Update on Poly-ADP-ribose polymerase inhibition for ovarian cancer treatment.

BACKGROUND: Despite standard treatment for epithelial ovarian cancer (EOC), that involves cytoreductive surgery followed by platinum-based chemotherapy, and initial high response rates to these, up to 80 % of patients experience relapses with a median progression-free survival of 12-18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and Poly(ADP-ribose) polymerase (PARP) inhibitors. Particularly, PARP inhibitors are active in cells that have impaired repair of DNA by the homologous recombination (HR) pathway. Cells with mutated breast related cancer antigens (BRCA) function have HR deficiency, which is also present in a significant proportion of non-BRCA-mutated ovarian cancer ("BRCAness" ovarian cancer). The prevalence of germline BRCA mutations in EOC has historically been estimated to be around 10-15 %. However, recent reports suggest that this may be a gross underestimate, especially in women with high-grade serous ovarian cancer (HGSOC). The emergence of the DNA repair pathway as a rational target in various cancers led to the development of the PARP inhibitors. The concept of tumor-selective synthetic lethality heralded the beginning of an eventful decade, culminating in the approval by regulatory authorities both in Europe as a maintenance therapy and in the United States treatment for advanced recurrent disease of the first oral PARP inhibitor, olaparib, for the treatment of BRCA-mutated ovarian cancer patients. Other PARP inhibitors are clearly effective in this disease and, within the next years, the results of ongoing randomized trials will clarify their respective roles. CONCLUSION: This review will discuss the different PARP inhibitors in development and the potential use of this class of agents in the future. Moreover, combination strategies involving PARP inhibitors are likely to receive increasing attention. The utility of PARP inhibitors combined with cytotoxic chemotherapy is of doubtful value, because of enhanced toxicity of this combination; while, more promising strategies include the combination with antiangiogenic agents, or with inhibitors of the P13K/AKT pathway and new generation of immunotherapy.

Cerebral Metastases in Patients with Left Atrial Myxoma.

We describe two cases of cardiac myxomas with cerebral metastases and review the literature on this subject. doi: 10.1111/jocs.12727 (J Card Surg 2016;31:289-293).

Focus on genetic and epigenetic events of colorectal cancer pathogenesis: implications for molecular diagnosis.

Originally, colorectal cancer (CRC) tumorigenesis was understood as a multistep process that involved accumulation of tumor suppressor genes and oncogenes mutations, such as APC, TP53 and KRAS. However, this assumption proposed a relatively limited repertoire of genetic alterations. In the last decade, there have been major advances in knowledge of multiple molecular pathways involved in CRC pathogenesis, particularly regarding cytogenetic and epigenetic events. Microsatellite instability, chromosomal instability and CpG island methylator phenotype are the most analyzed cytogenetic changes, while DNA methylation, modifications in histone proteins and microRNAs (miRNAs) were analyzed in the field of epigenetic alterations. Therefore, CRC development results from interactions at many levels between genetic and epigenetic amendments. Furthermore, hereditary cancer syndrome and individual or environmental risk factors should not be ignored. The difficulties in this setting are addressed to understand the molecular basis of individual susceptibility to CRC and to determine the roles of genetic and epigenetic alterations, in order to yield more effective prevention strategies in CRC patients and directing their treatment. This review summarizes the most investigated biomolecular pathways involved in CRC pathogenesis, their role as biomarkers for early CRC diagnosis and their possible use to stratify susceptible patients into appropriate screening or surveillance programs.

Correlation between fertility drugs use and malignant melanoma incidence: the state of the art.

The relationship between fertility, reproductive hormones, and risk of malignant melanoma has acquired much interest in recent years. Melanocytes are hormonally responsive cells, and some in vitro studies demonstrated that estrogen hormones stimulate the growth of melanocytes. Moreover, estrogen receptors have been identified in melanoma cells, as well as in melanocytic nevi and in normal skin. Some evidences suggest a possible link between fertility treatments and the increased risk of malignant melanoma. This article addresses this association through a scrupulous search of the literature published thus far. The aim of this review is to determine the incidence of malignant melanoma in women treated with fertility drugs and to examine if the exposure to fertility treatments really increases the risk of malignant melanoma. In particular, our analysis focused on the different types of drugs and different treatment schedules used. Finally, this study provides additional insights regarding the long-term relationships between fertility drugs and the risk of malignant melanoma.

An unusual case of spleen metastasis from carcinoma ex pleomorphic adenoma of the parotid gland.

