Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) Applied to Platinum-Resistant Recurrence of Ovarian Tumor: A Single-Institution Experience (ID: PARROT Trial).

BACKGROUND: We aimed to investigate the therapeutic efficacy and safety of Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in platinum-resistant recurrence of ovarian cancer and peritoneal carcinomatosis, while our secondary endpoint was to establish any changes in quality of life estimated via the EORTC QLQ-30 and QLQ-OV28 questionnaires. METHODS: In this monocentric, single-arm, phase II trial, women were prospectively recruited and every 28-42 days underwent courses of PIPAC with doxorubicin 2.1 mg/m2 followed by cisplatin 10.5 mg/m2 via sequential laparoscopy. RESULTS: Overall, 98 PIPAC procedures were performed on 43 women from January 2016 to January 2020; three procedures were aborted due to extensive intra-abdominal adhesions. The clinical benefit rate (CBR) was reached in 82% of women. Three cycles of PIPAC were completed in 18 women (45%), and 13 (32.5%) and 9 (22.5%) patients were subjected to one and two cycles, respectively. During two PIPAC procedures, patients experienced an intraoperative intestinal perforation. There were no treatment-related deaths. Nineteen patients showed no response according to the Peritoneal Regression Grading Score (PRGS) and 8 patients showed minor response according to the PRGS. Median time from ovarian cancer relapse to disease progression was 12 months (95% confidence interval [CI] 6.483-17.517), while the median overall survival was 27 months (95% CI 20.337-33.663). The EORTC QLQ-28 and EORTC QLQ-30 scores did not worsen during therapy. CONCLUSIONS: PIPAC seems a feasible approach for the treatment of this subset of patients, without any impact on their quality of life. Since this study had a small sample size and a single-center design, future research is mandatory, such as its application in addition to systemic chemotherapy.

Benzofused hydroxamic acids: useful fragments for the preparation of histone deacetylase inhibitors. Part 2: 7-fluorobenzothiophenes and benzofurans.

In the search for a new class of histone deacetylase inhibitors, we prepared a series of very simple benzofused hydroxamic acids to find an anchoring fragment of minimal molecular weight: they showed very good ligand efficiencies. Following these findings, classical fragment growing work was performed to increase binding energy and selective cytotoxicity. In the second phase of the work, information from the SARs of the benzothiophene series and data available in literature, we explored the in vitro pharmacological properties of the 6-substituted-7-fluoro-benzothiophene hydroxamates and the 5-susbtituted-benzofuran hydroxamates.

Impact of school-based educational programs on sexual behaviors among adolescents in northern Italy.

This article aimed to determine sexual behaviors among female and male adolescents in northern Italy. An anonymous self-administered questionnaire evaluating sexual attitudes was distributed in middle and high schools in northern Italy. Adolescents between 13 and 19 years of age were asked to participate at the survey. The study group included 664 participants. Overall, 164 (25%) adolescents had had at least one sexual intercourse. Among adolescents who have had sexual intercourse, 90 (55%) use condoms, 25 (15%) use hormonal contraception, and 49 (30%) do not use any contraception method. A total of 559 adolescents (84%) participated in school-based sexual education programs. This group had better knowledge on sexually transmitted diseases and contraception methods in comparison with adolescents who have never participated in such educational programs (p <.05), and no difference in high-risk sexual behaviors was observed (p = 1.0). School-based sexual education programs improve knowledge of sexual transmitted diseases and contraception methods. However, this knowledge does not correlate to high-risk sexual behaviors reduction.

Chemotherapy reduces para-aortic node recurrences in endometrial cancer with positive pelvic and unknown para-aortic nodes.

OBJECTIVE: The objective of this study was to evaluate how the administration of different adjuvant therapies influences the risk for developing recurrences in the para-aortic area in endometrial cancer (EC) with positive pelvic and unknown para-aortic nodes. METHODS: We retrospectively evaluated the data of 58 patients with EC affected by stage IIIC1 who had undergone pelvic but not para-aortic lymphadenectomy from January 1, 1990 to December 31, 2011. Survival outcomes within the first 5 years after surgery were assessed using the Kaplan-Meier model. RESULTS: Chemotherapy plus radiotherapy, chemotherapy only, and external radiotherapy only were administered in 12 (23%), 18 (34%), and 23 (43%) patients, respectively. Five (9%) patients, who were selected to forego adjuvant therapy due to poor performance status, were excluded from the analysis. Disease-free and overall survivals assessed at 5 years were 54%, and 61%, respectively. All para-aortic recurrences were observed among the patients with endometrioid EC, whereas no cases of para-aortic recurrences were found in patients with nonendometrioid histology (5/36 (14%) vs 0/17 (0%); P = 0.16); the latter were more likely to develop distant (hematogenous, peritoneal, and distant lymphatic) recurrences (P = 0.09). Type of adjuvant therapy was the only factor influencing para-aortic failure: chemotherapy (± radiotherapy) reduced the rate of para-aortic node recurrence in comparison with pelvic radiotherapy as a sole modality (P = 0.01). However, adjuvant therapy did not influence the 5-year survival outcomes (P > 0.05). CONCLUSIONS: In the absence of local treatment (ie, para-aortic lymphadenectomy and radiotherapy), the administration of chemotherapy seems effective in reducing recurrences in the para-aortic area among patients with stage IIIC1 endometrioid EC.

