Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix.

High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D/MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4, a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib (P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies.

The Role of TAP/RS Block in Minor Gynecologic Laparoscopic Surgery: A Randomized Clinical Trial.

OBJECTIVES: The aim of the study was to compare, in patients undergoing minor gynecological laparoscopic procedures, the effects of ultrasound (US)-guided transversus abdominis plane (TAP) + rectus sheath (RS) block versus no TAP/RS block in terms of post-surgical pain control using the numeric pain rating scale (NRS) and the degree of patient satisfaction, according to the main goals of Early Recovery After Surgery (ERAS) programs. The primary outcome is to value the postoperative abdominal pain using NRS in both groups. Secondary outcomes are to evaluate blood values, presence of postoperative nausea and vomiting (PONV), postoperative ileus, level of patient expected satisfaction, time of discharge, length of stay (LOS), and the amounts of additional analgesics required. DESIGN: In this prospective randomized controlled trial, patients were randomly assigned to loco-regional anesthesia (LRA) group, who received TAP and RS block under US guidance, or no loco-regional anesthesia (N-LRA) group. Enrolled patients were randomized 1:1 to either receive bilateral TAP/RS block with ropivacaine or sham treatment (patches were applied on the abdominal wall of the patients under general anesthesia). PARTICIPANTS: All patients aged between 18 and 75 years, with ASA (American Society of Anesthesiologists) physical status 1-2, undergoing laparoscopic minor gynecological surgery, were enrolled. SETTING: The study was conducted to the University of Campus Bio-Medico Hospital of Rome. METHODS: Half an hour before surgery, all patients received gabapentin 300 mg per os. Once the patient underwent general anesthesia, US-guided bilateral TAP/RS block was performed by the anesthesiology team, while the uterine manipulator was positioned by a gynecology resident (not involved in the study). In the operative room, all patients received the same standardized anesthetic regimen. Postoperative abdominal pain was assessed at rest, after palpation, during movement, and after a cough by evaluating the patient at 6, 12, 18, 24, 36, 48, and 72 h after surgery, using the NRS from 0 to 10 in both groups. The amount of drug used for analgesia in the first 48 h after surgery was recorded. Moreover, hemoglobin, white blood cells, and c-reactive protein levels were recorded at 24, 48, and 72 h. The presence of PONV and the postoperative ileus was recorded throughout convalescence. The expected level of patient satisfaction at discharge and finally the LOS were assessed. LIMITATIONS: The major weakness of this study is that 60 mL of 0.5% ropivacaine was administered to each patient, without considering weight differences, yet contemporary literature rarely suggests volume/dose titration in fascial blocks. RESULTS: A total of 104 women, undergoing gynecological minor laparoscopic surgery, were enrolled and assigned to LRA group (53 pts) and N-LRA group (51 pts). Postoperative pain was significantly reduced in patients who received TAP/RS block. A reduction in the intake of non-steroidal anti-inflammatory drugs after surgery was registered in LRA group (p < 0.01). Moreover, a significant reduction of LOS (45.97 ± 9.87 vs. 65.08 ± 17.32 h; p < 0.01) and PONV was observed in the LRA group, as well as a better level of patient satisfaction at discharge (9.43 ± 0.94 vs. 8.26 ± 1.19; p < 0.01), compared to the N-LRA group. CONCLUSIONS: US-guided TAP and RS block significantly reduces postoperative pain after minor gynecologic laparoscopic surgery and improves patients' post-operative recovery.

Efficacy of termoablative fractional CO2 laser (Monnalisa Touch) in stress urinary incontinence.

