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Article: Trabectedin and lurbinectedin: Mechanisms of action, clinical impact, and future perspectives in uterine and soft tissue sarcoma, ovarian carcinoma, and endometrial carcinoma.

Gadducci, Angiolo / Cosio, Stefania

2022 Volume 12, Page(s) 914342

Abstract: The ecteinascidins trabectedin and lurbinectedin are very interesting antineoplastic agents, with a favorable toxicity profile and peculiar mechanisms of action. These drugs form adducts in the minor groove of DNA, which produce single-strand breaks ( ... ...

Abstract	The ecteinascidins trabectedin and lurbinectedin are very interesting antineoplastic agents, with a favorable toxicity profile and peculiar mechanisms of action. These drugs form adducts in the minor groove of DNA, which produce single-strand breaks (SSBs) and double-strand breaks (DSBs) and trigger a series of events resulting in cell cycle arrest and apoptosis. Moreover, the ecteinascidins interact with the tumor microenvironment, reduce the number of tumor-associated macrophages, and inhibit the secretion of cytokines and chemokines. Trabectedin has been approved by the Federal Drug Administration (FDA) for patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-based regimen. Moreover, trabectedin in combination with pegylated liposomal doxorubicin (PLD) has been approved in the European Union for the treatment of platinum-sensitive recurrent ovarian cancer. Lurbinectedin has been approved by the FDA for patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. The review assesses
Language	English
Publishing date	2022-11-03
Publishing country	Switzerland
Document type	Systematic Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.914342
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Article ; Online: Screening for Ovarian Cancer in the General Population: State of Art and Perspectives of Clinical Research.

Gadducci, Angiolo / Cosio, Stefania

Anticancer research

2022 Volume 42, Issue 9, Page(s) 4207–4216

Abstract: Background/aim: Screening for ovarian cancer in the general population is a challenging issue. The aim of this review was to analyze both the studies based on serum CA125 assay and ultrasound (US) and the novel perspectives of clinical and biological ... ...

Abstract	Background/aim: Screening for ovarian cancer in the general population is a challenging issue. The aim of this review was to analyze both the studies based on serum CA125 assay and ultrasound (US) and the novel perspectives of clinical and biological research on this issue. Materials and methods: The trials on the combination of serum CA125 and vaginal/pelvic US as well as the investigations on microRNA (miRNA)s, circulating tumor DNA and tumor protein 53 (TP53) variants in DNA purified from Pap smears have been critically analyzed. Results: Two large randomized trials failed to detect a reduction in ovarian cancer-related deaths in women who underwent serum CA125- and US-based screening compared to those who had no screening. The United Kingdom Collaborative Trial of Ovarian Cancer Screening reported a 39.2% higher incidence of stage I-II and 10.2% lower incidence of stage III-IV disease in women who underwent annual multimodal screening with serum CA125 and vaginal US compared to women who had no screening, but this stage shifting did not translate into a survival benefit. A longitudinal, multiple biomarker algorithm-based strategy might improve ovarian cancer detection compared with serial CA125 alone. The use of serum tumor-associated autoantibodies, circulating tumor DNA and microRNA is still investigational. The identification of TP53 clonal variants in DNA purified from Pap smears can detect early steps of serous ovarian carcinogenesis. Conclusion: The availability of sensitive next-generation sequencing-based approaches for TP53 assessment in PAP smears may allow the reliability of this genetic marker for early detection of ovarian cancer to be verified.
MeSH term(s)	Biomarkers, Tumor/genetics ; CA-125 Antigen ; Carcinoma, Ovarian Epithelial ; Circulating Tumor DNA ; Early Detection of Cancer ; Female ; Humans ; MicroRNAs/genetics ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/genetics ; Reproducibility of Results
Chemical Substances	Biomarkers, Tumor ; CA-125 Antigen ; Circulating Tumor DNA ; MicroRNAs
Language	English
Publishing date	2022-08-29
Publishing country	Greece
Document type	Journal Article ; Review
ZDB-ID	604549-2
ISSN	1791-7530 ; 0250-7005
ISSN (online)	1791-7530
ISSN	0250-7005
DOI	10.21873/anticanres.15921
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Article: Pharmacological Treatment of Advanced, Persistent or Metastatic Endometrial Cancer: State of the Art and Perspectives of Clinical Research for the Special Issue "Diagnosis and Management of Endometrial Cancer".