Nerve-sparing versus conventional laparoscopic radical hysterectomy: a minimum 12 months' follow-up study.

OBJECTIVE: The objective of this study was to determinate whether the introduction of nerve-sparing (NS) procedure influences surgical and survival outcomes of cervical cancer patients undergoing laparoscopic radical hysterectomy (LRH). METHODS: Data of consecutive patients undergoing minimally invasive radical with or without NS surgery for cervical cancer were enrolled in the study. RESULTS: Sixty-three patients (66%) who had LRH were compared with 33 women (34%) undergoing NS-LRH. Among the NS group, 19 patients (57.6%) had surgery via minilaparoscopy (using 3-mm instruments). Baseline characteristics were similar between groups. Patients undergoing NS-LRH had shorter operative time (210 vs 257 minutes; P = 0.005) and higher number of pelvic lymph nodes yielded (29 [26-38] vs 22 [8-49]; P < 0.001) than patient in the control group. No differences in blood loss, complications, and parametrial width were observed. Patients were catheterized with an indwelling Foley catheter for a median of 3.5 days (2-7 days) and 5.5 days (4-7 days) in NS and non-NS groups, respectively (P = 0.01). Voiding dysfunctions occurred in 1 patient (3%) and 12 patients (19%) who underwent NS-LRH and standard LRH, respectively (P = 0.03). No differences in 3-year disease-free survival (P = 0.72) and overall survival (P = 0.71) were recorded. CONCLUSIONS: The beneficial effects (in terms of operative time and number of nodes harvested) of NS-LRH are likely determined by the expertise of the surgeon because NS approach was introduced after having acquired adequate background in conventional LRH. Our data show that in experienced hands NS-LRH is safe and feasible. Moreover, NS technique reduces catheterization time and the rate of postoperative urinary dysfunction.

Benzofused hydroxamic acids: useful fragments for the preparation of histone deacetylase inhibitors. Part 1: hit identification.

In the search for a new class of histone deacetylase inhibitors, we prepared a series of simple benzofused hydroxamic acids to find an anchoring fragment of minimal molecular weight. These initial hits, all belonging to the benzothiophene class, showed very good ligand efficiencies. Following these findings, a classical fragment growing approach was performed to increase binding affinity and cytotoxicity.

Synthesis and biological evaluation of rebeccamycin analogues modified at the imide moiety.

Glycosylated indolocarbazoles related to the antibiotic rebeccamycin represent an important class of antitumour drugs. In the course of our structure-activity relationship studies, new rebeccamycin analogues modified at the imide moiety were synthesised. The antiproliferative activity of the compounds was evaluated on three human cancer cell lines, A2780 (ovarian cancer), H460 (lung cancer), and GLC4 (small-cell lung cancer). The in vitro cytotoxicity of compounds 2 and 4, characterised respectively by a 1,3-dioxolan and (1,3-dioxolan-4-yl)methylene groups linked to the imide moiety, was higher than the reference compound, edotecarin. The effect of compound 2 in inducing tumour regression in the A2780 xenograft model was also investigated.

Alkyl piperidine and piperazine hydroxamic acids as HDAC inhibitors.

We report here the strategy used in our research group to find a new class of histone deacetylase (HDAC) inhibitors. A series of N-substituted 4-alkylpiperazine and 4-alkylpiperidine hydroxamic acids, corresponding to the basic structure of HDAC inhibitors (zinc binding moiety-linker-capping group) has been designed, prepared, and tested for HDAC inhibition. Linker length and aromatic capping group connection were systematically varied to find the optimal geometric parameters. A new series of submicromolar inhibitors was thus identified, which showed antiproliferative activity on HCT-116 colon carcinoma cells.

4-N-Hydroxy-4-[1-(sulfonyl)piperidin-4-yl]-butyramides as HDAC inhibitors.

A series of N-substituted 4-alkylpiperidine hydroxamic acids, corresponding to the basic structure of histone deacetylase (HDAC) inhibitors (zinc binding moiety-linker-capping group) has been previously reported by our group. Linker length and aromatic capping group connection were systematically varied to find the optimal geometric parameters. A new series of submicromolar inhibitors was thus identified, which showed antiproliferative activity on HCT-116 colon carcinoma cells. We report here the second part of the strategy used in our research group to find a new class of HDAC inhibitors, namely the SAR study for the compounds bearing a sulfonyl group on the piperidine nitrogen. In the present work, we have considered both sulfonamides and sulfonyl ureas.

