Publications by authors named "Pierluigi Benedetti Panici"

425 Publications

Peri-operative blood management of Jehovah's Witnesses undergoing cytoreductive surgery for advanced ovarian cancer.

Blood Transfus 2021 Feb 25. Epub 2021 Feb 25.

Department of Maternal and Child Health and Urological Sciences, Sapienza University, Policlinico Umberto I, Rome, Italy.

Background: The aim of this study was to evaluate the efficacy and feasibility of a peri-operative bloodless medicine and surgery (BMS) protocol in reducing severe post-operative anaemia (haemoglobin [Hb] <7 g/dL) in Jehovah's Witnesses undergoing cytoreductive surgery for advanced epithelial ovarian cancer.

Materials And Methods: This was a single-institution retrospective study enrolling Jehovah's Witnesses who underwent elective bloodless surgery for advanced epithelial ovarian cancer between October 2017 and April 2020. All patients followed a standardised bloodless medicine and surgery protocol based on ferric carboxymaltose and erythropoietin if indicated.

Results: Twenty-five patients with a mean age of 61.7 years (range, 35-80) were enrolled. Pre-operatively, ten patients (40%) were mildly anaemic (mean Hb of 10.2 g/dL [range, 9.2-11.4]) and received ferric carboxymaltose. Only four (16%) patients had severe anaemia after surgery (mean Hb of 6.1 g/dL [range, 4.1-6.9]) and received ferric carboxymaltose and erythropoietin. Compared to patients with a post-operative Hb ≥7 g/dL, those with Hb <7 g/dL had higher mean body mass index (25.8±1.8 vs 30.7±1.8 kg/m; p<0.001), mean baseline CA125 (236.1±184.5 vs 783.7±273.5 IU/mL; p<0.001), median surgical complexity score (2 vs 10; p<0.001), and rate of post-operative complications (14.3 vs 100%; p<0.001). Moreover, these patients had a longer mean operating time (3.4±0.6 vs 5.5±0.4 h; p<0.001), duration of stay in hospital (5.5±0.7 vs 24.0±9.8 days; p<0.001), and time to adjuvant chemotherapy (27.2±2.6 vs 65.3±13.4 days; p<0.001).

Discussion: The use of a multidisciplinary bloodless medicine and surgery protocol is safe and effective in reducing the rate of severe post-operative anaemia and improving surgical and oncological outcomes of Jehovah's Witnesses with advanced epithelial ovarian cancer. Further large-scale, prospective studies are required to confirm these data.
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http://dx.doi.org/10.2450/2021.0416-20DOI Listing
February 2021

OTX015 Epi-Drug Exerts Antitumor Effects in Ovarian Cancer Cells by Blocking GNL3-Mediated Radioresistance Mechanisms: Cellular, Molecular and Computational Evidence.

Cancers (Basel) 2021 Mar 25;13(7). Epub 2021 Mar 25.

Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.

Ovarian cancer (OC) is the most aggressive gynecological tumor worldwide and, notwithstanding the increment in conventional treatments, many resistance mechanisms arise, this leading to cure failure and patient death. So, the use of novel adjuvant drugs able to counteract these pathways is urgently needed to improve patient overall survival. A growing interest is focused on epigenetic drugs for cancer therapy, such as Bromodomain and Extra-Terminal motif inhibitors (BETi). Here, we investigate the antitumor effects of OTX015, a novel BETi, as a single agent or in combination with ionizing radiation (IR) in OC cellular models. OTX015 treatment significantly reduced tumor cell proliferation by triggering cell cycle arrest and apoptosis that were linked to nucleolar stress and DNA damage. OTX015 impaired migration capacity and potentiated IR effects by reducing the expression of different drivers of cancer resistance mechanisms, including GNL3 gene, whose expression was found to be significantly higher in OC biopsies than in normal ovarian tissues. Gene specific knocking down and computational network analysis confirmed the centrality of GNL3 in OTX015-mediated OC antitumor effects. Altogether, our findings suggest OTX015 as an effective option to improve therapeutic strategies and overcome the development of resistant cancer cells in patients with OC.
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http://dx.doi.org/10.3390/cancers13071519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059141PMC
March 2021

MiR-200c-3p Contrasts PD-L1 Induction by Combinatorial Therapies and Slows Proliferation of Epithelial Ovarian Cancer through Downregulation of β-Catenin and c-Myc.

Cells 2021 Mar 1;10(3). Epub 2021 Mar 1.

Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Conventional/targeted chemotherapies and ionizing radiation (IR) are being used both as monotherapies and in combination for the treatment of epithelial ovarian cancer (EOC). Several studies show that these therapies might favor oncogenic signaling and impede anti-tumor responses. MiR-200c is considered a master regulator of EOC-related oncogenes. In this study, we sought to investigate if chemotherapy and IR could influence the expression of miR-200c-3p and its target genes, like the immune checkpoint PD-L1 and other oncogenes in a cohort of EOC patients' biopsies. Indeed, PD-L1 expression was induced, while miR-200c-3p was significantly reduced in these biopsies post-therapy. The effect of miR-200c-3p target genes was assessed in miR-200c transfected SKOV3 cells untreated and treated with olaparib and IR alone. Under all experimental conditions, miR-200c-3p concomitantly reduced PD-L1, c-Myc and β-catenin expression and sensitized ovarian cancer cells to olaparib and irradiation. In silico analyses further confirmed the anti-correlation between miR-200c-3p with c-Myc and β-catenin in 46 OC cell lines and showed that a higher miR-200c-3p expression associates with a less tumorigenic microenvironment. These findings provide new insights into how miR-200c-3p could be used to hold in check the adverse effects of conventional chemotherapy, targeted therapy and radiation therapy, and offer a novel therapeutic strategy for EOC.
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http://dx.doi.org/10.3390/cells10030519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998372PMC
March 2021

Dienogest versus continuous oral levonorgestrel/EE in patients with endometriosis: what's the best choice?

Gynecol Endocrinol 2021 Mar 2:1-5. Epub 2021 Mar 2.

Department of Maternal and Child Health and Urology, University of Rome 'Sapienza', Rome, Italy.

Objective: Combined oral contraceptives (COC) and progestogens are widely used for the treatment of endometriosis. The objective of the study is to compare the efficacy of dienogest 2 mg vs continuous oral levonorgestrel/EE (levonorgestrel 0.1 mg/ethinyl estradiol 0.02 mg) on ovarian endometriomas, deep infiltrating endometriosis (DIE), chronic pelvic pain (CPP), dyspareunia, analgesic use, quality of life (QoL), compliance and side effects.

Methods: Prospective cohort study. Two cohorts of patients with endometriosis, 50 taking dienogest (group A) and 50 taking continuous levonorgestrel/EE (group B), were evaluated at the beginning of therapy (t0), after 3 (t3) and 6 months (t6). Size of endometriomas, DIE, QoL, pain symptoms, and side effects were assessed.