Gadducci, Angiolo / Cosio, Stefania

Cancers

2021 Volume 13, Issue 24

Abstract: Patients with metastatic or recurrent endometrial cancer (EC) not suitable for surgery and/or radiotherapy are candidates for pharmacological treatment frequently with unsatisfactory clinical outcomes. The purpose of this paper was to review the results ... ...

Abstract	Patients with metastatic or recurrent endometrial cancer (EC) not suitable for surgery and/or radiotherapy are candidates for pharmacological treatment frequently with unsatisfactory clinical outcomes. The purpose of this paper was to review the results obtained with chemotherapy, hormonal therapy, biological agents and immune checkpoint inhibitors in this clinical setting. The combination of carboplatin (CBDCA) + paclitaxel (PTX) is the standard first-line chemotherapy capable of achieving objective response rates (ORRs) of 43-62%, a median progression-free survival (PFS) of 5.3-15 months and a median overall survival (OS) of 13.2-37.0 months, respectively, whereas hormonal therapy is sometimes used in selected patients with slow-growing steroid receptor-positive EC. The combination of endocrine therapy with m-TOR inhibitors or cyclin-dependent kinase 4/6 inhibitors is currently under evaluation. Disappointing ORRs have been associated with epidermal growth factor receptor (EGFR) inhibitors, HER-2 inhibitors and multi-tyrosine kinase inhibitors used as single agents, and clinical trials evaluating the addition of bevacizumab to CBDCA + PTX have reported conflicting results. Immune checkpoint inhibitors, and especially pembrolizumab and dostarlimab, have achieved an objective response in 27-47% of highly pretreated patients with microsatellite instability-high (MSI-H)/mismatch repair (MMR)-deficient (-d) EC. In a recent study, the combination of lenvatinib + pembrolizumab produced a 24-week response rate of 38% in patients with highly pretreated EC, ranging from 64% in patients with MSI-H/MMR-d to 36% in those with microsatellite stable/MMR-proficient tumors. Four trials are currently investigating the addition of immune checkpoint inhibitors to PTX + CBDCA in primary advanced or recurrent EC, and two trials are comparing pembrolizumab + lenvatinib versus either CBDCA + PTX as a first-line treatment of advanced or recurrent EC or versus single-agent chemotherapy in advanced, recurrent or metastatic EC after one prior platinum-based chemotherapy.
Language	English
Publishing date	2021-12-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13246155
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Article ; Online: The Prognostic Relevance of Computed Tomography-assessed Skeletal Muscle Index and Skeletal Muscle Radiation Attenuation in Patients With Gynecological Cancer.

Gadducci, Angiolo / Cosio, Stefania

Anticancer research

2021 Volume 41, Issue 1, Page(s) 9–20

Abstract: The evaluation of the whole skeletal muscle area at the level of the third lumbar vertebra on computed tomography (CT) scans has often detected loss of skeletal muscle mass, defined as sarcopenia, and reduced skeletal muscle radiation attenuation (SMRA) ... ...

Abstract	The evaluation of the whole skeletal muscle area at the level of the third lumbar vertebra on computed tomography (CT) scans has often detected loss of skeletal muscle mass, defined as sarcopenia, and reduced skeletal muscle radiation attenuation (SMRA) in patients with different malignancies. Baseline sarcopenia has been detected in 33.3%-51.8% of patients with advanced cervical cancer, 33.6%-50% of those with endometrial cancer, and 11%-64% of those with advanced ovarian cancer. We reviewed the literature data on the clinical relevance of CT-assessed skeletal muscle status in gynecological malignancies. Overall, baseline skeletal muscle index and SMRA have an uncertain prognostic relevance, whereas their changes during treatment usually correlate with progression-free survival and overall survival. Multicenter clinical trials are strongly warranted to assess the effects of pharmacological agents and physical exercise in the management of skeletal muscle damage in patients with gynecological cancer.
MeSH term(s)	Biomarkers ; Female ; Genital Neoplasms, Female/diagnosis ; Genital Neoplasms, Female/mortality ; Genital Neoplasms, Female/radiotherapy ; Humans ; Muscle, Skeletal/diagnostic imaging ; Muscle, Skeletal/pathology ; Muscle, Skeletal/radiation effects ; Neoplasm Grading ; Neoplasm Staging ; Organ Size ; Organ Specificity ; Prognosis ; Tomography, X-Ray Computed/methods
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-01-08
Publishing country	Greece
Document type	Journal Article ; Review
ZDB-ID	604549-2
ISSN	1791-7530 ; 0250-7005
ISSN (online)	1791-7530
ISSN	0250-7005
DOI	10.21873/anticanres.14747
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Zs.A 1642: Show issues

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Article ; Online: Randomized Clinical Trials and Real World Prospective Observational Studies on Bevacizumab, PARP Inhibitors, and Immune Checkpoint Inhibitors in the First-Line Treatment of Advanced Ovarian Carcinoma: A Critical Review.

