The Impact of Diagnosis of Human Papillomavirus (HPV) Infection and Electrosurgical Excision Procedure (LEEP) for Cervical Intraepithelial Neoplasia 3 (CIN3) on Women's Sexual Lives.

The aim of the study was to assess sexual health in women who underwent Loop Electrosurgical Excisional Procedure (LEEP) for the treatment of cervical intraepithelial neoplasia 3 (CIN 3). One hundred thirty-one women were enrolled, and the Female Sexual Function Index (FSFI) questionnaire was administered before LEEP and 6 months after the procedure. In almost all of the participants, data revealed a statistically significant worsening in sexual quality of life after LEEP. Therefore, clinicians should be aware of these possible negative effects on sexual behavior, and provide women with appropriate, wide-ranging, and detailed counseling. The data obtained in the present study should help to plan appropriate counseling from communicating HPV diagnosis and medical treatment to CIN3 surgical procedure.

Oxetan-3-ols as 1,2-bis-Electrophiles in a Brønsted-Acid-Catalyzed Synthesis of 1,4-Dioxanes.

Annulations that combine diacceptors with bis-nucleophiles are uncommon. Here, we report the synthesis of 1,4-dioxanes from 3-aryloxetan-3-ols, as 1,2-bis-electrophiles and 1,2-diols. Brønsted acid Tf2NH catalyzes both the selective activation of the oxetanol, to form an oxetane carbocation that reacts with the diol, and intramolecular ring opening of the oxetane. High regio- and diastereoselectivity are achieved with unsymmetrical diols. The substituted dioxanes and fused bicyclic products present interesting motifs for drug discovery and can be further functionalized.

Systemic Treatments for Advanced Small Bowel Adenocarcinoma: A Systematic Review.

Small bowel adenocarcinoma (SBA) is a rare disease for which scarce evidence is available. We summarized data available on systemic treatment of advanced SBA. METHODS: Scientific literature was evaluated to find phase II or phase III clinical trials on systemic treatment for advanced SBA. MeSH terms were selected and combined for the initial search, then inclusion and exclusion criteria were set in a search protocol. Four medical oncologists looked for evidence on Medline, EMBASE and Cochrane databases. Moreover, abstracts from 2016 to June 2021 from the American Society for Clinical Oncology, European Society for Medical Oncology, Gastrointestinal Cancer Symposium and World Congress on Gastrointestinal Cancer were browsed. The selected studies, matching the inclusion and exclusion criteria, were finally tabulated and analyzed. RESULTS: The trials finally selected were 18 phase II/III clinical trials. Four small phase II trials support the activity of oxaliplatin-based doublets in first-line treatment (CAPOX and mFOLFOX). CONCLUSION: No good level evidence is available on the use of bevacizumab, anti-epidermal growth factor receptor, targeted agents or immunotherapy. First-line treatments are largely derived from colorectal cancer protocols, mainly oxaliplatin-based doublets.

Mass Spectrometry Based Approach for Organic Synthesis Monitoring.

Current mass spectrometry-based methodologies for synthetic organic reaction monitoring largely use electrospray ionization (ESI), or other related atmospheric pressure ionization-based approaches. Monitoring of complex, heterogeneous systems may be problematic because of sampling hardware limitations, and many relevant analytes (neutrals) exhibit poor ESI performance. An alternative monitoring strategy addressing this significant impasse is condensed phase membrane introduction mass spectrometry using liquid electron ionization (CP-MIMS-LEI). In CP-MIMS, a semipermeable silicone membrane selects hydrophobic neutral analytes, rejecting particulates and charged chemical components. Analytes partition through the membrane, and are then transported to the LEI interface for sequential nebulization, vaporization, and ionization. CP-MIMS and LEI are both ideal for continuous monitoring applications of hydrophobic neutral molecules. We demonstrate quantitative reaction monitoring of harsh, complex reaction mixtures (alkaline, acidic, heterogeneous) in protic and aprotic organic solvents. Also presented are solvent-membrane compatibility investigations and, in situ quantitative monitoring of catalytic oxidation and alkylation reactions.

Morphologic shift associated with aberrant cytokeratin expression in a GIST patient after tyrosine kinase inhibitors therapy. A case report with a brief review of the literature.