Carcinoma ex pleomorphic adenoma is a rare tumor arising from the salivary glands that spreads through direct extension, through the lymphatic vessels, and, rarely, hematogenously. When distant metastases have been found, they have been reported mainly in the lung. We present an unusual case of carcinoma ex pleomorphic adenoma of the parotid gland with splenic metastases. The patient presented with a primary carcinoma ex pleomorphic adenoma of the parotid gland and he underwent a total parotidectomy with laterocervical lymphadenectomy ipsilateral and adjuvant radiation therapy to the right parotid area. One year later, the patient showed an ipsilateral supraclavicular lymph node recurrence, treated with surgery and radiation therapy. Two more years later, the patient developed lung and splenic lesions, detected through CT and PET. He underwent splenectomy and pathologic assessment of the specimen showed metastatic carcinoma ex pleomorphic adenoma. To our knowledge, there is no reported case of a carcinoma ex pleomorphic adenoma metastasizing to the spleen. Patients treated for carcinoma ex pleomorphic adenoma should be investigated for distant metastases with a long-term follow-up examination for local and distant metastases and new splenic lesions in these patients should be investigated.

Plerixafor and autologous stem cell transplantation: impressive result in a chemoresistant testicular cancer patient treated with high-dose chemotherapy.

Plerixafor, a CXCR4 antagonist, induces the rapid release of hematopoietic progenitor stem cells from the bone marrow into peripheral blood; it is approved for autologous hematopoietic progenitor stem cell mobilization in multiple myeloma and non-Hodgkin's lymphoma patients. We report the case of a 34-year-old patient with metastatic testicular embryonal carcinoma who was extensively and in vain pretreated with chemotherapy and failed to mobilize an adequate number of hematopoietic progenitor stem cells following high-dose chemotherapy, with the support of granulocyte colony-stimulating factors. After a cycle of high-dose cyclophosphamide associated with granulocyte colony-stimulating factors, plerixafor was administered to the patient, with the clinical evidence of an increase in hematopoietic progenitor stem cells in the peripheral blood. The patient achieved a complete engraftment following two cycles of high-dose chemotherapy (paclitaxel, ifosfamide, carboplatin, etoposide), with the support of hematopoietic progenitor stem cells; the patient showed discrete tolerability to the treatment. At biochemical control, the ß-human chorionic gonadotropin value decreased from 86 to less than 1.2 mUI/ml and total body PET-CT scan showed a complete response to chemotherapy. According to this experience, we believe that in patients with advanced germ cell cancer, it is essential to explore the possibility of the use of high-dose chemotherapy to induce a stable and permanent response; in this context, plerixafor, with the support of granulocyte colony-stimulating factors, may be an innovative option for satisfactory mobilization during high-dose chemotherapy protocols.

Family history of cancer as surrogate predictor for immunotherapy with anti-PD1/PD-L1 agents: preliminary report of the FAMI-L1 study.

AIM: Tumors related to hereditary susceptibility seem to have an immunosensitive phenotype. MATERIALS & METHODS: We conducted a multicenter retrospective study, to investigate if family history of cancer, multiple neoplasms and early onset of cancer could be related to clinical outcomes of anti-PD-1/PD-L1 therapy. Activity and efficacy data of 211 advanced cancer patients (kidney, non-small-cell lung cancer, melanoma, urothelium, colorectal and HeN), treated at seven Italian centers with anti-PD-1/PD-L1 agents, were analyzed. RESULTS: In this preliminary report at multivariate analyses, positive family history of cancer showed a statistically significant relationship with a better objective response rate (p = 0.0024), disease control rate (p = 0.0161), median time to treatment failure (p = 0.0203) and median overall survival (p = 0.0221). Diagnosis of multiple neoplasms significantly correlates only to a better disease control rate, while interestingly non-early onset of cancer and sex (in favor of female patients) showed significant correlation with a better median overall survival (p = 0.0268 and p = 0.0272, respectively). CONCLUSION: This pilot study seems to individuate easily available patient's features as possible predictive surrogates of clinical benefit for anti-PD-1/PD-L1 treatments. These preliminary results need to be confirmed with a greater sample size, in prospective trials with immunotherapy.

INfluenza Vaccine Indication During therapy with Immune checkpoint inhibitors: a transversal challenge. The INVIDIa study.