Gadducci, Angiolo / Cosio, Stefania

Anticancer research

2021 Volume 41, Issue 10, Page(s) 4673–4685

Abstract: Platinum/paclitaxel-based chemotherapy is able to obtain a clinical response in up to 80% of patients with advanced ovarian carcinoma, but most of them will subsequently develop recurrent disease. Several therapeutic approaches, including prolonged ... ...

Abstract	Platinum/paclitaxel-based chemotherapy is able to obtain a clinical response in up to 80% of patients with advanced ovarian carcinoma, but most of them will subsequently develop recurrent disease. Several therapeutic approaches, including prolonged administration of the first-line regimen and the concomitant or sequential addition of a third cytotoxic agent to standard chemotherapy, failed to improve the clinical outcome of patients. In the last years, the implementation of the biological knowledge on ovarian carcinoma and the introduction of bevacizumab (BEV) and poly(ADP-ribose) polymerase inhibitors (PARPi) in first-line treatment have improved patient prognosis. In this review, we have analyzed the randomized clinical trials and real world observational studies on these issues, with the aim to suggest an algorithm for a rational use of BEV and PARPi in patients with newly diagnosed advanced ovarian carcinoma.
MeSH term(s)	Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Bevacizumab/therapeutic use ; Carcinoma, Ovarian Epithelial/drug therapy ; Female ; Humans ; Immune Checkpoint Inhibitors/therapeutic use ; Observational Studies as Topic ; Ovarian Neoplasms/drug therapy ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Randomized Controlled Trials as Topic
Chemical Substances	Immune Checkpoint Inhibitors ; Poly(ADP-ribose) Polymerase Inhibitors ; Bevacizumab (2S9ZZM9Q9V)
Language	English
Publishing date	2021-10-01
Publishing country	Greece
Document type	Journal Article ; Review
ZDB-ID	604549-2
ISSN	1791-7530 ; 0250-7005
ISSN (online)	1791-7530
ISSN	0250-7005
DOI	10.21873/anticanres.15281
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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Hyperthermic Intraperitoneal Chemotherapy in the Management of Primary Epithelial Ovarian Cancer: A Debated Issue for Gynecologic Oncologists.

Gadducci, Angiolo / Cosio, Stefania / Lippolis, Piero Vincenzo

Anticancer research

2022 Volume 42, Issue 10, Page(s) 4659–4665

Abstract: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been widely investigated in patients with peritoneal carcinomatosis, including those with epithelial ovarian cancer (EOC), with conflicting results. The hyperthermia enhances drug tissue penetration, ... ...

Abstract	Hyperthermic intraperitoneal chemotherapy (HIPEC) has been widely investigated in patients with peritoneal carcinomatosis, including those with epithelial ovarian cancer (EOC), with conflicting results. The hyperthermia enhances drug tissue penetration, synergizes with several cytotoxic drugs including cisplatin, degrades BRCA2, suppresses homologous recombination, and elicits an anticancer immune response. A meta-analysis of retrospective studies including both patients with primary advanced EOC and those with recurrent platinum-sensitive EOC failed to detect a benefit in terms of progression-free survival (PFS) or overall survival (OS) from the addition of HIPEC after surgery. The aim of the present review was to analyze the recent randomized clinical trials designed to assess the value of HIPEC in the management of patients with primary advanced EOC. Although not free from criticism and bias, the available data from two phase III trials seem to suggest that the addition of HIPEC to interval debulking surgery after neoadjuvant chemotherapy significantly improves PFS and OS. Conversely, HIPEC does not appear to offer any advantage after primary debulking surgery. Several phase III trials are currently ongoing on these issues and the use of HIPEC is still a matter of debate in the scientific community. Additional translational research is strongly warranted to detect biological variables able to identify a subset of patients who may have a major benefit from this therapeutic approach. In particular, the clinical outcome of patients who undergo HIPEC should be correlated with BRCA status and homologous recombination repair status.
MeSH term(s)	Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carcinoma, Ovarian Epithelial/drug therapy ; Cisplatin ; Combined Modality Therapy ; Cytoreduction Surgical Procedures/methods ; Female ; Humans ; Hyperthermia, Induced/methods ; Hyperthermic Intraperitoneal Chemotherapy ; Neoplasm Recurrence, Local/drug therapy ; Oncologists ; Ovarian Neoplasms/drug therapy ; Retrospective Studies
Chemical Substances	Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2022-10-03
Publishing country	Greece
Document type	Journal Article ; Review
ZDB-ID	604549-2
ISSN	1791-7530 ; 0250-7005
ISSN (online)	1791-7530
ISSN	0250-7005
DOI	10.21873/anticanres.15970
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Zs.A 1642: Show issues