Risk of Pre-Malignancy or Malignancy in Postmenopausal Endometrial Polyps: A CHAID Decision Tree Analysis.

BACKGROUND AND AIMS: Postmenopausal endometrial polyps are commonly managed by surgical resection; however, expectant management may be considered for some women due to the presence of medical co-morbidities, failed hysteroscopies or patient's preference. This study aimed to identify patient characteristics and ultrasound morphological features of polyps that could aid in the prediction of underlying pre-malignancy or malignancy in postmenopausal polyps. METHODS: Women with consecutive postmenopausal polyps diagnosed on ultrasound and removed surgically were recruited between October 2015 to October 2018 prospectively. Polyps were defined on ultrasound as focal lesions with a regular outline, surrounded by normal endometrium. On Doppler examination, there was either a single feeder vessel or no detectable vascularity. Polyps were classified histologically as benign (including hyperplasia without atypia), pre-malignant (atypical hyperplasia), or malignant. A Chi-squared automatic interaction detection (CHAID) decision tree analysis was performed with a range of demographic, clinical, and ultrasound variables as independent, and the presence of pre-malignancy or malignancy in polyps as dependent variables. A 10-fold cross-validation method was used to estimate the model's misclassification risk. RESULTS: There were 240 women included, 181 of whom presented with postmenopausal bleeding. Their median age was 60 (range of 45-94); 18/240 (7.5%) women were diagnosed with pre-malignant or malignant polyps. In our decision tree model, the polyp mean diameter (≤13 mm or >13 mm) on ultrasound was the most important predictor of pre-malignancy or malignancy. If the tree was allowed to grow, the patient's body mass index (BMI) and cystic/solid appearance of the polyp classified women further into low-risk (≤5%), intermediate-risk (>5%-≤20%), or high-risk (>20%) groups. CONCLUSIONS: Our decision tree model may serve as a guide to counsel women on the benefits and risks of surgery for postmenopausal endometrial polyps. It may also assist clinicians in prioritizing women for surgery according to their risk of malignancy.

Sabarubicin (MEN10755)-induced apoptosis is independent from mtDNA in A2780 human ovarian tumor cells.

BACKGROUND: The role of mitochondrial DNA (mtDNA) in anthracycline-induced apoptosis is controversial. Sabarubicin accumulates in the mitochondria of A2780 human ovarian tumor cells. The effects of this new anthracycline on the structure and the functionality of mtDNA, as well as on the apoptosis of mtDNA-depleted cells have been investigated. MATERIALS AND METHODS: Sabarubicin-induced mtDNA cleavage was detected by Southern blotting and mitochondrial mRNA expression was analyzed by real-time PCR. Apoptosis was studied in mtDNA-depleted (theta0) and parental (theta+) A2780 cells detecting nuclear DNA fragmentation using ELISA and cytofluorimetrically using Annexin V/PI staining. Mitochondrial membrane potential was studied using the cyanine dye JC-1. RESULTS: Sabarubicin induced mtDNA cleavage in the A2780 cells, but this damage did not affect mitochondrial mRNA expression. Apoptosis was induced by sabarubicin in theta0 as well as in theta+ cells. CONCLUSION: The results showed that mtDNA did not influence anthracycline-induced apoptosis in A2780 cells.

Induction of a less aggressive phenotype in human colon carcinoma HCT116 cells by chronic exposure to HDAC inhibitor SAHA.

Histone deacetylase inhibitors (HDACis) are anticancer molecules that epigenetically modulate cell functions. Chronic exposure of HCT116 colon cancer cells to SAHA has been investigated for a better understanding of resistance mechanisms but, surprisingly, a less aggressive tumor phenotype both in vitro and in vivo was obtained after exposure to increasing concentrations of SAHA. Indeed, HCT116/SAHA cells when injected into nude mice showed a reduced engraftment and growth with respect to HCT116 cells. This difference was not observed inoculating the cells into NOD/SCID mice that, differently from nude mice, lack NK activity, thus suggesting the involvement of the native immune response in impairment of HCT116/SAHA cell growth. In agreement with this result, a growing induction of NKG2D ligand expression, MICA and MICB, that are molecular mediators of NK cell killing, was confirmed in HCT116/SAHA chronically exposed to SAHA. A reduced clonogenic efficiency was also observed in HCT116/SAHA with respect to HCT116 cells. Interestingly, even after chronic exposure to SAHA, HCT116/SAHA cells developed only a moderate resistance to SAHA both in vitro and in vivo and they acquired a collateral sensitivity to anthracyclines. These results are of note and probably rely on the fact that, having simultaneously many different targets, HDACis would require many different mutations to display high resistance index. Moreover, to understand the molecular basis of HCT116/SAHA cell phenotype a gene expression profile of cancer genes was evaluated in HCT116 incubated with SAHA for 24 h and in HCT116/SAHA cells to identify selectively regulated genes.