PURPOSE: Usually, in stress urinary incontinence (SUI), nonsurgical therapy such as pelvic floor muscle training (PFMT) and lifestyle changes are proposed before surgical treatment. Laser therapy has recently been recommended for the treatment of SUI, helping to reconstruct the collagen that supports the vagina and the pelvic floor. The aim of the study was to evaluate the efficacy of SUI treatment with a CO2 intravaginal laser in patients waiting for anti-incontinence surgery (TVT-O). METHODS: This is a prospective, case-control study. Fifty-two patients have been included in our study and we divided them into two groups: atrophy and no atrophy. We also adopted a control group retrospectively identified from our database of patients undergoing PFMT. The subjective estimation of SUI symptoms before and after treatment was evaluated using the Visual Analog Scale before and after 1, 6, and 12 months of treatment. The objective evaluation with the urodynamic study with the stress test and a 3-day voiding diary to count the number of episodes of incontinence, before and after treatment. RESULTS: The intravaginal CO2 laser improved all the parameters considered for SUI in both groups. Its results were more relevant in the atrophy group, in comparison to the no atrophy group, even if they were both statistically significant. There were no statistically significant differences for all the parameters evaluated for SUI between laser treatment and PFMT in the control group. CONCLUSION: The CO2 laser is well-tolerated, minimally invasive, safe, and showing efficacy for SUI. More studies are needed to consider it as first-instance therapy, like PFMT, or at least, as a bridge therapy to surgery.

Role of Protopine and Nuciferine in the Management of Nocturia, Urgency, and Dysuria in Pre- and Postmenopausal Women: A Prospective Pilot Study.

OBJECTIVES: Nocturia was commonly treated with drugs burdened with high costs and numerous side effects; in fact, more than 70% of patients drop out of long-term treatment. Protopine and nuciferine are two alkaloids that have different effects on the neurotransmitter receptors involved in the regulation mechanism of the onset of urinary stimuli. The aim of the study was to evaluate the efficacy in controlling primarily nocturia and secondarily urgency and dysuria after 3 months of treatment with combination therapy of protopine and nuciferine syrup. DESIGN: This is a prospective cohort study in which all patients were diagnosed with overactive bladder syndrome (OAB) and the presence of the following symptoms: nocturia, urgency, and dysuria. Thirty patients were administered 10 mL/die (16.6 mg of nuciferine, 0.09 mg of protopine) of syrup for 3 months. Patients were evaluated at baseline (T0) with the International Consultation on Incontinence Questionnaire (ICIQ), Visual Analogue Scale (VAS) for the evaluation of dysuria, Patient Perception of Intensity of Urgency Scale (PPIUS) and at 3 months (T1) with the Patients' Global Impression of Change (PGI-C) scale, PPIUS, VAS, and ICIQ. PARTICIPANTS: Women with diagnosis of OAB; the presence of nocturia, urgency, and dysuria symptoms agreeing to undergo treatment and compiling informed consent; and the absence of contraindications to the use of active ingredients were included in the study. SETTING: Patients were recruited at T0 during the visit to the Uro-Gynecology clinic of the University of "Campus Bio-Medico" and visited again 3 months (T1) after the initiation of therapy. METHODS: We explored survey data by descriptive statistics: in particular, continuous values (i.e., ICIQ) have been summarized by mean and standard deviation of discrete ordinal values (i.e., VAS, PPIUS, and bladder diary parameters at T0 and T1) by median, minimum, and maximum reported scores. Where we could assume normality in distribution, assessed by the Shapiro-Wilk test and the evaluation of the QQ plot, we compared the observation of T0 and T1 with the paired Student's t test; otherwise, we tested differences in distribution with the paired Mann-Whitney U test. RESULTS: Thirty patients completed a 3-month therapy. The ICIQ and VAS questionnaires for the assessment of dysuria, both, reported an improvement in dysuria at T1 (p < 0.001). The PPIUS questionnaire reported an improvement in urinary urgency at T1 (p < 0.001). The PGI-C scale in T1 indicated an improvement in symptoms: 93% for nocturia, 70% for urinary urgency, and 63% for dysuria. LIMITATIONS: The weaknesses of this study are the small number of patients; as a pilot study, the study design was not randomized with a placebo and without blinding; and the short follow-up. CONCLUSIONS: Protopine and nuciferine can be an interesting alternative to primarily treat and reduce nocturia episodes, in addition to improving OAB-related urgency and dysuria.

The use of sealing hemostat patch (HEMOPATCH®) in laparotomic myomectomy: a prospective case-control study.