AIM: Considering the unmet need for the counseling of cancer patients treated with immune checkpoint inhibitors (CKI) about influenza vaccination, an explorative study was planned to assess flu vaccine efficacy in this population. METHODS: INVIDIa was a retrospective, multicenter study, enrolling consecutive advanced cancer outpatients receiving CKI during the influenza season 2016-2017. RESULTS: Of 300 patients, 79 received flu vaccine. The incidence of influenza syndrome was 24.1% among vaccinated, versus 11.8% of controls; odds ratio: 2.4; 95% CI: 1.23-4.59; p = 0.009. The clinical ineffectiveness of vaccine was more pronounced among elderly: 37.8% among vaccinated patients, versus 6.1% of unvaccinated, odds ratio: 9.28; 95% CI: 2.77-31.14; p < 0.0001. CONCLUSION: Although influenza vaccine may be clinically ineffective in advanced cancer patients receiving CKI, it seems not to negatively impact the efficacy of anticancer therapy.

[Innovations in the treatment of ovarian cancer. Analysis of the therapeutic development: from platinum to immunotherapy.] / Innovazioni terapeutiche nel trattamento del tumore ovarico. Analisi del percorso per lo sviluppo terapeutico: dal platino all'immunoterapia.

Ovarian cancer is the seventh most common cancer in women. The therapeutic approach provides for an appropriate integration between surgery and chemotherapy. Surgery is an important step for diagnosis, staging and therapy, aiming at the complete cytoreduction of all macroscopic visible disease. At the moment, adjuvant and first-line chemotherapy has as a standard the carboplatin-paclitaxel combination. Further, the addition of bevacizumab in the advanced stage (IIIB-IV) is strongly recommended. Despite the initial effectiveness, however, 70-80% of patients develop relapsed disease within the first two years and require subsequent treatment lines that have palliative, rather than curative purposes and that seek to reach a chronic state for the disease. Among the causes of recurrences, one of the most studied is related to the stem cells that, due to a quiescent state, are resistant to chemotherapy. The choice of these treatments must consider several factors, including the probability of extending the PFS and OS, the residual toxicity, symptoms control, and the improvement of quality of life, and always remains subject to platinum free interval (PFI). There are not standard therapy. Pegylated liposomal doxorubicin (PLD) as a single agent or in combination with other drugs is one of several treatment modalities that may be considered for relapsed ovaria cancer. In addition, in about 15% to 20% of epithelial tumors, there is a mutation of the BRCA1 and 2 genes. This is fundamental to identify immediately a therapeutic opportunity represented by PARP inhibitors. These drugs, such as olaparib and niraparib, used in maintenance after a previous platinum-response, even partial, have also shown in upfront an activity in BRCA wild type, homologous recombination deficent (HRD) and homologous recombination proficient (HRP). Therefore, after 20 years of chemotherapy alone, new targeted therapies are emerging that will help changing the therapeutic approach, making treatments increasingly personalized.

Niraparib in ovarian cancer: results to date and clinical potential.

Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2, two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA-mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy. Interestingly, was niraparib showed to be efficacious not only in BRCA-mutated patients, but also in patients with other alterations of the homologous recombination (HR) system and in patients with unknown alterations. These results position niraparib as the first PARP-inhibitor with clinically and statistically significant results also in patients with no alterations in BRCA 1/2 and other genes involved in the DNA repair system. Even if the results are potentially practice-changing, the action of niraparib must be further studied and deepened.

Bevacizumab in ovarian cancer: A critical review of phase III studies.

Bevacizumab (BV) is a humanized monoclonal antibody targeting vascular endothelial growth factor and it is the first molecular-targeted agent to be used for the treatment of ovarian cancer (OC). Randomized Phase III trials evaluated the combination of BV plus standard chemotherapy for first-line treatment of advanced OC and for platinum-sensitive and platinum-resistant recurrent OC. These trials reported a statistically significant improvement in progression-free survival but not in overall survival. Furthermore, BV effectively improved the quality of life with regard to abdominal symptoms in recurrent OC patients. Bevacizumab is associated with adverse events such as hypertension, bleeding, thromboembolism, proteinuria, delayed wound healing, and gastrointestinal events. However, most of these events can be adequately managed. This review describes the latest evidence for BV treatment of OC and selection of patients for personalized treatment.

Breast metastasis and lung large-cell neuroendocrine carcinoma: first clinical observation.