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Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article: Therapeutic Approach to Low-Grade Serous Ovarian Carcinoma: State of Art and Perspectives of Clinical Research.

Gadducci, Angiolo / Cosio, Stefania

Cancers

2020 Volume 12, Issue 5

Abstract: Low-grade serous ovarian carcinoma (LGSOC) is a distinct pathologic and clinical entity, characterized by less aggressive biological behavior, lower sensitivity to chemotherapy and longer survival compared with high-grade serous ovarian carcinoma. LGSOC ... ...

Abstract	Low-grade serous ovarian carcinoma (LGSOC) is a distinct pathologic and clinical entity, characterized by less aggressive biological behavior, lower sensitivity to chemotherapy and longer survival compared with high-grade serous ovarian carcinoma. LGSOC often harbors activating mutations of genes involved in mitogen activated protein kinase (MAPK) pathway. Patients with disease confined to the gonad(s) should undergo bilateral salpingo-oophorectomy, total hysterectomy and comprehensive surgical staging, although fertility-sparing surgery can be considered in selected cases. Women with stage IA-IB disease should undergo observation alone after surgery, whereas observation, chemotherapy or endocrine therapy are all possible options for those with stage IC-IIA disease. Patients with advanced disease should undergo primary debulking surgery with the aim of removing all macroscopically detectable disease, whereas neoadjuvant chemotherapy followed by interval debuking surgery. After surgery, the patients can receive either carboplatin plus paclitaxel followed by endocrine therapy or endocrine therapy alone. Molecularly targeted agents, and especially MEK inhibitors and Cyclin-dependent kinase (CDK) inhibitors, are currently under evaluation. Additional research on the genomics of LGSOC and clinical trials on the combination of MEK inhibitors with hormonal agents, other molecularly targeted agents or metformin, are strongly warranted to improve the prognosis of patients with this malignancy.
Language	English
Publishing date	2020-05-23
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12051336
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Article: Perivascular epithelioid cell tumors (PEComa) of the female genital tract: A challenging question for gynaecologic oncologist and pathologist.

Gadducci, Angiolo / Zannoni, Gian Franco

Gynecologic oncology reports

2020 Volume 33, Page(s) 100603

Abstract: Perivascular epithelioid cell tumors (PEComa)s are mesenchymal neoplasms composed of perivascular epithelioid cells, which express both melanocytic and myogenic markers. These neoplastic cells are thought to arise from undifferentiated cells of the ... ...

Abstract	Perivascular epithelioid cell tumors (PEComa)s are mesenchymal neoplasms composed of perivascular epithelioid cells, which express both melanocytic and myogenic markers. These neoplastic cells are thought to arise from undifferentiated cells of the neural crest, or from myoblastic cells harbouring a molecular alteration leading to expression of melanocytic markers, or from pericytic cells. The majority of cases are benign, but a small subset behaves in a malignant fashion. Unfortunately, given their rarity, reliable criteria for predicting malignancy have yet to be established. PEComas of the female genital tract account for nearly 25% of PEComas of all body sites, and the most common site of occurrence is the uterine corpus; less common sites include the cervix, adnexa, vagina/vulva or broad or round ligament exceptionally. The present review aims to elucidate the clinical, pathological and molecular features of gynecological PEComas. Moreover, prognostic and therapeutic implications are also discussed.
Language	English
Publishing date	2020-07-06
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2818505-5
ISSN	2352-5789
ISSN	2352-5789
DOI	10.1016/j.gore.2020.100603
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Article ; Online: Locally advanced squamous cell carcinoma of the vulva: A challenging question for gynecologic oncologists.