PURPOSE: Uterine myomas are the most common gynecological disease. In these cases, a myomectomy is performed traditionally laparotomically. However, alternatives have been widely used, including laparoscopic, endoscopic, and robotic surgery. During these techniques, diffuse parenchymatous bleeding remains one of the main intraoperative and postoperative complications and sometimes requires unplanned hysterectomies. Recently, hemostatic agents and sealants have been used to prevent excessive blood loss during surgical repair. METHODS: We propose a prospective case-control study on the use of a sealing hemostat patch (HEMOPATCH®) on uterine sutures in laparotomic myomectomy. In the period between July 2016 and April 2017, 46 patients with symptomatic uterine fibromatosis underwent surgery. They were divided into two groups of 23 patients, with different treatments in the hemostatic phase of oozing bleeding. HEMOPATCH® is applied in group A, and spray electrocoagulation is applied in group B. RESULTS: In group A, we achieve faster hemostasis (p < 0.05), than in group B. We report a significantly lower C-reactive protein value on the second and third days after surgery for group A compared to group B. CONCLUSIONS: HEMOPATCH®, during laparotomic myomectomy, is a valid alternative solution for obtaining rapid hemostasis and consequently intraoperative and postoperative bleeding. Furthermore, we suggest that a lower inflammatory peritoneal state is probably correlated with the barrier effect of the patch on the suture.

Front-line chemo-immunotherapy with carboplatin-paclitaxel using oregovomab indirect immunization in advanced ovarian cancer: A randomized phase II study.

BACKGROUND: This randomized phase II study tested the hypothesis that schedule dependent chemo-immunotherapy with oregovomab improves progression free survival (PFS) and overall survival (OS) in optimally resected, Stage III/IV ovarian cancer. METHODS: Patients from both academic centers and private practice in the US and Italy with Stage III/IV optimally cytoreduced ovarian cancer were randomized to standard six cycle IV carboplatin-paclitaxel chemotherapy (CP) versus CP plus four immunizations with oregovomab (CPO). A translational assessment of a cellular immune response was the primary endpoint; PFS and OS were measured as secondary endpoints. FINDINGS: 97 patients at thirteen centers were accrued to the protocol, 47 to CPO and 50 to CP. Technical issues led to inconsistent performance of the primary CA125 ELISPOT leading to unevaluable results. At a median follow up of 42 months, PFS and OS outcomes revealed an unexpectedly large treatment effect for CPO relative to CP alone, with median PFS of 41.8 months (95% C.I.: 21.8 - N.E.) for CPO and 12.2 months (10.4-18.6) for CP (p = 0.0027, HR 0.46, CI 0.28-0.7). For OS, the median for CPO has not yet been reached (NE) (45.2-NE) and for CP was 43.2 months (31.8-NE) (p = 0.043, HR 0.35, CI 0.16-0.74). The oregovomab treatment resulted in no change in toxicity profile from CP. INTERPRETATION: The previously identified potential clinical benefit of IV CP when administered with oregovomab was further refined in this randomized phase II study. Increases of PFS and OS of statistically and clinically significant magnitude were evident in this study of a front line chemo-immunotherapy treatment of ovarian cancer.

European Menopause and Andropause Society (EMAS) and International Gynecologic Cancer Society (IGCS) position statement on managing the menopause after gynecological cancer: focus on menopausal symptoms and osteoporosis.

Worldwide, it is estimated that about 1.3 million new gynecological cancer cases are diagnosed each year. For 2018, the predicted annual totals were cervix uteri 569 847, corpus uteri 382 069, ovary 295 414, vulva 44 235, and va​gina 17 600. Treatments include hysterectomy with or without bilateral salpingo-oophorectomy, radiotherapy, and chemotherapy. These can result in loss of ovarian function and, in women under the age of 45 years, early menopause. The aim of this position statement is to set out an individualized approach to the management, with or without menopausal hormone therapy, of menopausal symptoms and the prevention and treatment of osteoporosis in women with gynecological cancer. Our methods comprised a literature review and consensus of expert opinion. The limited data suggest that women with low-grade, early-stage endometrial cancer may consider systemic or topical estrogens. However, menopausal hormone therapy may stimulate tumor growth in patients with more advanced disease, and non-hormonal approaches are recommended. Uterine sarcomas may be hormone dependent, and therefore estrogen and progesterone receptor testing should be undertaken to guide decisions as to whether menopausal hormone therapy or non-hormonal strategies should be used. The limited evidence available suggests that menopausal hormone therapy, either systemic or topical, does not appear to be associated with harm and does not decrease overall or disease-free survival in women with non-serous epithelial ovarian cancer and germ cell tumors. Caution is required with both systemic and topical menopausal hormone therapy in women with serous and granulosa cell tumors because of their hormone dependence, and non-hormonal options are recommended as initial therapy. There is no evidence to contraindicate the use of systemic or topical menopausal hormone therapy by women with cervical, vaginal, or vulvar cancer, as these tumors are not considered to be hormone dependent.