BACKGROUND AND AIMS: The lung large-cell neuroendocrine carcinoma (LCNEC) is a very rare aggressive neuroendocrine tumor with a high propensity to metastasize and very poor prognosis. We report an atypical presentation of lung LCNEC was diagnosed from a metastatic nodule on the breast. METHODS: Our patient is a 59-years-old woman that presented in March 2014 nonproductive cough. A CT scan showed multiple brain, lung, adrenal gland and liver secondary lesions; moreover, it revealed a breast right nodule near the chest measuring 1.8 cm. The breast nodule and lung lesions were biopsied and their histology and molecular diagnosis were LCNEC of the lung. To our knowledge, this is the first documented case of breast metastasis from LCNEC of the lung. RESULTS: Furthermore, breast metastasis from extramammary malignancy is uncommon and its diagnosis is difficult but important for proper management and prediction of prognosis. Therefore, a careful clinical history with a thorough clinical examination is needed to make the correct diagnosis. Moreover, metastasis to the breast should be considered in any patient with a known primary malignant tumor history who presents with a breast lump. Anyhow, pathological examination should be performed to differentiate the primary breast cancer from metastatic tumor. CONCLUSION: Therefore, an accurate diagnosis of breast metastases may not only avoid unnecessary breast resection, more importantly it is crucial to determine an appropriate and systemic treatment.

Targeting angiogenesis in endometrial cancer - new agents for tailored treatments.

INTRODUCTION: Endometrial carcinoma represents the most frequent gynecologic tumor in developed countries. The majority of women presents with low-grade tumors but a significant subset of women experience recurrence and do not survive their disease. Patients with stage III/ IV or recurrent endometrial cancer have a poor prognosis. Identification of active and tolerable new targeted agents versus specific molecular targets is a priority objective. Angiogenesis is a complex process that plays a crucial role in the development of many types of cancer and in particular endometrial cancer. AREAS COVERED: In this review, the authors highlight the main angiogenetic molecular pathways and the anti-angiogenic agents in Phase II clinical trials for endometrial cancer treatment. The authors focus on reports from recent years on angiogenesis inhibitors used in endometrial cancer, including anti- vascular endothelial growth factor (VEGF) monoclonal antibodies (bevacizumab and aflibercept), mammalian target of rapamycin inhibitors (mTORi) (everolimus, temsirolimus and ridaforolimus), PI3 K inhibitors (BKM120), tyrosine kinase inhibitors (brivanib, sunitinib, dovitinib and nintedanib) and thalidomide. EXPERT OPINION: These anti-angiogenic drugs, while used either alone or in combination with chemotherapy, have presented mixed results in treating endometrial cancer patients. Challenges for the future include the identification of new pathways, early identification and overcoming resistance and the use of these molecules in combination with old and new chemotherapeutic and targeted agents.

Old Tyrosine Kinase Inhibitors and Newcomers in Gastrointestinal Cancer Treatment.

Gastrointestinal cancer treatment is based more on molecular biology that has provided increasing knowledge about cancer pathogenesis on which targeted therapy is being developed. Precisely, targeted therapy is defined as a "type of treatment that uses drugs, such as monoclonal antibodies or tyrosine kinase inhibitors, to identify and attack specific cancer cells". Nowadays, the United States Food and Drug Administration has approved many targeted therapies for gastrointestinal cancer treatment, as many are in various phases of development as well. In a previous review we discussed the main monoclonal antibodies used and studied in gastrointestinal cancer. In addition to monoclonal antibodies, tyrosine kinase inhibitors represent another class of targeted therapy and following the approval of imatinib for gastrointestinal stromal tumours, other tyrosine kinase inhibitors have been approved for gastrointestinal cancers treatment such as sunitinib, regoragenib, sorafenib and erlotinib. Moving forward, the purpose of this review is to focus on the efficacy data of main tyrosine kinase inhibitors commonly used in the personalized treatment of each gastrointestinal tumour and to provide a comprehensive overview about experimental targeted therapies ongoing in this setting.

Triple-negative breast cancer: investigating potential molecular therapeutic target.

INTRODUCTION: Triple-negative breast cancer (TNBC) makes up about 10 - 20% of all breast cancers and the lack of hormone receptors and human epidermal growth factor receptor-2/Neu expression is responsible for poor prognosis, no targeted therapies and trouble in the clinical management. Tumor heterogeneity, also within the same tumor, is a major cause for this difficulty. Based on the introduction of new biological drugs against different kinds of tumor, many efforts have been made for classification of genetic alterations present in TNBC, leading to the identification of several oncogenes and tumor suppressor genes involved in breast cancer carcinogenesis. AREAS COVERED: In this review we investigated the molecular alteration present in TNBC which could lead to the creation of new targeted therapies in the future, with the aim to counteract this disease in the most effective way. EXPERT OPINION: In this context some hormone receptors like G-protein-coupled receptor 30 and androgen receptors may be a fascinating area to investigate; also, angiogenesis, represented not only by the classical VEGF/VEGFR relationship, but also by other molecules, like semaphorins, fibroblast growth factor and heparin-binding-EGF-like, is a mechanism in which new developments are expected. In this perspective, one technique that may show promise is the gene therapy; in particular the gene transfer could correct abnormal genetic function in cancer cells.