After an initial benefit from tyrosine kinase inhibitors (TKI), most gastrointestinal stromal tumors (GISTs) eventually develop disease progression or secondary resistance. An altered tumor (immune)phenotype with anaplasia and morphological changes secondary to therapy have occasionally been described in the literature. We present a 52-year old patient, diagnosed with high risk, spindle-cell, GIST (CD117 positive, Pankeratin negative) in 2003, showing a c-Kit exon 11 mutation. After TKI therapy, he developed drug resistance and disease progression. Pathological assessment of the last surgical specimen showed a pure epithelioid/clear cell histology, without evidence of cellular anaplasia. Tumor cells were CD117 positive, DOG1 positive but also E-cadherin positive and Pankeratin positive, whereas molecular analysis confirmed the presence of the c-Kit exon 11 mutation, with no additional mutations. We describe an unusual case of GIST showing peculiar (immuno)phenotypic changes under therapy, different from the vast majority of therapy-driven changes, which include marked cellular pleomorphisms and KIT immunonegativity. Possible molecular explanations to understand these phenomena and a brief review of the literature are also addressed.

Grade 4 unclassified renal cell carcinoma with sarcomatoid component expressing S-100 protein. A case report with peculiar diagnostic and therapeutic implications.

Grade 4 unclassified renal cell carcinoma, with a sarcomatoid component (URCCSC) is a rare high grade tumor presumptively derived from all histological subtypes of renal cell carcinoma (RCC). Even though rare, URCCSC generates a great deal of interest, as it is a particularly aggressive variant of RCC, that is poorly responsive to chemo-immunotherapy. Whether it originates from a separate sarcomatoid cell clone within the tumor or from true cell dedifferentiation from RCC has yet to be established. The diagnosis of URCCSC is usually based on morphological and immunohistochemical characteristics of the neoplastic cells which show transitional epithelial/mesenchymal features. In fact, the frequent loss of epithelial markers and gain of mesenchymal phenotypes, can result in difficulties in interpreting diagnostic data. Consequently assigning the optimal therapeutic treatments can be hindered due to this biological "complexity." Here we present the clinicopathological records of a 51 year-old patient who underwent an excision of a periureteral retroperitoneal mass, and whose first pathological diagnosis was malignant peripheral nerve sheath tumor (MPNST). Eleven months after surgery, a CT-scan revealed a local recurrence of the disease. Later on the patient was admitted to our hospital and a systemic, sarcoma-oriented, treatment was initiated. A partial remission was observed but only with a dacarbazine based regimen administered as a third line therapy, after which a second surgery took place. The removed tumor was diagnosed as URCCSC based on the peculiar morphologic and immunohistochemical characteristics of the cells. Pathological assessment of the first intervention was re-evaluated, resulting in a diagnosis of URCCSC. This case-report therefore highlights the implications that an erroneous pathologic diagnosis can have for the clinical management of this disease. Furthermore, the unexpected response to a dacarbazine based regimen, indicates that this drug should be included among the therapeutic options available against this type of renal carcinoma.

Is postoperative computed tomography evaluation a prognostic indicator in patients with optimally debulked advanced ovarian cancer?

OBJECTIVE: To compare the surgeon's intraoperative assessment of residual tumor (RT) disease with that identified on postoperative computed tomography (CT) in patients undergoing optimal primary surgical cytoreduction (RT <1 cm) and to identify the prognostic significance of postoperative CT scan of RT. METHODS: Patients with FIGO stage III-IV ovarian cancer treated at the Gynecologic Oncology Unit of the National Cancer Institute between November 2011 and March 2013, who underwent optimal primary cytoreduction and were entered in prospective controlled clinical trials requiring a baseline postoperative CT evaluation within 30 days, were enrolled. All CT scans were reviewed by a dedicated radiologist to evaluate RT. Median follow-up was 16 months. RESULTS: 64 out of 160 patients met the eligibility criteria. RT = 0, 0.1 < RT < 0.5 cm, and 0.6 < RT < 1 cm was reported in 53 (82.8%), 9 (14.1%) and 2 (3.1%) cases, respectively. Postoperative CT disagreed with RT in 13 out of 64 (20.3%) cases. Progression-free survival (PFS) of patients with a positive and negative postoperative CT scan of RT was 5 months (95% CI 1-15 months) and 28 months (95% CI 2-46 months), respectively (p < 0.0001). Evidence of the disease using postoperative CT was an independent prognostic factor in multivariate analysis (HR = 8.87, 95% CI = 3.23-24.31, p < 0.0001). CONCLUSIONS: Evidence of the disease using postoperative CT was associated with a significant decrease in PFS in patients who underwent optimal primary cytoreduction. RT status as evaluated with early postoperative CT may have an important role in prognostic assessment.