Results: Dienogest was significantly effective on CPP ( = .002), dyspareunia ( = .021) ovarian endometriomas ( = .015) and DIE lesions reduction ( = .014). Levonorgestrel/EE was significantly effective on dyspareunia ( = .023). Analgesics consumption significantly decreased in both groups ( < .001). Both treatments significantly improved the QoL. Over 6 months a significant improvement was found, more frequently in patients taking dienogest. The only side effect that both groups complained about was vaginal bleeding, present in the first 3 months of treatment ( < .001).

Conclusions: Both treatments are effective and safe for patients with endometriosis. Patients compliance and side effects are similar in both groups, however, there was a significantly higher reduction in endometriotic lesions, pain symptoms, and improvement of the QoL in women taking dienogest than in women taking continuous COC.
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http://dx.doi.org/10.1080/09513590.2021.1892632DOI Listing
March 2021

Response to Neoadjuvant Chemotherapy in Locally Advanced Cervical Cancer: The Role of Immune-related Factors.

In Vivo 2021 Mar-Apr;35(2):1277-1283

Department of Maternal and Child Health and Urological Sciences, Sapienza University, Policlinico Umberto I, Rome, Italy.

Background/aim: Treatment of locally advanced cervical cancer (LACC) consists of concomitant chemoradiation or neoadjuvant chemotherapy (NACT) plus radical surgery (RS). This study analyzed the prognostic role of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), tumor infiltrating lymphocytes (TILs), and PD-L1 expression in LACC patients, treated with NACT+RS.

Patients And Methods: We prospectively analyzed 37 LACC patients treated from December 2016 to September 2019. Patients were submitted to pelvic examination, biopsy and imaging.

Results: In 65% of cases, a nodal involvement was present at pre-treatment MRI. All cancers showed the presence of stromal TILs and PD-L1 staining of inflammatory cells. No significant correlations were found between clinicopathological parameters and the number of TILs and PDL-1 at baseline. After NACT, 29 patients (78%) were submitted to RS; 28% of patients showed pathological complete response, 62% partial response and 10% stable disease. Seven (24%) patients reported a positive node. Patients with high levels of stromal TILs and low NLR and PLR showed a significantly better response to NACT. No significant correlation was observed between PD-L1 expression and response to NACT.

Conclusion: The number of TILs, the expression of PDL1, and NLR and PLR ratios correlate significantly with the response of LACC patients to NACT.
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http://dx.doi.org/10.21873/invivo.12379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045068PMC
December 2020

Impact of clinical factors and surgical outcome on long-term survival in high-grade serous ovarian cancer: a multicenter analysis.

Int J Gynecol Cancer 2021 Feb 9. Epub 2021 Feb 9.

Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

Introduction: Long-term survivors of ovarian cancer are a unique group of patients in whom prognostic factors for long-term survival have been poorly described. Such factors may provide information for a more personalized therapeutic approach. The objective of this study is to determine further characteristics of long-term survivors with high-grade serous ovarian cancer.

Methods: Long-term survivors were defined as patients living longer than 8 years after first diagnosis and were recruited within seven high volume centers across Europe from November 1988 to November 2008. The control group included patients with high-grade serous ovarian cancer with less than 5 years' survival identified from the systematic 'Tumorbank ovarian cancer' database. A subanalysis of Charité patients only was performed separately for in-depth analysis of tumor dissemination. Propensity score matching with nearest-neighbor caliper width was used to match long-term survivors and the control group regarding age, FIGO stage, and residual tumor.

Results: A total of 276 patients with high-grade serous ovarian cancer were included, divided into 131 long-term survivors and 145 control group patients. After propensity score matching and multivariable adjustment, platinum sensitivity (p=0.002) was an independent favorable prognostic factor whereas recurrence (p<0.001) and ascites (p=0.021) were independent detrimental predictors for long-term survival. Significantly more long-term survivors tested positive for mutation in the BRCA1 gene than the BRCA2 gene (p=0.016). Intraoperatively, these patients had less tumor involvement of the upper abdomen at initial surgery (p=0.024). Complexity of surgery and surgical techniques were similar in both cohorts.

Conclusion: Platinum sensitivity constitutes a favorable factor for long-term survival whereas tumor involvement of the upper abdomen, ascites, and recurrence have a negative impact. Based on clinical estimation, long-term survival is associated with combinations of clinical, surgical, and molecular factors.
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http://dx.doi.org/10.1136/ijgc-2020-002023DOI Listing
February 2021

Capecitabine in treating patients with advanced, persistent, or recurrent cervical cancer: an active and safe option?

Expert Opin Drug Saf 2021 Feb 15:1-10. Epub 2021 Feb 15.

Department of Maternal and Child Health and Urological Sciences, Policlinico "Umberto I", University of Rome "Sapienza" , Rome, Italy.

: Advanced, persistent or recurrent cervical cancer in patients not amenable to curative surgery or radiotherapy predicts a dismal prognosis. Systemic chemotherapy based on paclitaxel/cisplatin ± bevacizumab is the current standard of care. However, once progression occurs, the possibility of alternative treatment options is very limited. : The usefulness of capecitabine has been well-established against several cancer types, including head and neck, breast, and colorectal cancer. This review covers current literature evidence on the clinical efficacy and safety of capecitabine in cervical cancer treatment, either as monotherapy or combined with other agents or chemo-radiotherapy. : Recent clinical data, albeit scant, suggested a promising role for capecitabine both as monotherapy in patients with platinum-resistant cervical cancer and in combination with cisplatin in chemotherapy-naïve patients with metastatic or recurrent cervical cancer. In our opinion, capecitabine, especially in combination regimens, could represent a valid treatment option and further research is warranted to better understand its effectiveness in these challenging patients.
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http://dx.doi.org/10.1080/14740338.2021.1887850DOI Listing
February 2021

High-risk HPV-positive and -negative high-grade cervical dysplasia: Analysis of 5-year outcomes.

Gynecol Oncol 2021 Apr 26;161(1):173-178. Epub 2021 Jan 26.

Gynecological Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

Objective: To evaluate the outcomes of high-risk (HR) HPV-positive and -negative women affected by high-grade cervical dysplasia.

Methods: This is a retrospective multi-institutional study. Medical records of consecutive patients with high-grade cervical dysplasia undergoing conization between 2010 and 2014 were retrieved. All patients included had at least 5 years of follow-up. A propensity-score matching was adopted in order to reduce the presence of confounding factors between groups. Kaplan-Meir and Cox hazard models were used to estimate 5-year outcomes.

Results: Overall, data of 2966 women, affected by high-grade cervical dysplasia were reviewed. The study population included 1478 (85%) and 260 (15%) women affected by HR-HPV-positive and HR-HPV-negative high-grade cervical dysplasia. The prevalence of CIN2 and CIN3 among the HR-HPV-positive and -negative cohort was similar (p = 0.315). Patients with HR-HPV-positive high-grade cervical dysplasia were at higher risk of 5-year recurrence (after primary conization) that HR-HPV-negative patients (p < 0.001, log-rank test). Via multivariate analysis, HR-HPV-negative women were at low risk of recurrence (HR: 1.69 (95%CI: 1.05, 4.80); p = 0.018, Cox Hazard model). A propensity-score matched comparison was carried out in order to reduce biases that are related to the retrospective study design. In comparison to HR-HPV-negative patients, thosewith HR-HPV-positive CIN3 was associate with a 8-fold increase in the risk of recurrence (p < 0.001, log-rank test).