Triple-negative breast cancer: new perspectives for targeted therapies.

Breast cancer is a heterogeneous disease, encompassing a large number of entities showing different morphological features and having clinical behaviors. It has became apparent that this diversity may be justified by distinct patterns of genetic, epigenetic, and transcriptomic aberrations. The identification of gene-expression microarray-based characteristics has led to the identification of at least five breast cancer subgroups: luminal A, luminal B, normal breast-like, human epidermal growth factor receptor 2, and basal-like. Triple-negative breast cancer is a complex disease diagnosed by immunohistochemistry, and it is characterized by malignant cells not expressing estrogen receptors or progesterone receptors at all, and human epidermal growth factor receptor 2. Along with this knowledge, recent data show that triple-negative breast cancer has specific molecular features that could be possible targets for new biological targeted drugs. The aim of this article is to explore the use of new drugs in this particular setting, which is still associated with poor prognosis and high risk of distant recurrence and death.

Beyond bevacizumab: investigating new angiogenesis inhibitors in ovarian cancer.

INTRODUCTION: Ovarian cancer is the most lethal gynecological cancer, mainly because of the advanced stage of the disease at diagnosis, with recent research investigating novel targets and agents into the clinical practice, with the aim to improve prognosis and quality of life. Angiogenesis is a significant target for ovarian cancer therapy. AREAS COVERED: Areas covered in this review include the most common molecular pathways of angiogenesis, which have provided novel targets for tailored therapy in ovarian cancer patients. These therapeutic strategies comprise monoclonal antibodies and tyrosine kinase inhibitors. These drugs have as molecular targets such as vascular endothelial growth factor (VEGF), VEGF receptor, platelet-derived growth factor, fibroblast growth factor, angiopoietin and Ephrin type-A receptor 2. EXPERT OPINION: The expansion in understanding the molecular biology that characterizes cancer cells has led to the rapid development of new agents to target important pathways, but the heterogeneity of ovarian cancer biology indicates that there is no predominant defect. This review attempts to discuss progress till date in tackling a more general target applicable to ovarian cancer angiogenesis.

Malignant transformation of well-differentiated papillary mesothelioma 13 years after the diagnosis: a case report.

Well-differentiated papillary mesothelioma (WDPM) is a rare mesothelial tumour affecting mostly the peritoneum of women in their reproductive age, but it may occur also at other sites, including the pleura. It is considered a specific pathological entity different from diffuse malignant mesothelioma as it displays a characteristic histological pattern and is associated with a slowly progressive clinical course. We report the case of a 79-year-old man with a history of right pleural WDPM at age 64, which was successfully treated with chemotherapy, radiotherapy and talc pleurodesis. Thirteen years after the first diagnosis, he presented with mediastinal lymph nodes metastasis and with an extremely rare pattern of tracheal and bronchial infiltration that was detected at bronchoscopy. Biopsy samples revealed loss of histological differentiation of the neoplastic cells. This case report highlights that WDPM is a tumour of uncertain malignant potential that may undergo transformation over many years. Finally, the role of immunohistochemistry in the diagnosis of WDPM and the possible mechanisms leading to this unique way of metastatisation are discussed.

Angiogenesis and antiangiogenic agents in cervical cancer.

Standard treatment of cervical cancer (CC) consists of surgery in the early stages and of chemoradiation in locally advanced disease. Metastatic CC has a poor prognosis and is usually treated with palliative platinum-based chemotherapy. Current chemotherapeutic regimens are associated with significant adverse effects and only limited activity, making identification of active and tolerable novel targeted agents a high priority. Angiogenesis is a complex process that plays a crucial role in the development of many types of cancer. The dominant role of angiogenesis in CC seems to be directly related to human papillomavirus-related inhibition of p53 and stabilization of hypoxia-inducible factor-1α. Both of these mechanisms are able to increase expression of vascular endothelial growth factor (VEGF). Activation of VEGF promotes endothelial cell proliferation and migration, favoring formation of new blood vessels and increasing permeability of existing blood vessels. Since bevacizumab, a recombinant humanized monoclonal antibody binding to all isoforms of VEGF, has been demonstrated to significantly improve survival in gynecologic cancer, some recent clinical research has explored the possibility of using novel therapies directed toward inhibition of angiogenesis in CC too. Here we review the main results from studies concerning the use of antiangiogenic drugs that are being investigated for the treatment of CC.