Retreatment with trastuzumab after progression on lapatinib-based therapy in heavily pretreated HER2-positive metastatic breast cancer: a single-institution experience.

AIMS: The study aimed to determine if retreatment with trastuzumab after progression on treatment with lapatinib is feasible in a previously heavily pretreated population of HER2-positive metastatic breast cancer patients and if some range of activity and an acceptable toxicity profile could be shown. METHODS AND STUDY DESIGN: Women with HER2-positive metastatic breast carcinoma whose disease progressed after antracycline, taxane and trastuzumab-based regimens were treated at progression with lapatinib plus capecitabine. At progression on this combination, retreatment with trastuzumab combined with different cytotoxic agents was offered to most patients. The outcome of these patients was evaluated. RESULTS: Between April 2007 and February 2013, a total of 77 patients with HER2-positive metastatic breast cancer were identified who had been treated with lapatinib plus capecitabine at our institution. At progression, 43 (55%) were treated again with a trastuzumab-based regimen, mostly gemcitabine and vinorelbine. One complete response (CR) and 17 partial responses plus 4 prolonged stable periods longer than 6 months for a 51.1% overall clinical benefit were observed. No severe toxicities were encountered except one case of heart failure reported in a heavily antracycline-pretreated patient, who, however, recovered from this toxicity. CONCLUSIONS: Even if our sample is a favorably selected population of HER2-positive patients responding to sequential targeted therapies, our data suggest that trastuzumab can be used again in association with a different cytotoxic agent in patients heavily pretreated with trastuzumab and after progression on lapatinib plus capecitabine, without any significant toxicity and with an encouraging clinical benefit rate, suggesting there is an opportunity to continue blockade of the HER2 receptor.

Phase I trial of docetaxel, oxaliplatin, and capecitabine (DOC) in untreated gastric cancer patients.

BACKGROUND: A combination of docetaxel (D), oxaliplatin (O), and capecitabine (C) (DOC) was studied in this dose-escalation phase Ib trial in patients with untreated advanced gastric cancer. METHODS: Dose-limiting toxicity (DLT) included any grade 4 hematological or any grade 3 non-hematological toxicity, besides alopecia and nausea or vomiting. Cohorts of three patients, expanded to six if one DLT occurred, were studied. Two DLTs out of three patients, or ≥3 out of six patients defined the toxic level. The preceding level, maximum tolerated dose (MTD), was further expanded to nine patients. The primary objective was to establish the MTD of the DOC regimen. RESULTS: Twenty-one patients entered four dose levels. Levels I, II, and IIb were considered safe and included 3, 6, and 6 patients, respectively. Level III defined our toxic level with three analyzed patients. Therefore, level IIB was expanded to 9 patients. No other DLTs were recorded. CONCLUSIONS: Fractionation of doses and the use of less toxic and more convenient derivatives are the rationales for this new combination. The MTD (mg/m(2)) was: D, 30 and O, 70, both on days 1 and 8, i.v.; C 1000 per day, days 2-15, p.o.; all given every 3 weeks. A cooperative phase II study has been opened.

Lapatinib-based therapy in heavily pretreated HER2-positive metastatic breast cancer: a single institution experience.

