Objective This study was undertaken to evaluate whether the current clinical presentation of hydatidiform mole changed in the recent years compared with an historic group. Study Design We retrieved ...500 patients from our database. We compared the clinical presentation of 189 cases followed-up between 1992-2004 (“later” group) with that of a previous series of 311 patients (“earlier” group, 1970-1982). A Pearson χ2 test was performed analyzing the following variables: uterine volume, ovarian cysts, vaginal bleeding, hyperemesis, preeclampsia, and maternal age; we considered P < .05 to be significant. Results Uterine volume corrected for gestational age ( P < .0001), vaginal bleeding ( P < .0001) and presence of ovarian cysts ( P = .03) were significantly predominant in the “earlier” group, whereas the incidence of preeclampsia and hyperemesis were not significantly different. Conclusions The depiction of increased uterine volume, ovarian theca lutein cysts, and vaginal bleeding in hydatidiform mole at presentation is significantly less frequent since the extensive dissemination of ultrasound in obstetrics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
Adrenocortical carcinomas (ACCs) are rare endocrine tumors with poor prognosis. They overexpress insulin-like growth factor 2 (IGF2), that drives a proliferative autocrine loop by binding to ...IGF1R and IR, with molecular dynamics still poorly identified. Although promising, IGF1R/IR-targeted therapies have demonstrated a limited efficacy in clinical trials in ACC patients. The cytoskeleton actin-binding protein filamin A (FLNA) was shown to impair IR and IGF1R signalling in melanoma and neural progenitor cells, respectively. The aims of this study were to test in ACC cells: 1) FLNA involvement in regulating IGF1R and IR expression and signalling; 2) FLNA role in modulating responsiveness to IGF1R and IGFR/IR inhibitors; 3) FLNA expression in ACCs and correlation with IGF system. In ACC cells we found by immunoprecipitation that both IGF1R and IR interacted with FLNA in basal condition, with an increased or decreased FLNA recruitment to IGF1R and to IR, respectively, after IGF2 stimulation. Genetic silencing of FLNA in ACC cell lines H295R and SW13 induced a significant increase of IGF1R expression (1.4- and 2.3-fold, respectively) and a reduction of IR (-85.5±9.1%, p<0.001 and -32±19.1%, respectively, p<0.05), with a downstream effect of increased cell proliferation (130±13.4%, p<0.01 in H295R and 144.3±23.3%, p<0.01 in SW13 cells) accompanied by an enhanced ERK phosphorylation. Accordingly, in ACC primary cultured cells FLNA silencing increased IGF1R levels (2.9-fold) and enhanced IGF2 effects on ERK phosphorylation by 2.2-fold. In addition, FLNA knockdown potentiated the antiproliferative effects of IGF1R/IR inhibitor Linsitinib and IGF1R specific inhibitor NVP-ADW742 in H295R cells and SW13. This key role of FLNA was even more evident in A7/M2 melanoma cell model, since IGF2 and Linsitinib exerted the expected effects on ERK phosphorylation in M2 cells, lacking FLNA, but not in FLNA-expressing counterpart (A7 cells). Finally, western blot analysis showed significantly lower, although variable, FLNA expression in ACCs (n=10) than in adrenocortical adenomas (ACAs) (n=10) (FLNA/GAPDH ratio 0.37±0.38 and 0.90±0.63, respectively, p<0.05). Interestingly, FLNA/IGF1R ratio inversely correlated with ERK phosphorylation status in ACCs (p<0.05) but not in ACA. In conclusion, we demonstrated that low levels of FLNA enhance both IGF2 proliferative effects and IGF1R/IR inhibitors efficacy in ACC cells, suggesting FLNA as a new factor possibly influencing tumor clinical behavior and the response to the therapy with IGF1R/IR-targeted drugs.
Abstract
Dopamine receptor type 2 (DRD2) agonists are the first-choice treatment for PRL-secreting pituitary tumors but are poorly effective in non-functioning pituitary neuroendocrine tumors ...(NF-PitNETs). DRD2 reduces AKT phosphorylation in lactotrophs, but no data are available in NF-PitNETs. DRD2 effects on AKT are mediated by a β-arrestin 2-dependent mechanism in mouse striatum.
The aim of this study was to investigate DRD2 effects on AKT phosphorylation and cell proliferation in human primary cultured NF-PitNET cells and in rat tumoral lactotroph cells MMQ, and to test β-arrestin 2 involvement.
We found that DRD2 agonist BIM53097 induced a reduction of p- AKT /total-AKT ratio in MMQ (-32.8±17.6%, p<0.001 vs basal) and in a subset (n=15/41,36.6%) of NF-PitNETs (subgroup 1). In the remaining NF-PitNETs (subgroup 2), BIM53097 induced an increase of p- AKT. The ability of BIM53097 to reduce p-AKT correlated to its antimitotic effect, since the majority of subgroup 1 NF-PitNETs was responsive to BIM53097 and nearly all subgroup 2 NF-PitNETs were resistant. β-arrestin2 was expressed in MMQ and in 80% of subgroup 1 NF-PitNETs, whereas it was undetectable in 77% of subgroup 2 NF-PitNETs.