Diet and Chemotherapy: The Effects of Fasting and Ketogenic Diet on Cancer Treatment.

INTRODUCTION: Diet may influence various aspects of human health. In fact, it is well known that diet can favour or not the development of various human pathologies, like diabetes, hypertension, and hypercholesterolaemia. Interestingly, diet has an influence in cancer development too (e.g., this relation has been studied for pancreatic, colonic, gastric, and breast cancers). Between the mechanisms that could explain this relation, there is epigenetic. In fact, thanks to epigenetic reprogramming, certain substances introduced with diet could affect gene expression, especially of those genes involved in cells' proliferation and growth. In recent years, some studies have been published about the role that diet could have on chemotherapy outcome. Especially, various studies have analysed the effects of fasting and ketogenic diet (KD) during chemotherapy. The aim of this study is to summarize scientific evidences about diet and its effects on chemotherapy on humans and to better understand if these approaches deserve to be further investigated and might be suitable and beneficial during cancer treatment. MATERIALS AND METHODS: We performed an electronic literature search of the PubMed database, using the combination of following terms: "fasting" or "ketogenic" with "chemotherapy," "cancer treatment." We included studies on humans about fasting and KD during chemotherapy, excluding reviews, case series including <10 patients, studies conducted on animals or limited to radiotherapy treatment, and studies that were mostly about molecular mechanisms. Results/Discussion In our analysis we included 4 studies (1 randomized controlled trial, 1 retrospective study, and 2 prospective pilot studies) about KD and 4 studies (1 prospective cohort study, 1 case series report, and 2 randomized trials) about fasting during oncological treatments. Authors suggested an improvement of quality of life (QoL) and fatigue in patients under chemotherapy, especially in the 8 days after chemotherapy treatment. We found that both fasting and KD demonstrated to be tolerable and feasible during oncological treatments. Conversely, data about survival outcomes are still controversial, but it should be underlined that it was not the outcome of these preliminary studies. CONCLUSIONS: All comparatives studies have demonstrated that even fasting then KD results in a reduction of collateral effects of adjuvant chemotherapy (due to reduction of drugs toxicity) and a better QoL than in patients that follow no diet. Unfortunately, despite the fact that various laboratory and animal studies confirm advantages from KD and fasting, few data are today disposable on humans: further studies are needed to confirm data exposed in this review.

Role of human epididymis protein 4 (HE4) in detecting recurrence in CA125 negative ovarian cancer patients.

OBJECTIVE: There are no current guidelines regarding evaluation of patients with normal CA125 at initial diagnosis during routine surveillance after completion of treatment. Thus, the purpose of this study was to evaluate the role of human epididymis protein 4 (HE4) in the detection of recurrence in patients with ovarian cancer and a negative CA125 at diagnosis. METHODS: All patients with ovarian cancer with a negative CA125 referred to the Division of Gynecologic Oncology of the University Campus Bio-Medico of Rome were included in the study. Inclusion criteria were: age between 18 and 70 years old, diagnosis of epithelial ovarian cancer, optimal primary surgery (residual tumor <1 cm), and normal CA125 at initial diagnosis. Patients with other malignancies or chronic diseases were excluded from the study. Statistical analysis was based on the calculation of percentages, means, medians, and ranges of the values. RESULTS: A total of eight patients were included in the study. The median age was 53 years (range 40-75). All patients had a normal CA125 at initial diagnosis while seven (87.5%) patients had abnormal HE4 levels at diagnosis. The International Federation of Gynecology and Obstetrics (FIGO) stages at enrollment varied from IC to IIIC (IB (1), IC (3), IIC (1), IIIC (3)). The most common histologic subtype was serous (62.5%). Seven patients recurred and had abnormal HE4 and normal CA125 values. The median HE4 at recurrence was 107 pmol/L. The median disease-free interval was 55 months (range 5-108) and all the patients underwent optimal cytoreductive surgery. CONCLUSIONS: HE4 levels may serve as a marker for recurrence in patients with a normal CA125 at initial diagnosis. Future studies are needed to evaluate the role of HE4 levels in earlier detection of recurrent ovarian cancer.