Conclusions: HR-HPV-negative high-grade cervical dysplasia is not uncommon, accounting for 15% of our study population. Those patients experience more favorable outcomes than patients with documented HR-HPV infection(s). Further prospective studies are needed to corroborate our data.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.020DOI Listing
April 2021

Sentinel node mapping vs. sentinel node mapping plus back-up lymphadenectomy in high-risk endometrial cancer patients: Results from a multi-institutional study.

Gynecol Oncol 2021 Apr 20;161(1):122-129. Epub 2021 Jan 20.

Gynecological Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy.

Objective: Sentinel node mapping (SLN) has replaced lymphadenectomy for staging surgery in apparent early-stage low and intermediate risk endometrial cancer (EC). Only limited data about the adoption of SNM in high risk EC is still available. Here, we evaluate the outcomes of high-risk EC undergoing SNM (with or without back-up lymphadenectomy).

Methods: This is a multi-institutional international retrospective study, evaluating data of high-risk (FIGO grade 3 endometrioid EC with myometrial invasion >50% and non-endometrioid histology) EC patients undergoing SNM followed by back-up lymphadenectomy and SNM alone.

Results: Chart of consecutive 196 patients were evaluated. The study population included 83 and 113 patients with endometrioid and non-endometrioid EC, respectively. SNM alone and SNM followed by back-up lymphadenectomy were performed in 50 and 146 patients, respectively. Among patients having SNM alone, 14 (28%) were diagnosed with nodal disease. In the group of patients undergoing SNM plus back-up lymphadenectomy 34 (23.2%) were diagnosed with nodal disease via SNM. Back-up lymphadenectomy identified 2 (1%) additional patients with nodal disease (in the para-aortic area). Back-up lymphadenectomy allowed to remove adjunctive positive nodes in 16 (11%) patients. After the adoption of propensity-matched algorithm, we observed that patients undergoing SNM plus back-up lymphadenectomy experienced similar disease-free survival (p = 0.416, log-rank test) and overall survival (p = 0.940, log-rank test) than patients undergoing SLN alone.

Conclusions: Although the small sample size, and the retrospective study design this study highlighted that type of nodal assessment did not impact survival outcomes in high-risk EC. Theoretically, back-up lymphadenectomy would be useful in improving the removal of positive nodes, but its therapeutic value remains controversial. Further prospective evidence is needed.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.008DOI Listing
April 2021

Endometriosis-associated infertility: surgery or IVF?

Minerva Obstet Gynecol 2021 Apr 13;73(2):226-232. Epub 2021 Jan 13.

Department of Obstetrics and Gynecology, Sapienza University, Rome, Italy.

Endometriosis is a chronic disease frequently associated with female infertility. The choice of treatment in case of endometriosis is one of the most discussed topics in Reproductive Medicine. The approach to the patient with endometriosis and infertility should be tailored based on different parameters. The localization of the disease, the severity of symptoms and the age of the patient are just some of them. Management options include surgery, in-vitro fertilization (IVF), or a combination of both. Data, mostly uncontrolled, would favor surgery at any stage of endometriosis, increasing the chances of natural conception compared to expectant management. Laparoscopic excision of the ovarian endometrioma should be the treatment of choice when there is associated pain. Surgery should be performed following appropriate techniques to reduce the possible damage to the ovarian reserve. Pregnancy rates around 50% have been consistently reported after surgery, which compare favorably with those obtained with IVF. IVF, on the other hand, may be preferred in case of associated male or tubal factor, in case of a reduced ovarian reserve, or if previous surgery has failed, particularly if there is no associated pain, and when the ultrasonographic features of the ovarian cyst are reassuring. Sometimes IVF may be preceded by surgery, when a difficult access to follicles at pick-up, due to the size and location of the ovarian cyst, or to severe adhesions, is anticipated. Due to the lack of solid evidence in the scenario of endometriosis-associated infertility, robust data from randomized clinical trials (RCTs) are strongly needed.
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http://dx.doi.org/10.23736/S0026-4784.20.04765-6DOI Listing
April 2021

Role of BRCA Mutation and HE4 in Predicting Chemotherapy Response in Ovarian Cancer: A Retrospective Pilot Study.

Biomedicines 2021 Jan 8;9(1). Epub 2021 Jan 8.

Department of Obstetrics and Gynecology, University ''Campus Bio-Medico'' of Rome, Via Alvaro del Portillo, 200-00128 Rome, Italy.

Even though 80% of patients with High-Grade Serous Ovarian Cancer respond to standard first-line chemotherapy, a majority of them could relapse in the following five years due to a resistance to platinum. Human Epididymis protein 4 (HE4) is one of the most promising markers in predicting platinum therapy response. This pilot study aims to evaluate the potential role of HE4 value in predicting chemotherapy response in mutated patients and in wild-type (non-mutated) ones. We selected 69 patients, affected by High-Grade Serous Ovarian Cancer, and optimally debulked and submitted to standard chemotherapy protocols. HE4 was dosed during every chemotherapy course. Patients were classified as platinum-resistant and platinum-sensitive. According to mutation test, patients were further divided into wild-type (53 patients), and mutated (16 patients). 35 patients out of 69 (52%) were platinum-sensitive (recurrence > 12 months), while 33 patients (48%) were platinum-resistant (recurrence < 12 months). Thus, in the total population, HE4 performed as a marker of chemosensitivity with a sensibility of 79% and a specificity of 97%. In the WT group, 23 patients out of 53 (43%) were platinum-sensitive, while 30 patients out of 53 (57%) were platinum-resistant. In the WT group, HE4 performed as a predictive marker of chemosensitivity with a sensibility of 80% and a specificity of 100%. In the mutated group, 13 patients out of 16 (82%) were platinum-sensitive, while 3 patients (18%) were platinum-resistant. In the mutated group, HE4 performed as a predictive marker of chemosensitivity in all patients. The ability to detect platinum-resistant patients before tumor relapse probably could open new therapeutic scenarios.
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http://dx.doi.org/10.3390/biomedicines9010055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827362PMC
January 2021

Vulvovaginal atrophy of menopause and its impact on sexual function in an Italian clinical cohort of post-menopausal women.

J Obstet Gynaecol 2021 Feb 12;41(2):290-297. Epub 2021 Jan 12.

University of Rome "Sapienza", Department of Gynaecological-Obstetric Sciences and Urological Sciences, Umberto I Hospital, Rome, Italy.