In MMQ, β-arrestin 2 silencing prevented DRD2 inhibitory effects on p-AKT and cell proliferation. Accordingly, β-arrestin 2 transfection in subgroup 2 NF-PitNETs conferred to BIM53097 the ability to inhibit both p-AKT and cell growth.
In conclusion, we demonstrated that β-arrestin 2 is required for DRD2 inhibitory effects on AKT phosphorylation and cell proliferation in MMQ and NF-PitNETs, paving the way for a potential role of β-arrestin 2 as a biomarker predicting NF-PitNETs responsiveness to treatment with dopamine agonists.
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor that originates from parafollicular thyroid C cells, accounting for 5% -10% of thyroid cancers. In all inherited cases of MTC, and in ...about 40% of sporadic cases, activating mutations of the receptor tyrosine kinase proto-oncogene RET are found. Constitutively active RET triggers signaling pathways involved in cell motility, proliferation and survival, but the mechanisms underlying malignant transformation of C-cells have been only partially elucidated. Cofilin is a key regulator of actin cytoskeleton dynamics. A crucial role of cofilin in tumor development, progression, invasion and metastasis has been demonstrated in different human cancers, but no data are available in MTC. Interestingly, RET activation upregulates cofilin gene expression. The aim of this study was to investigate cofilin contribution in invasiveness and growth of MTC cells, and its relevance in the context of mutant RET signaling. We found that cofilin transfection in human MTC cell line TT significantly increased migration (178.5±44%, p<0.001), invasion (194±27%, p<0.05) and proliferation (145.9±18%, p<0.001), accompanied by an increase of ERK1/2 phosphorylation (1.8-fold) and cyclin D1 levels (1.43-fold). Accordingly, all these responses were significantly reduced after genetic silencing of cofilin (-55±10% migration, p<0.001, -40.7±8% invasion, p<0.001, -17±2.6% proliferation, p<0.001). The inhibition of constitutively active RET in TT cells by both the RET pharmacological inhibitor RPI-1 and the transfection of dominant negative RET mutant (RETΔTK) resulted in a reduction of cofilin expression (-30.8±11%, p<0.01 and -31±16%, p<0.01, respectively). Furthermore, RPI-1 inhibitory effects on TT cell migration (-70±18%, p<0.001) and proliferation (-29.4±9% , p<0.01) were completely abolished in cells transfected with cofilin. In conclusion, these data indicate that an unbalanced cofilin expression, induced by oncogenic RET, contributes to promote MTC invasiveness and growth, suggesting the possibility of targeting cofilin pathway for more effective treatment of MTC.
Introduction
Being able to have children could have an important positive effect on the future lives of pediatric cancer survivors. Working at a cancer institute makes us responsible for filling the ...gaps in our knowledge in this area of patient care.
Methods
We describe our activities in a series of young females diagnosed with cancer and evaluated for fertility preservation options. We discuss the developed skills and organization as well as the practical difficulties encountered in managing fertility preservation.
Results
Since September 2012, laparoscopy and cryopreservation of cortical ovarian tissue has been performed in 16 girls (with ovary transposition in 3, and after several cycles of chemotherapy in 5) and egg banking in 4 young women (before chemotherapy in 2 and several years after treatment in 2).
Conclusions
Recommendations on fertility preservation indicate that discussing the problems early on is crucial to future success. It is unthinkable to simply provide information and offer the opportunity to choose a fertility preserving technique without helping and accompanying patients and their families in their decisions and choices on the matter.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Abstract Introduction : Endometrial carcinoma (EC) is a frequent cancer in developed countries, but with evidence for discrepant clinical management. Under the auspices of the Italian Society of ...Gynecologic Oncology (SIOG), we conducted a survey among Italian centers with ≥20 surgeries for gynecological cancer per year, trying to depict a reliable picture of EC management in our country. Methods : The questionnaire focused on preoperative/surgical staging and adjuvant treatment. Of the 283 questionnaires delivered, 35% were sent back. Results : Diagnostic hysteroscopy is performed in 78% of centers. In clinical stage I, 52% adopt a laparotomic access, 15% totally laparoscopic, 9% laparoscopic/vaginal, 2% vaginal, 22% tailored approach. Elective use of laparoscopy significantly differs between institutions ( p < 0.001): 40% (≥20 EC/yr) vs. 12% (<20). Pelvic and aortic lymphadenectomy is selectively performed by 77% and 68% of centers, respectively, depending on pre/intraoperative factors. Non-endometrioid histology, poor-grade and deep myoinvasion are indicated as the highest-risk factors. Adjuvant therapy is given to pathologically node-negative patients by 60%, and to intermediate-risk patients by 47%. Elective adjuvant treatment is still radiotherapy, but chemotherapy is adopted, mostly combined with radiation, by 40%. There is a multidisciplinary team in 64% of centers, but in 59% adjuvant treatment is to be administered outside the institution. Conclusions : These data demonstrate a significant improvement in the clinical care achieved over the last decades in Italy. Centralization of EC treatment would not be feasible neither useful. High-risk cases could be selected by an appropriate clinical screening, and these only referred to reference centers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
Clear cell (CC) and papillary serous carcinoma (PS) are histotypes at high risk of recurrence. We analyse patients’ survival in a retrospective series of 128 CC and PS endometrial cancer ...cases.