Assessing HPV vaccination perceptions with online social media in Italy.

OBJECTIVE: Because of the widespread availability of the internet and social media, people often collect and disseminate news online making it important to understand the underlying mechanisms to steer promotional strategies in healthcare. The aim of this study is to analyze perceptions regarding the human papillomavirus (HPV) vaccine in Italy. METHODS: From August 2015 to July 2016, articles, news, posts, and tweets were collected from social networks, posts on forums, blogs, and pictures about HPV. Using other keywords and specific semantic rules, we selected conversations presenting the negative or positive perceptions of HPV. We divided them into subgroups depending on the website, publication date, authors, main theme, and transmission modality. RESULTS: Most conversations occurred on social networks. Of all the conversations regarding HPV, more than 50% were about vaccination. With regard to conversations exclusively on the HPV vaccine, 47%, 32%, and 21% were positive, negative and neutral, respectively. Only 9% of the conversations mentioned the vaccine trade name and, in these conversations, perception was almost always negative. We observed many peaks in positive conversation trends compared with negative trends. The peaks were related to the web dissemination of particular news regarding HPV vaccination. CONCLUSIONS: In this study we have shown how mass media influences the diffusion of both negative and positive perceptions about HPV vaccines and suggest better ways to inform people about the importance of HPV vaccination.

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

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.

Anterior colporrhaphy plus inside-out tension-free vaginal tape for associated stress urinary incontinence and cystocele: 10-year follow up results.

AIMS: We report the success rate and complications rate of combined ultralateral anterior Colporrhaphy plus Tension-free Vaginal Tape (TVT-O) in a long-term (10 year) follow-up prospective survey. METHODS: Patients previously treated for associated stress urinary incontinence (SUI) and cystocele were subjected to annual follow-up for 10 year with a complete urogynecologic evaluation. Furthermore, an urodynamic assessment and a quality of life questionnaire (ICIQ-UI SF) were recorded at the 5th and 10th year of follow up. RESULTS: Fifty patients treated between June 2004 and May 2006 were included in the analysis. Five patients did not return to 5-yr follow-up: two patients developed a median tape erosion and three patients withdraw. At 10-yr follow-up two more patients withdraw for a total of seven patients lost to follow-up. After 10 years patients objectively cured from cystocele were 41 (95%) while patients objectively cured from SUI were 39 (91%). At 10th year follow-up 38 patients (89%) result cured from both SUI and cystocele, 3 (7%) patients result cured only from prolapse, 1 (2%) patient only from SUI, and 1 (2%) patient result objectively failed for both SUI and cystocele. The ICIQ-UI SF scores at 10th year follow-up was 6.2 ± 3.7. The late complication rate at 10th year follow-up was 32% (OAB symptoms 20%; Mixed incontinence 2%; Bladder outlet obstruction 0%; Dyspareunia 6%; Chronic pelvic pain 0%; Vaginal tape erosion 4%; Detrusor hyperactivity 0%). CONCLUSIONS: The combined procedures shown proved to be an effective and safe procedure to treat concomitant SUI and cystocele.

Assessment of Quality of Life and Urinary and Sexual Function After Radical Hysterectomy in Long-Term Cervical Cancer Survivors.

