 3. Response was graded according to Response Evaluation Criteria in Solid Tumors (RECIST). nResults: A total of 32 patients completed planned 6 cycles of chemotherapy. A complete response was achieved in 6%, partial response in 20%, stable disease in 37% and progression in 9% of patients. No cutaneous toxicity was reported. nConclusion: LEDC is a well tolerated drug and a valid therapeutic option for patients with ovarian cancer suffering from doxil-related cutaneous toxicity.

Implementing the Risk of Endometrial Malignancy Algorithm (REM) adding obesity as a predictive factor: Results of REM-B in a single-center survey

OBJECTIVEnIn 2013, our group assessed a risk stratification tool of endometrial cancer (EC), called REM (Risk of Endometrial Malignancy). A well known risk factor for EC is body mass index (BMI). In fact, (BMIu202f>u202f30 and <35u202fkg/m2) and severe obesity (BMIu202f>u202f35u202fkg/m2) were associated with a 2.6-fold and a 4.7-fold increase in EC risk, respectively. Therefore, in the present study we aim to improve the performance of REM, including BMI and developing a new scoring system, called REM-B (Risk of Endometrial Malignancy score associated to BMI), to classify patients into high risk or low risk groups for EC.nnnSTUDY DESIGNnWomen, between 45 and 80 years, diagnosed with ultrasound endometrial abnormalities and scheduled to have surgery were enrolled on a prospective study at Department of Gynaecologic Oncology of Campus Bio-Medico of Rome. Preoperative clinical, ultrasound and laboratory features were taken into account.nnnRESULTSnA total of 675 patients (88 with EC and 587 with benign endometrial disease) were divided in training set (TS) and verification set (VS). Age, symptom, BMI, HE4 levels and ultrasound endometrial thickness were found statistically significant and included into multivariate logistic regression model in order to determine the probability to have EC. REM-B showed an overall sensitivity of 94.7% (versus 92% of REM) and a specificity of 97.4% (versus 96% of REM).nnnCONCLUSIONSnOur data support the use of REM-B to triage patients into low and high risk of EC, even if an external validation of model is needed.