Methods
All women with a histologically confirmed CC and PS endometrial cancer who underwent primary surgery in five institutions in Lombardy, Italy, were eligible for this study. A total of 77 (60.2 %) were PS endometrial cancer cases, 45 (35.2 %) CC cases and 6 (4.6 %) cases had mixed CC and PS histotype.
Results
54 (42 %) cases were diagnosed at stage I, 10 (8 %) at stage II, 47 (37 %) at stage III and 17 (13 %) at stage IV. Recurrence was observed in 49 cases (38.3 %). The median time at recurrence was 12 months (interquartile range 7–18). The rate of recurrence was 20.3 % in cases at stage I–lI and 56.2 % in cases at stage III–IV (
p
< 0.0001). With regard to the site of recurrence 24 recurrences were in and 52 outside the pelvis. Finally, the rate of recurrence was 32.6 % (14 cases) in CC cases, 43.1 % (31 cases) in PS cases and 66.7 % (4 cases) in cases with mixed histotype. The 5-year progression-free survival was 59.5 % (67.4 % for CC cases, 55.1 % for PS and mixed cases).
Conclusion
In this study including CC and PS endometrial cancers, the 5-year survival from surgery was 72.7 % and the 5-year progression-free survival was 59.5 %.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To analyze the effect of different doses of paclitaxel with fixed doses of carboplatin in the treatment of ovarian cancer.
Patients with histologically confirmed epithelial ovarian cancer, ...International Federation of Gynecology and Obstetrics stages IIB to IV, were eligible for this randomized, multicenter study. Women were randomly assigned to treatment with (1) carboplatin at the dose (in milligrams) corresponding to the following formula: target area under the free carboplatin plasma concentration versus time curve (AUC) = 6 x (glomerular filtration rate + 25) mg/m(2) (AUC6) plus paclitaxel 175 mg/m(2) for six cycles every 21 days or (2) carboplatin AUC6 plus paclitaxel 225 mg/m(2) for six cycles every 21 days. A total of 502 women entered the study.
Pathologic complete response was documented in 132 patients (63.8%) in the 175 mg/m(2) group and in 127 cases (55.7%) in the 225 mg/m(2) group (chi(2) P =.090). The 4-year progression-free survival rate was 41.5% (SE = 3.5) in the 175-mg group and 39.2% (SE = 3.5) in the 225-mg group. The corresponding 4-year survival rates were 46.2% (based on 115 deaths) and 47.3% (based on 113 deaths), respectively.
This randomized trial suggests that paclitaxel 175 mg/m(2) plus carboplatin AUC6 is the schedule with a more favorable profile than paclitaxel 225 mg/m(2) plus carboplatin AUC6.
Objective. The aim of the study was to analyze the benefit/toxicity profile of a second-line treatment with carboplatin alone or carboplatin plus another non-cross-resistant drug (epidoxorubicin) in ...ovarian cancer patients sensitive to cisplatin-based chemotherapy at first-line treatment.
Methods. We conducted a randomized clinical trial. Women with epithelial ovarian cancer FIGO Stage II–IV who had a complete or partial response to first-line treatment with cisplatin or carboplatin-based regiments and subsequently progressed or relapsed more than 6 months after discontinuation of first-line treatment were eligible for the study. A total of 190 subjects entered the study. They were randomly allocated to either 300 mg/m2 of carboplatin every 28 days for five cycles (95 patients) or 120 mg/m2 of epidoxorubicin and 300 mg/m2 of carboplatin every 28 days for five cycles (95 patients).
Results. A complete response was reported, respectively, in 32 (36%) women allocated to carboplatin alone and in 28 (31.8%) of those allocated to carboplatin plus epidoxorubicin. The corresponding figures for partial response were 18 (20.2%) and 26 (29.9%). Comparing the frequency of complete response, partial response, no change, and progression, the differences between the two groups were not significant (χ23 5.10, P = 0.16). The median duration of response was 16 months in the carboplatin alone and 20 months in the carboplatin plus epidoxorubicin group (P = not significant). The 3-year percentage of survival was 29% in the carboplatin alone and 42% in the carboplatin plus epidoxorubicin group; this difference was not statistically significant. The frequency of leukopenia, anemia, and thrombocytopenia grade 3–4 was higher in the epidoxorubicin plus carboplatin than in the carboplatin alone group. Alopecia G3 was present in 88% of women treated with epidoxorubicin plus carboplatin.
Conclusions. The general results of this study do not show any marked differences in response to second-line treatment among women treated with single-agent (carboplatin) or multiagent (carboplatin plus epidoxorubicin) schedules. Toxicity, particularly hematological, was more relevant in women treated with the multiagent schedule.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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