AIMS AND BACKGROUND: Lapatinib in combination with capecitabine is feasible in patients with HER2-positive metastatic breast cancer pretreated with anthracyclines, taxanes and trastuzumab, but inferior results were reported in the global lapatinib expanded access program in comparison with the phase III registration trial. METHODS: and study design. Women with HER2-positive metastatic breast carcinoma after antracycline, taxane and trastuzumab-based regimens were treated at progression with lapatinib plus capecitabine. The outcome of these patients was evaluated. From April 2007 to August 2010, 68 patients were treated overall. RESULTS: Median progression-free survival was 6 months (range, 1-29), and median overall survival was 26 months (range, 1-39). Eight (12%; 95% CI, 4-25) patients experienced a complete response. Partial response was observed in 22 patients (31%; 95% CI, 20-42), for an overall response rate of 43% (95% CI, 31-55). The treatment with lapatinib plus capecitabine was well tolerated, with grade 3-4 toxicity reported in few patients, and no treatment-related deaths were noted. Of note, no cardiac toxicity was reported in this highly pretreated group of patients or in the subgroup of 10 elderly patients. CONCLUSIONS: Our data confirm that lapatinib plus capecitabine is an active regimen even in heavily pretreated patients with visceral and brain metastases and is feasible and active also in selected elderly patients.

Trastuzumab and Gemcitabine in Pretreated HER2 Overexpressing Metastatic Breast Cancer Patients: Retrospective Analysis of Our Series.

Trastuzumab-based regimes improved clinical outcome in women with overexpressing HER2 metastatic breast cancer, mainly due to the availability of different combination therapies, clinically active and well tolerated. In this study we retrospectively evaluated clinical activity and toxicity of trastuzuamb plus gemcitabine regimen in heavily pretreated HER2 positive metastatic breast cancer patients. Although the observed population was heavily pretreated, the evaluated regimen was notably effective in terms of response rate, time to progression and survival, with very mild toxicity. These data suggest that in over expressing HER2 metastatic breast cancer patients, sequential trastuzumab based chemotherapeutic regimens can achieve good response rate with prolonged TTP in responding patients, even after other target therapy such as lapatinib based combinations.

Yin Yang 1 overexpression in diffuse large B-cell lymphoma is associated with B-cell transformation and tumor progression.

Yin Yang 1 (YY1), a multifunctional transcription factor, has been shown to be involved in the pathogenesis of several cancer types. However, its role in hematological malignancies has not yet been fully investigated. In the present study, using computational methods, we showed that YY1 transcript levels were significantly increased in the high-grade lymphomas, including Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL), compared with those of both low-grade lymphomas and normal B-cells. The significant increase in gene expression resulted in a significant increase also at protein level in three NHL cell lines. The association of YY1 expression with some clinical-pathological features in DLBCL showed a positive correlation between a high level of YY1 mRNA and high levels of BCL-6 protein. Moreover, by analyzing the large series of DLBCL in the Hummel dataset, we identified the transcription factor PAX-5 among the top 50 genes positively correlated with YY1. These findings are also supported by the biological network analysis in which the top network, with the highest score, associated with YY1 expression levels in DLBCL is cellular movement, hematological system development and function, and immune response. overall these data suggest that YY1 is involved in B cells transformation which gives rise to high-grade lymphomas through a dysregulation in the normal development of B cells affecting cell cycle and cellular motility.

Melanoma: molecular pathogenesis and emerging target therapies (Review).

Malignant melanoma is an aggressive tumor of the skin with a poor prognosis for patients with advanced disease. It is resistant to current therapeutic approaches. In melanoma, both the Ras/Raf/MEK/ERK (MAPK) and the PI3K/AKT (AKT) signalling pathways are constitutively activated through multiple mechanisms. Mutations of BRAF have been proposed to contribute to melanoma development. Increased activity of the MAPK pathway prevents apoptosis and induces cell cycle progression. PTEN deletion results in Akt activation. Akt activation can result in the phosphorylation and inactivation of Raf. This decrease in downstream MEK and ERK activation may lead to loss of differentiation or senescence. This review summarizes the most relevant studies focused on the signalling pathways involved in melanomagenesis. New therapeutic strategies are also reported.

The involvement of the transcription factor Yin Yang 1 in cancer development and progression.

The Yin Yang 1 (YY1) transcription factor has a pivotal role in normal biological processes such as development, differentiation, replication and cell proliferation exerting its effects on a huge number of genes involved in these processes. Mechanisms of YY1 action are related to its ability to initiate, activate, or repress transcription depending upon the context in which it binds. The role of YY1 played in cancer has been recently explored. This article summarizes the most relevant studies focused on YY1 regulation and dwells on the way how its overexpression may affect the clinical behavior of several cancer types. Furthermore, the contribution of the upregulation of YY1 exerted in response to therapeutic-induced apoptosis is discussed.