AIMS: The aim of this study was to evaluate long-term quality of life and urinary and sexual function in long-term cervical cancer survivors previously treated with radical hysterectomy (RH) type C2/type III. METHODS: All patients who presented at Campus Bio-Medico of Rome for RH type C2/type III for cervical cancer were considered eligible for this retrospective study protocol. We included exclusively patients with complete response to primary treatment with at least 36 months of follow up. Included subjects were interviewed with the European Organization for Research and Treatment of Cancer QLQ-CX24 Questionnaire, European Organization for Research and Treatment of Cancer QLQ-C30, and an Incontinence Impact Questionnaire 7. RESULTS: From January 2004 to June 2014, 251 patients affected by locally advanced cervical cancer were treated at Campus Bio-Medico of Rome treated with type C2/type III RH. At time point of March 2017, 90 patients were included with a mean age of 55.6 ± 8.5 years. The questionnaires were administered after a median follow-up of 49 months after the end of therapy. The symptoms of fatigue, nausea and vomiting, appetite loss, pain, insomnia, and dyspnea, as well as a negative financial impact, were reported as not frequent and rarely disabling. On the contrary, patients frequently reported gastrointestinal complaints. Diarrhea was present in 6% of patients and was referred as mild; constipation was present in 75% of women and was reported as mild in 30% of cases, moderate in 30%, and severe in 15%. Concerning sexual activity, data indicated a good level of sexual enjoyment with a slight worsening of sexual activity. Incontinence was reported in 28% of cases and appeared to be mild and rarely disabling (all mean values <2). CONCLUSIONS: Waiting for ongoing randomized controlled trials, this study confirmed that RH may be considered as a useful treatment plan, according to its negligible long-term impact on quality of life, urinary dysfunction, and sexual function.

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.

The role of HE4 in endometrial cancer recurrence: how to choose the optimal follow-up program.

The aim of this study was to evaluate for the first time in the literature the role of HE4, at primary diagnosis, compared to CA125 as an indicator of endometrial cancer (EC) recurrence. Our study is a retrospective analysis of 252 EC patients treated, between January 2009 and July 2013, at the Division of Gynaecologic Oncology of Campus Bio-Medico University of Rome. Thirty-seven patients experienced recurrence. Median follow-up was 38 months. HE4 and CA125 levels were analyzed at primary diagnosis, during follow-up and either after histological or radiological confirmation of recurrent disease or at last registered visit, when patients returned to our Department with no evidence of recurrent disease. A statistically significant difference was observed between HE4 values at primary diagnosis and at recurrence, respectively, comparing recurrent and non-recurrent patients (p < 0.05), while CA125 values resulted not statistically significant (p = 0.08) at each time point. Considering the poor specificity of HE4 at threshold of 70 pmol/L at primary diagnosis, in our cohort of patients, we found out that HE4 cut-off of 201.3 pmol/L is able to correctly classify patients at high or low risk of EC recurrence, with a sensitivity of 80 % and a specificity of 91 % (PPV = 90.3 % and NPV = 90.8 %). In particular, HE4 performance improves in cases of endometrioid histotype. HE4 levels at primary diagnosis correlate with an increased risk of EC recurrence, particularly in cases of endometrioid histotype, and they may help to recognize patients who may need a more intensive follow-up.

The challenge of preoperative identification of uterine myomas: Is ultrasound trustworthy? A prospective cohort study.

PURPOSE: To correlate preoperative ultrasound examination with intraoperative and anatomo-pathological findings, including estimation of number, localization and size of uterine myomas, uterine diameters and volume. METHODS: A prospective study on 126 women undergoing surgery for uterine myomatosis at Campus Bio-medico between May 2013 and April 2014. The patients were divided into two groups: one submitted to hysterectomy and the other submitted to open myomectomy. Ultrasound scans were performed 1 day before surgery by the same expert sonographer. The number of myomas at ultrasound was compared to intraoperative visualization and anatomo-pathological findings. Wilcoxon Test was applied to compare data registered with each technique. RESULTS: There was no significant difference between the number of myomas recorded at visualization and at ultrasound, while there was a significant difference between visualization and anatomo-pathology (p = 0.0006). The analysis showed a non-significant difference between myoma number at ultrasound and at anatomo-pathology in the two groups, if the number of myomas was less than or equal to six. Contrarily, we observed a significant difference if the number of myomas was more than six (p = 0.003). CONCLUSIONS: Our data show that ultrasound has limits in identifying the exact number of uterine myomas. This mapping is particularly needed in a minority of patients with usually desiring fertility who need a debulking procedure due to the large size and/or number of myomas or myoma location causing symptomatology. In patients with more than six myomas, voluminous uterus, a second-level examination such as Magnetic Resonance may be helpful.