The aim of current study was to estimate the impact of vulvovaginal atrophy (VVA) on sexual function in a clinical population of Italian postmenopausal women. Women aged 45-75 years with at least one VVA symptom completed three questionnaires: Day-to-Day Impact of Vaginal Aging (DIVA), Female Sexual Function Index (FSFI) and Female Sexual Distress Scale revised (FSDS-R). A gynaecological examination was performed for VVA confirmation. Among the 1,066 evaluable patients, VVA was confirmed in around 90% of the sample. Sexual function impairment was significantly higher in patients with confirmed VVA as observed by significant differences in the sexual function component of the DIVA questionnaire ( = .014), the FSDS-R ( < .0005), and the FSFI ( < .0005), as well as for all the FSFI subdomains: desire ( < .0005), arousal ( < .0005), lubrication ( < .0005), orgasm ( < .0005), satisfaction ( < .0005) and pain ( < .0005). Significant impairment of sexual function was demonstrated in Italian postmenopausal women who were clinically confirmed with signs of VVA through gynaecological examination.IMPACT STATEMENT At least half of postmenopausal women report VVA associated symptoms with significant impact on sexual function and ultimately on sexual activity. As compared with patients without confirmed VVA, the negative impact on sexual function was significantly higher in patients with confirmed VVA. This difference was observed for the sexual function component (DIVA-C) of the DIVA questionnaire, for the overall FSDS-R result, and for the overall FSFI score, as well as for all the FSFI subdomains (desire, arousal, lubrication, orgasm, satisfaction and pain). An impairment of sexual function is significantly associated with VVA diagnosis in Italian post-menopausal women, especially when diagnosis was objectively confirmed by clinical signs of VVA visible in the gynaecological examination. In addition, this study demonstrates that inquiring about VVA using a structured questionnaire may increase the diagnosis of VVA related changes in sexual function.
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http://dx.doi.org/10.1080/01443615.2020.1832973DOI Listing
February 2021

Protein-protein interaction network analysis applied to DNA copy number profiling suggests new perspectives on the aetiology of Mayer-Rokitansky-Küster-Hauser syndrome.

Sci Rep 2021 Jan 11;11(1):448. Epub 2021 Jan 11.

Department of Experimental Medicine, Sapienza Università Di Roma, Viale del Policlinico, 155, 00161, Rome, Italy.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare disease, characterised by the aplasia of vagina and uterus in women with a 46,XX karyotype. Most cases are sporadic, but familial recurrence has also been described. Herein, we investigated an Italian cohort of 36 unrelated MRKH patients to explore the presence of pathogenic copy number variations (CNVs) by array-CGH and MLPA assays. On the whole, aberrations were found in 9/36 (25%) patients. Interestingly, one patient showed a novel heterozygous microduplication at Xp22.33, not yet described in MRKH patients, containing the PRKX gene. Moreover, a novel duplication of a specific SHOX enhancer was highlighted by MLPA. To predict the potential significance of CNVs in MRKH pathogenesis, we provided a network analysis for protein-coding genes found in the altered genomic regions. Although not all of these genes taken individually showed a clear clinical significance, their combination in a computational network highlighted that the most relevant biological connections are related to the anatomical structure development. In conclusion, the results described in the present study identified novel genetic alterations and interactions that may be likely involved in MRKH phenotype determination, so adding new insights into the complex puzzle of MRKH disease.
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http://dx.doi.org/10.1038/s41598-020-79827-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801512PMC
January 2021

Preoperative frailty assessment in patients undergoing gynecologic oncology surgery: A systematic review.

Gynecol Oncol 2021 Apr 5;161(1):11-19. Epub 2021 Jan 5.

Department of Maternal and Child Health and Urological Sciences, University of Rome Sapienza, Policlinico Umberto I, Rome, Italy.

Objective: The aim of the present article was to discuss currently available evidence on the impact of frailty assessment on adverse postoperative outcomes and survival in patients undergoing surgery for gynecological cancer.

Methods: Systematic search of Medline (PubMed) and Embase databases until September 30, 2020. Key inclusion criteria were: (1) randomized or observational studies; (2) patients undergoing non-emergent surgery for gynecological malignancies; (3) preoperative frailty assessment.

Results: Through the process of evidence acquisition, twelve studies including 85,672 patients were selected and six tools were evaluable: 30-item frailty index, 40-item frailty index, modified frailty index (mFI), John Hopkins Adjusted Clinical Groups index, Fried frailty criteria, Driver's tool. The prevalence of frailty varied roughly from 6.1% to 60% across different series included. The mFI was the most adopted and predictive instrument. Pooled results underlined that frail patients were more likely to develop 30-day postoperative complications (OR:4.16; 95%CI 1.49-11.65; p:0.007), non-home discharge (OR:4.41; 95%CI: 4.09-4.76; p < 0.001), ICU admission (OR:3.99;3.76-4.24; p < 0.001) than the non-frail counterpart. Additionally, frail patients experienced worse oncologic outcomes (disease-free and overall survivals) than non-frail patients.

Conclusion: The present systematic review demonstrated that preoperative frailty assessment among gynecologic oncology patients is essential to predict adverse outcomes and tailor a personalized treatment. The mFI appeared as the most used and feasible tool in daily practice, suggesting that tailored therapeutic strategies should be considered for patients with 3 or more frailty-defining items.
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http://dx.doi.org/10.1016/j.ygyno.2020.12.030DOI Listing
April 2021

The role of alpha lipoic acid in female and male infertility: a systematic review.

Gynecol Endocrinol 2020 Dec 21:1-9. Epub 2020 Dec 21.

Departments of Obstetrics and Gynecology, "Sapienza" University of Rome, Rome, Italy.

Objective: Infertility is an increasingly frequent health condition, which may depend on female or male factors. Oxidative stress (OS), resulting from a disrupted balance between reactive oxygen species (ROS) and protective antioxidants, affects the reproductive lifespan of men and women. In this review, we examine if alpha lipoic acid (ALA), among the oral supplements currently in use, has an evidence-based beneficial role in the context of female and male infertility.

Methods: We performed a search from English literature using PubMed database with the following keywords: 'female infertility', 'male infertility', 'semen', 'sperm', 'sub-fertile man', 'alpha-lipoic acid', ' alpha lipoic acid', 'lipoid acid', 'endometriosis', 'chronic pelvic pain', 'follicular fluid' and 'oocytes'. We included clinical trials, multicentric studies and reviews. The total number of references found after automatically and manually excluding duplicates was 180. After primary and secondary screening, 28 articles were selected.

Results: The available literature demonstrates the positive effects of ALA in multiple processes from oocyte maturation (0.87 ± 0.9% of oocyte in MII vs 0.81 ± 3.9%;  < .05) to fertilization, embryo development (57.7% vs 75.7% grade 1 embryo;  < .05) and reproductive outcomes. Its regular administration both in sub-fertile women and men shows to reduce pelvic pain in endometriosis ( < .05), regularize menstrual flow and metabolic disorders ( < .01) and improve sperm quality ( < .001).

Conclusions: ALA represents a promising new molecule in the field of couple infertility. More clinical studies are needed in order to enhance its use in clinical practice.
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http://dx.doi.org/10.1080/09513590.2020.1843619DOI Listing
December 2020

Cabergoline as an adjuvant to standard heart failure treatment in peripartum cardiomyopathy: A case report and review of the literature.