Gadducci, Angiolo / Aletti, Giovanni Damiano

Gynecologic oncology

2020 Volume 158, Issue 1, Page(s) 208–217

Abstract: Squamous cell carcinoma of the vulva is a rare female malignancy, with an incidence increasing with age. Unfortunately, one third of the patients are diagnosed with locally advanced disease, which constitutes a clinical challenge for the clinicians who ... ...

Abstract	Squamous cell carcinoma of the vulva is a rare female malignancy, with an incidence increasing with age. Unfortunately, one third of the patients are diagnosed with locally advanced disease, which constitutes a clinical challenge for the clinicians who treat these patients. The main challenges are represented by: 1. The primary site of the disease, which can be proximal to anatomical structures like the anal canal posteriorly, or the urethra and the bladder anteriorly, that in some circumstances cannot be spared without a bowel and/or urinary stoma; 2. The locoregional nodes that can be involved by the tumor, and they can be bulky, fixed or ulcerated; 3. The clinical condition of the patient, who may carry several comorbidities. Treatment modalities include radiation with or without chemotherapy, and surgery. In order to preserve the bowel and the urinary function without a permanent stoma, a personalized management with a multimodality approach is warranted. In this systematic review, we first clarify the different definitions of "locally advanced vulvar carcinoma". Secondly, we evaluated the different treatment modalities described in the literature, and the impact of the different treatment strategies on prognosis and on preservation of bowel/urinary function. Finally, we offer a possible algorithm that may help the clinicians in treating patients with these uncommon and challenging situations with a multidisciplinary approach.
MeSH term(s)	Carcinoma, Squamous Cell/diagnosis ; Carcinoma, Squamous Cell/therapy ; Combined Modality Therapy ; Female ; Humans ; Precision Medicine ; Vulvar Neoplasms/diagnosis ; Vulvar Neoplasms/therapy
Language	English
Publishing date	2020-05-25
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2020.05.021
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Zs.A 885: Show issues

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Article ; Online: Endometriosis-associated Extraovarian Malignancies: A Challenging Question for the Clinician and the Pathologist.

Gadducci, Angiolo / Zannoni, Gian Franco

Anticancer research

2020 Volume 40, Issue 5, Page(s) 2429–2438

Abstract: Endometriosis is an estrogen-dependent disease, which affects 10% of women in the reproductive age. Malignant transformation is an uncommon event, which affects approximately 0.7-2.5% of women, and, when it occurs, it involves ovarian and extraovarian ... ...

Abstract	Endometriosis is an estrogen-dependent disease, which affects 10% of women in the reproductive age. Malignant transformation is an uncommon event, which affects approximately 0.7-2.5% of women, and, when it occurs, it involves ovarian and extraovarian sites in 75% and 25% of the cases, respectively. Endometriosis correlates with presentation of clear cell and endometrioid carcinoma of the ovary. Activation of phosphatidylinositol 3-kinase (PIK3) - protein kinase B (AKT) - mammalian target of rapamycin (mTOR) pathway, aberrant chromatin remodeling due to AT-rich interactive domain-containing protein 1A (ARID1A) mutation and inactivation of estrogen receptor-α signaling seem to play a major role in the carcinogenesis. To date, little data are available regarding endometriosis-associated extraovarian malignancies. The aim of the present study was to review the clinical, pathological and prognostic features of endometriosis-related neoplasms arising from extraovarian sites, with particular focus on intestinal malignancies, urinary tract malignancies and tumors arising from surgical scars.
MeSH term(s)	Biopsy ; Carcinoma, Endometrioid/diagnosis ; Carcinoma, Endometrioid/etiology ; Carcinoma, Endometrioid/therapy ; Case-Control Studies ; Cell Transformation, Neoplastic ; Disease Progression ; Endometriosis/complications ; Endometriosis/etiology ; Endometriosis/metabolism ; Endometriosis/pathology ; Female ; Humans ; Immunohistochemistry ; Neoplasm Grading ; Neoplasm Staging ; Pathologists
Language	English
Publishing date	2020-05-03
Publishing country	Greece
Document type	Journal Article ; Review
ZDB-ID	604549-2
ISSN	1791-7530 ; 0250-7005
ISSN (online)	1791-7530
ISSN	0250-7005
DOI	10.21873/anticanres.14212
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