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

OBJECTIVE: The 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 DESIGN: Starting 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. RESULTS: Starting from January 2012 to February 2015, a total of 79 patients were considered for the analysis and randomly divided into Group A (n = 38) and Group B (n = 41). 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 (TVS + HE4 96.3 vs. 91 % for MRI and 85 % for the TVS). CONCLUSION: Our 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 Predictive Score for Secondary Cytoreductive Surgery in Recurrent Ovarian Cancer (SeC-Score): A Single-Centre, Controlled Study for Preoperative Patient Selection.

BACKGROUND: The standard treatments of patients with platinum-sensitive recurrent ovarian cancer (ROC) remains poorly defined. Chemotherapy (CT) and secondary cytoreductive surgery (SCS) represent both valid options, even if several studies demonstrated a greater survival benefit, with survival rates up to 62 months, for platinum-sensitive patients undergoing complete SCS. The purpose of the present study was to develop a predictive model, named SeC-Score (SeC-s), to assess the risk of optimal SCS, including, for the first time in literature, HE4. METHODS: All patients affected by suspicious ROC at radiologic imaging, referred to the Department of Gynecology of Campus Bio-medico of Rome, were prospectively included in the study. The preoperative variables considered in our predictive model were: age, residual tumour (RT) at primary cytoreduction (0 vs. >0 cm), preoperative CA125 and HE4, and ascites at recurrence. After exploratory laparotomy, patients were submitted to secondary SCS (Group A) or addressed to CT (Group B). RESULTS: A total of 135 patients with ROC were considered for the analysis. Preoperative CA125, HE4, ascites, and RT at first surgery were found statistically significant and included into a multivariate logistic regression model to determine the risk to not optimal SCS. In the overall cohort of patients, SeC-s reported sensitivity and specificity of 82 and 83 %, respectively (PPV = 0.79, NPV = 0.81). CONCLUSIONS: Our data support the use of SeC-s to preoperative triage patients suitable of optimal SCS, even if external validation is needed.

Quality of Life in Platinum-Sensitive Recurrent Ovarian Cancer: Chemotherapy Versus Surgery Plus Chemotherapy.

PURPOSE: This study was designed to compare quality of life in a sample of Italian patients affected by platinum-sensitive recurrent ovarian cancer and submitted to chemotherapy alone or secondary cytoreductive surgery plus chemotherapy through validated questionnaires. METHODS: From January 2007 to December 2012, consecutive patients with suspicious recurrence of ovarian cancer, referred to the Division of Gynecologic Oncology at the University Campus Bio-Medico of Rome, were assessed for this prospective, case-control study. After a diagnostic laparoscopy, surgical resectable patients were enrolled in group A (surgery plus chemotherapy). Patients not suitable for optimal debulking surgery and all patients who refused surgery were enrolled in group B (chemotherapy alone). At beginning of treatment, after the third and sixth cycle of chemotherapy, all eligible patients were asked to fill in QLQ-C30 (version 3.0) and EORTC QLQ-OV28 questionnaires. RESULTS: Group A included 38 patients and underwent SCS followed by chemotherapy; group B included 16 patients that were submitted to chemotherapy alone. Quality-of-life scores of both questionnaires were comparable between groups, with the exception of constipation and pain, which resulted significantly worsened in Group A at 3 months. This difference was no longer present at 6 months. Median overall survival was 72 % for Group A and 56 % in Group B at median follow-up of 35 months for Group A and 32 months for Group B. CONCLUSIONS: Both surgery followed by chemotherapy and chemotherapy alone seem to have a negligible impact on QOL. SCS plus chemotherapy seems to be an effective and tolerable therapeutic option in platinum-sensitive recurrences.

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.