Case Rep Womens Health 2021 Jan 7;29:e00277. Epub 2020 Dec 7.

Department of Maternal and Child Health and Urological Sciences, University of Rome "Sapienza", Policlinico "Umberto I", Rome, Italy.

Introduction: Peripartum cardiomyopathy (PPCM) is a rare and idiopathic form of dilated cardiomyopathy presenting late in pregnancy or early postpartum. Since the 16-kDa fragment of prolactin has been identified as a key factor in the pathophysiology of PPCM, prolactin inhibitors have been used as an adjuvant to standard heart failure treatment. Although bromocriptine is the current first choice, promising results have been reported with cabergoline, albeit scant.

Case Presentation: We presented the case of a 41-year-old woman who received a diagnosis of PPCM one week after delivery and was successfully treated with cabergoline, finally experiencing a complete recovery.

Conclusion: The case adds to the scant evidence supporting the use of cabergoline in PPCM patients. We argue that the favorable pharmacokinetic and metabolic profiles of this drug should prompt its consideration as a valid alternative prolactin inhibitor in these critical patients.
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http://dx.doi.org/10.1016/j.crwh.2020.e00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736906PMC
January 2021

Reducing the radicality of surgery for vulvar cancer: are smaller margins safer?

Minerva Obstet Gynecol 2021 Apr 11;73(2):160-165. Epub 2020 Dec 11.

Department of Medical and Surgical Sciences and Translational Medicine, Sapienza University, Rome, Italy.

Introduction: Vulvar cancer accounts for ~4% of all gynecological malignancies and the majority of tumors (>90%) are squamous cell (keratinizing, ~60% and warty/basaloid, ~30%). Surgical excision forms the foundation of treatment, with resection margin status being the single most influential factor when predicting clinical outcome. There has been a paradigm shift concerning surgical approaches and radicality when managing vulvar cancer within recent times, largely owing to a desire to preserve vulvar structure and function without compromising oncological outcome. As such the safety of the size of resection margin has been called into question. In this narrative review we consider the current literature on the safety of resection margins for vulvar cancer.

Evidence Acquisition: PubMed, Medline and the Cochrane Database were searched for original peer-reviewed primary and review articles, from January 2005 to January 2020. The following search terms were used vulvar cancer surgery, vulvar squamous cell carcinoma, excision margins, adjuvant radiation.

Evidence Synthesis: A pathological tumor margin of <8 mm has been widely considered to indicate "close" margins. This measurement after fixation of the tumor is considered comparable to a surgical resection margin of around 1cm, following an estimated 20% tissue shrinkage after formalin fixation and a 1-2cm clinical surgical margin in order to achieve the 8 mm final pathological margin.

Conclusions: A surgical resection margin of 2-3mm does not appear to be associated with a higher rate of local recurrence than the widely used limit of 8 mm. As such the traditional practice of re-excision or adjuvant radiotherapy based on "close" surgical margins alone needs to be closely evaluated, since the attendant morbidity associated with these procedures may not be outweighed by oncological benefit.
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http://dx.doi.org/10.23736/S0026-4784.20.04743-7DOI Listing
April 2021

Minimally invasive surgery in cervical cancer.

Minerva Obstet Gynecol 2021 Apr 11;73(2):145-148. Epub 2020 Dec 11.

National Cancer Institute of Milan (INT), Milan, Italy.

In recent years, minimally invasive surgery has replaced open surgery for almost all surgical indications in gynecological practice. Recently, the results of the laparoscopic approach to cervical cancer (LACC) trial questioned the role of minimally invasive surgery for patients affected by early-stage cervical cancer. In the present paper, we discussed the current evidence regarding the adoption of minimally invasive surgery for patients with cervical cancer. We evaluated the current evidence focusing on four interesting features: 1) the impact of tumor volume; 2) reasons explaining worse outcomes of patients undergoing minimally invasive surgery; 3) methods to reduce the risk of recurrence during minimally invasive surgery; and 4) the effect of minimally invasive surgery in patients with locally advanced cervical cancer. At the moment, in the light of current evidence, minimally invasive radical hysterectomy should be offered only in the context of clinical trials. Extensive counseling and appropriate patients' selection are needed. Further prospective evidence is warranted to identify the better approach for cervical cancer patients.
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http://dx.doi.org/10.23736/S0026-4784.20.04726-7DOI Listing
April 2021

Assessing the Long-Term Role of Vaccination against HPV after Loop Electrosurgical Excision Procedure (LEEP): A Propensity-Score Matched Comparison.

Vaccines (Basel) 2020 Dec 1;8(4). Epub 2020 Dec 1.

Department of Gynecological, Obstetrical and Urological Sciences, "Sapienza" University of Rome, 00185 Rome, Italy.

: Primary prevention through vaccination is a prophylactic approach aiming to reduce the risk of developing human papillomavirus (HPV)-related lesions. No mature and long-term data supported the adoption of vaccination in women undergoing conization. This is a retrospective multi-institutional study. Charts of consecutive patients undergoing conization between 2010 and 2014 were collected. All patients included had at least 5 years of follow-up. We compared outcomes of patients undergoing conization plus vaccination and conization alone. A propensity-score matching algorithm was applied in order to reduce allocation biases. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models. : Overall, charts of 1914 women were analyzed. The study group included 116 (6.1%) and 1798 (93.9%) women undergoing conization plus vaccination and conization alone, respectively. Five-year recurrence rate was 1.7% ( = 2) and 5.7% ( = 102) after conization plus vaccination and conization alone, respectively ( = 0.068). After the application of a propensity-score matching, we selected 100 patients undergoing conization plus vaccination and 200 patients undergoing conization alone. The crude number of recurrences was 2 (2%) and 11 (5.5%) for patients undergoing conization plus vaccination and conization alone, respectively ( = 0.231). Vaccination had no impact on persistent lesions (no negative examination between conization and new cervical dysplasia; = 0.603), but reduced the risk of recurrent disease (patients who had at least one negative examination between conization and the diagnosis of recurrent cervical dysplasia; = 0.031). Patients having vaccination experience a slightly lower risk of recurrence than women who had not, although not statistically significantly different. Further evidence is needed to assess the cost effectiveness of adopting vaccination in this setting.
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http://dx.doi.org/10.3390/vaccines8040717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711506PMC
December 2020

Ovarian Cancer Metastasis to the Breast: A Case Report and Review of the Literature.

Case Rep Oncol 2020 Sep-Dec;13(3):1317-1324. Epub 2020 Oct 27.

Department of Maternal and Child Health and Urological Sciences, Sapienza University, Policlinico Umberto I, Rome, Italy.

Although ovarian cancer often presents as a widespread disease, metastases to the breast and/or axillary lymph nodes are a very rare event, accounting for only 0.03-0.6% of all breast cancers. Its early recognition and accurate distinction from primary breast cancer are of crucial importance to choose an adequate systemic therapy over unnecessary surgeries. We presented the case of a 53-year-old woman who was diagnosed with breast metastases 2 years after the diagnosis of advanced primary serous ovarian cancer. The patient underwent primary cytoreductive surgery and platinum-based chemotherapy in combination with bevacizumab, followed by bevacizumab maintenance for 18 months. After 2 years of negative follow-ups, the disease unexpectedly spread to the left breast and axillary lymph nodes. No axillary lymph node dissection or breast surgery was performed. The patient received axillary radiotherapy and multiple chemotherapy lines: gemcitabine/cisplatin, liposomal doxorubicin, topotecan, olaparib/cediranib, paclitaxel, and cisplatin. Unfortunately, none of these treatments improved her prognosis and she died 3 years after the disease recurrence. Ovarian cancer metastasis to the breast reveals a disseminated disease with a poor prognosis. Currently, no valid treatment options are available as the disease shows multidrug chemoresistance. In the era of precision medicine, the characterization of genetic and molecular markers may play a role in offering new promising targeted therapies.
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http://dx.doi.org/10.1159/000509770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670356PMC
October 2020

Modified fragility index and surgical complexity score are able to predict postoperative morbidity and mortality after cytoreductive surgery for advanced ovarian cancer.

Gynecol Oncol 2021 Apr 19;161(1):4-10. Epub 2020 Nov 19.

Department of Maternal and Child Health and Urological Sciences, "Sapienza" University of Rome, Rome, Italy.

Objective: The aim of this study was to assess the impact of surgical complexity on postoperative complications and mortality, according to patient's frailty (mFI) following surgery for ovarian cancer.

Methods: Patients undergoing cytoreductive surgery for ovarian cancer from 2008 to 2018 were identified from our database. A surgical complexity score from 1 to 3 was used to assess the extent of surgery (simple to complex, respectively). mFI with 11 variables, based on mapping the Canadian Study of Health and Aging Frailty Index to the NSQIP comorbidities was evaluated. Data were analyzed using Fisher exact test, independent sample t-test, and logistic regression.

Results: Of 263 patients identified, 33% reported at least one postoperative complication and 6% had severe complications. BMI ≥ 30 (p = 0.04) increased mFI (p = 0.04) and high-complexity surgery (p < 0.001) were independent predictors of severe complications (G3-G5). Patients with high frailty index score (mFI ≥ 3) who underwent intermediate or high-complexity surgery were at higher risk of severe complications ranging from 29.4% to 50.

Conclusions: The combined evaluation of mFI and surgical complexity expected may identify patients at higher risk for severe morbidity allowing to stratify patients who are less likely to tolerate a surgical extensive treatment.
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http://dx.doi.org/10.1016/j.ygyno.2020.08.022DOI Listing
April 2021

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

Chemotherapy 2020 16;65(3-4):77-84. Epub 2020 Nov 16.

Department of Obstetrics and Gynaecology, Campus Bio-Medico, University of Rome, Rome, Italy.

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.
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http://dx.doi.org/10.1159/000510839DOI Listing
November 2020

Relationship between cervical excisional treatment for cervical intraepithelial neoplasia and obstetrical outcome.

Minerva Obstet Gynecol 2021 Apr 3;73(2):233-246. Epub 2020 Nov 3.

Department of Maternal and Child Health and Urological Sciences, Umberto I Hospital, Sapienza University, Rome, Italy.

Introduction: The aim of our systematic review was the assessment of effects of excisional treatments for the management of cervical intraepithelial neoplasia (CIN) on preterm delivery (PD), lower birth weight (LBW), preterm premature rupture of membrane (PPROM) and obstetrical outcomes.

Evidence Acquisition: A structured search was carried out in PubMed-Medline, Embase, and Cochrane Controlled Trials Register databases through November 30, 2019. The search included a combination of the following terms: "loop electrosurgical excision procedure (LEEP)," "large loop excision of transformation zone (LLETZ)," "cold-knife conization (CKC)," "laser cervical conization (CLC)," "preterm delivery" and "neonatal outcome."

Evidence Synthesis: Thirty-two of 561 publications considered were included: 28 retrospective series, 2 prospective studies and 2 multicenter trials. Globally in several studies there was a significant increase in PD, measured by the relative risk, in the women underwent a surgical procedure for the CIN. In their majority, the studies were retrospective and therefore a high risk of bias.

Conclusions: This systematic review shows that the surgical treatment of the CIN was associated with an increased risk of PD, LBW and pPROM before 37 pregnancy weeks compared to untreated women, especially in a CKC and LLETZ procedure. Moreover, the increase of the of PD was associated with cone size, cervical length, repeated treatment and a short conization-to-pregnancy interval.
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http://dx.doi.org/10.23736/S0026-4784.20.04678-XDOI Listing
April 2021

Update on surgical treatment of female stress urinary incontinence.

Minerva Obstet Gynecol 2021 Apr 26;73(2):140-144. Epub 2020 Oct 26.

Department of Maternal and Child Health and Urological Sciences, Umberto I Polyclinic Hospital, Sapienza University, Rome, Italy.

Introduction: Urinary incontinence is a common condition that negatively impacts quality of life of millions of women. It is a result of a synergy between the structures of pelvic floor in particular levator ani muscle and pelvic connective tissues. Urinary incontinence, increasing with age, is associated with considerable personal and societal expenditure.

Evidence Acquisition: Systematic data search performed using PubMed/Medline database up to August 20, 2020. Focus was only for English language publications of original studies on urinary incontinence and in particular stress urinary incontinence.

Evidence Synthesis: Given the basis of published evidence and the consensus of European experts, this study provides an updated overview on clinical applications and surgical procedures of urinary incontinence.

Conclusions: Urinary incontinence is an underestimated health problem. Many surgical options exist for women with stress urinary incontinence. Nevertheless, new strategies need to be evaluated in order to improve quality of life of patients.
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http://dx.doi.org/10.23736/S0026-4784.20.04658-4DOI Listing
April 2021

The V-Y gluteal fold advancement flap: Outcomes following radical surgery for vulvar malignancies.

Int J Gynaecol Obstet 2021 Mar 20;152(3):421-424. Epub 2020 Nov 20.

The Simpson Centre for Reproductive Medicine-Gynaecological Oncology Unit, Royal Infirmary Edinburgh, University Hospitals of Edinburgh, Edinburgh, UK.

Objective: To evaluate the feasibility and complication rate of the V-Y gluteal fold flap in surgery for vulvar cancer.

Methods: From June 2015 to June 2018, 62 patients surgically treated for vulvar cancer were included in the study. Twenty-three (37.1%) underwent plastic reconstructive surgery with V-Y advancement flaps.

Results: The mean surgical time was longer for patients undergoing V-Y flap surgery. The margins were positive in six patients (9.7%), close (<8 mm) in 10 (16.1%), and adequate (>8 mm) in 46 (74.2%). Six (9.7%) patients had dehiscence and two (3.2%) patients suffered from necrosis. In patients undergoing V-Y flap reconstruction, two (8.7%) had a wound dehiscence, no patients had necrosis. In patients undergoing direct closure, four (10.3%) had wound dehiscence and two (5.1%) had necrosis.

Conclusions: V-Y gluteal fold advancement technique is a safe procedure, performed in a single surgical session with minimal increase in surgical time and low wound healing complications. Use of this technique was correlated with an increased rate of adequate surgical margins (<8 mm) and reduced need for adjuvant radiotherapy.
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http://dx.doi.org/10.1002/ijgo.13430DOI Listing
March 2021

Pregnant women's knowledge and behaviour to prevent cytomegalovirus infection: an observational study.

J Perinat Med 2021 Mar 23;49(3):327-332. Epub 2020 Oct 23.

Department of Maternal and Child Health and Urological Sciences, Umberto I Hospital, Sapienza University of Rome, Rome, Italy.

Objectives: Congenital cytomegalovirus (cCMV) infection can negatively affect pregnancy outcomes, but may be prevented by simple precautions. Literature suggests that gynaecologists do not always adequately inform about preventive behaviour and most pregnant women have a low-level knowledge regarding cCMV infection. The aim of this study is to evaluate knowledge and risk behaviours related to cCMV infection in an unselected group of pregnant women.

Methods: An institutional based cross-sectional study was conducted in three Maternal and Fetal Divisions in Rome between November and February 2019 on 296 pregnant women, their knowledge on cCMV was measured using six cytomegalovirus (CMV) related questions.

Results: Out of the 296 respondents, 59.1% had heard, read or seen information about cCMV infection. Regarding the way of transmission, 96/296 (32.4%) correctly recognize children as a potential source of the infection but only 25/296 (8.44%) knew all prevention practices, 28/296 (9.5%) of women reported that they have never performed cCMV test during pregnancy.

Conclusions: The results of this survey show that knowledge on cCMV infection among pregnant women is poor. This highlights the need to improve counselling on all preventive practices for cCMV infection during perinatal care consultation.
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http://dx.doi.org/10.1515/jpm-2020-0301DOI Listing
March 2021

Impact of COVID-19 in gynecologic oncology: a Nationwide Italian Survey of the SIGO and MITO groups.

J Gynecol Oncol 2020 11;31(6):e92

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

Objective: Coronavirus disease 2019 (COVID-19) has caused rapid and drastic changes in cancer management. The Italian Society of Gynecology and Obstetrics (SIGO), and the Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) promoted a national survey aiming to evaluate the impact of COVID-19 on clinical activity of gynecologist oncologists and to assess the implementation of containment measures against COVID-19 diffusion.

Methods: The survey consisted of a self-administered, anonymous, online questionnaire. The survey was sent via email to all the members of the SIGO, and MITO groups on April 7, 2020, and was closed on April 20, 2020.

Results: Overall, 604 participants completed the questionnaire with a response-rate of 70%. The results of this survey suggest that gynecologic oncology units had set a proactive approach to COVID-19 outbreak. Triage methods were adopted in order to minimize in-hospital diffusion of COVID-19. Only 38% of gynecologic surgeons were concerned about COVID-19 outbreak. Although 73% of the participants stated that COVID-19 has not significantly modified their everyday practice, 21% declared a decrease of the use of laparoscopy in favor of open surgery (19%). However, less than 50% of surgeons adopted specific protection against COVID-19. Additionally, responders suggested to delay cancer treatment (10%-15%), and to perform less radical surgical procedures (20%-25%) during COVID-19 pandemic.

Conclusions: National guidelines should be implemented to further promote the safety of patients and health care providers. International cooperation is of paramount importance, as heavily affected nations can serve as an example to find out ways to safely preserve clinical activity during the COVID-19 outbreak.
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http://dx.doi.org/10.3802/jgo.2020.31.e92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593217PMC
November 2020

Investigating Patterns of Immune Interaction in Ovarian Cancer: Probing the O-glycoproteome by the Macrophage Galactose-Like C-type Lectin (MGL).

Cancers (Basel) 2020 Oct 1;12(10). Epub 2020 Oct 1.

Department of Experimental Medicine, "Sapienza" University of Rome, Viale Regina Elena, 00185 Rome, Italy.

Glycosylation, the posttranslational linking of sugar molecules to proteins, is notoriously altered during tumor transformation. More specifically in carcinomas, GalNAc-type -glycosylation, is characterized by biosynthetically immature truncated glycans present on the cancer cell surface, which profoundly impact anti-tumor immune recognition. The tumor-associated glycan pattern may thus be regarded as a biomarker of immune modulation. In epithelial ovarian cancer (EOC) there is a particular lack of specific biomarkers and molecular targets to aid early diagnosis and develop novel therapeutic interventions. The aim of this study was to investigate the ovarian cancer -glycoproteome and identify tumor-associated glycoproteins relevant in tumor-dendritic cell (DC) interactions, mediated by macrophage galactose-like C type lectin (MGL), which recognizes the tumor-associated Tn -glycan. Lectin weak affinity chromatography (LWAC) was employed to probe the -glycopeptidome by MGL and agglutinin (VVA) lectin using glycoengineered ovarian cancer cell lines and ovarian cancer tissues as input material. Biochemical and bioinformatics analysis gave information on the glycan arrangement recognized by MGL in tumor cells. The potential MGL binders identified were located, as expected, at the cell membrane, but also within the intracellular compartment and the matrisome, suggesting that MGL in vivo may play a complex role in sensing microenvironmental cues. The tumor glycoproteins binders for MGL may become relevant to characterize the interaction between the immune system and tumor progression and contribute to the design of glycan targeting-based strategies for EOC immunotherapeutic interventions.
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http://dx.doi.org/10.3390/cancers12102841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600217PMC
October 2020

DCLK1, a Putative Stem Cell Marker in Human Cholangiocarcinoma.

Hepatology 2021 Jan;73(1):144-159

Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.

Background And Aims: Cholangiocarcinoma (CCA) is a very aggressive cancer showing the presence of high cancer stem cells (CSCs). Doublecortin-like kinase1 (DCLK1) has been demonstrated as a CSC marker in different gastroenterological solid tumors. Our aim was to evaluate in vitro the expression and the biological function of DCLK1 in intrahepatic CCA (iCCA) and perihilar CCA (pCCA).

Approach And Results: Specimens surgically resected of human CCA were enzymatically digested, submitted to immunosorting for specific CSC markers (LGR5 [leucine-rich repeat-containing G protein-coupled receptor], CD [clusters of differentiation] 90, EpCAM [epithelial cell adhesion molecule], CD133, and CD13), and primary cell cultures were prepared. DCLK1 expression was analyzed in CCA cell cultures by real-time quantitative PCR, western blot, and immunofluorescence. Functional studies have been performed by evaluating the effects of selective DCLK1 inhibitor (LRRK2-IN-1) on cell proliferation (MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay, cell population doubling time), apoptosis, and colony formation capacity. DCLK1 was investigated in situ by immunohistochemistry and real-time quantitative PCR. DCLK1 serum concentration was analyzed by enzyme-linked immunosorbent assay. We describe DCLK1 in CCA with an increased gene and protein DCLK1 expression in pCCA and in iCCA cells compared with unsorted cells. LRRK2-IN-1 showed an anti-proliferative effect in a dose-dependent manner. LRRK2-IN-1 markedly impaired cell proliferation, induced apoptosis, and decreased colony formation capacity and colony size in both iCCA and pCCA compared with the untreated cells. In situ analysis confirmed that DCLK1 is present only in tumors, and not in healthy tissue. Interestingly, DCLK1 was detected in the human serum samples of patients with iCCA (high), pCCA (high), HCC (low), and cirrhosis (low), but it was almost undetectable in healthy controls.

Conclusions: DCLK1 characterizes a specific CSC subpopulation of iCCA and pCCA , and its inhibition exerts anti-neoplastic effects in primary CCA cell cultures. Human DCLK1 serum might represent a serum biomarker for the early CCA diagnosis.
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http://dx.doi.org/10.1002/hep.31571DOI Listing
January 2021

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

Authors:
Daniele Di Mascio Cihat Sen Gabriele Saccone Alberto Galindo Amos Grünebaum Jun Yoshimatsu Milan Stanojevic Asım Kurjak Frank Chervenak María José Rodríguez Suárez Zita Maria Gambacorti-Passerini María de Los Angeles Anaya Baz Esther Vanessa Aguilar Galán Yolanda Cuñarro López Juan Antonio De León Luis Ignacio Cueto Hernández Ignacio Herraiz Cecilia Villalain Roberta Venturella Giuseppe Rizzo Ilenia Mappa Giovanni Gerosolima Lars Hellmeyer Josefine Königbauer Giada Ameli Tiziana Frusca Nicola Volpe Giovanni Battista Luca Schera Stefania Fieni Eutalia Esposito Giuliana Simonazzi Gaetana Di Donna Aly Youssef Anna Nunzia Della Gatta Mariano Catello Di Donna Vito Chiantera Natalina Buono Giulio Sozzi Pantaleo Greco Danila Morano Beatrice Bianchi Maria Giulia Lombana Marino Federica Laraud Arianna Ramone Angelo Cagnacci Fabio Barra Claudio Gustavino Simone Ferrero Fabio Ghezzi Antonella Cromi Antonio Simone Laganà Valentina Laurita Longo Francesca Stollagli Angelo Sirico Antonio Lanzone Lorenza Driul Fabiana Cecchini D Serena Xodo Brian Rodriguez Felipe Mercado-Olivares Deena Elkafrawi Giovanni Sisti Rosanna Esposito Antonio Coviello Marco Cerbone Maddalena Morlando Antonio Schiattarella Nicola Colacurci Pasquale De Franciscis Ilaria Cataneo Marinella Lenzi Fabrizio Sandri Riccardo Buscemi Giorgia Gattei Francesca Della Sala Eleonora Valori Maria Cristina Rovellotti Elisa Done Gilles Faron Leonardo Gucciardo Valentina Esposito Flaminia Vena Antonella Giancotti Roberto Brunelli Ludovico Muzii Luigi Nappi Felice Sorrentino Lorenzo Vasciaveo Marco Liberati Danilo Buca Martina Leombroni Francesca Di Sebastiano Luciano Di Tizio Diego Gazzolo Massimo Franchi Quintino Cesare Ianniciello Simone Garzon Giuliano Petriglia Leonardo Borrello Albaro Josè Nieto-Calvache Juan Manuel Burgos-Luna Caroline Kadji Andrew Carlin Elisa Bevilacqua Marina Moucho Pedro Viana Pinto Rita Figueiredo José Morales Roselló Gabriela Loscalzo Alicia Martinez-Varea Vincente Diago Jesús S Jimenez Lopez Alicia Yeliz Aykanat Stefano Cosma Andrea Carosso Chiara Benedetto Amanda Bermejo Otto Henrique May Feuerschuette Ozlem Uyaniklar Sakine Rahimli Ocakouglu Zeliha Atak Reyhan Gündüz Esra Tustas Haberal Bernd Froessler Anupam Parange Peter Palm Igor Samardjiski Chiara Taccaliti Erhan Okuyan George Daskalakis Renato Augusto Moreira de Sa Alejandro Pittaro Maria Luisa Gonzalez-Duran Ana Concheiro Guisan Şerife Özlem Genç Blanka Zlatohlávková Anna Luengo Piqueras Dolores Esteban Oliva Aylin Pelin Cil Olus Api Panos Antsaklis Liana Ples Ioannis Kyvernitakis Holger Maul Marcel Malan Albert Lila Roberta Granese Alfredo Ercoli Giuseppe Zoccali Andrea Villasco Nicoletta Biglia Ciuhodaru Madalina Elena Costa Caroline Daelemans Axelle Pintiaux Elisa Cueto Eran Hadar Sarah Dollinger Noa A Brzezinski Sinai Erasmo Huertas Pedro Arango Amadeo Sanchez Javier Alfonso Schvartzman Liviu Cojocaru Sifa Turan Ozhan Turan Maria Carmela Di Dedda Rebeca Garrote Molpeceres Snezana Zdjelar Tanja Premru-Srsen Lilijana Kornhauser Cerar Mirjam Druškovič Valentina De Robertis Vedran Stefanovic Irmeli Nupponen Kaisa Nelskylä Zulfiya Khodjaeva Ksenia A Gorina Gennady T Sukhikh Giuseppe Maria Maruotti Silvia Visentin Erich Cosmi Jacopo Ferrari Alessandra Gatti Daniela Luvero Roberto Angioli Ludovica Puri Marco Palumbo Giusella D'Urso Francesco Colaleo Agnese Maria Chiara Rapisarda Ilma Floriana Carbone Antonio Mollo Giovanni Nazzaro Mariavittoria Locci Maurizio Guida Attilio Di Spiezio Sardo Pierluigi Benedetti Panici Vincenzo Berghella Maria Elena Flacco Lamberto Manzoli Giuseppe Bifulco Giovanni Scambia Fulvio Zullo Francesco D'Antonio

J Perinat Med 2020 11;48(9):950-958

Centre for High Risk Pregnancy and Fetal Care, University of Chieti, Department of Obstetrics and Gynaecology, Chieti, Italy.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6±9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; p<0.001), birthweight (OR: 1.17, 95% CI 1.09-1.12.7 per 100 g decrease; p=0.012) and maternal ventilatory support, including either need for oxygen or CPAP (OR: 4.12, 95% CI 2.3-7.9; p=0.001) were independently associated with composite adverse fetal outcome. Conclusions Early gestational age at infection, maternal ventilatory supports and low birthweight are the main determinants of adverse perinatal outcomes in fetuses with maternal COVID-19 infection. Conversely, the risk of vertical transmission seems negligible.
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http://dx.doi.org/10.1515/jpm-2020-0355DOI Listing
November 2020