Validation of an Accurate and Noninvasive Tool to Exclude Female Precocious Puberty: Pelvic Ultrasound With Uterine Artery Pulsatility Index.

OBJECTIVE. The purpose of this study is to validate the accuracy of pelvic ultrasound (US) with the evaluation of uterine artery pulsatility index (PI) to exclude female precocious puberty. MATERIALS AND METHODS. Tanner breast development score, luteinizing hormone (LH) peak after gonadotropin-releasing hormone (GnRH) stimulation, and uterine and ovarian volumes and diameters were assessed with pelvic US in 495 girls at a single institution. The study population was divided as follows: prepubertal (n = 207), pubertal with physiologic activation of the hypothalamic-pituitary-ovarian axis (n = 176), and central precocious puberty (CPP; n = 112). PI was measured with spectral Doppler US at the ascending branches of the right uterine artery (50-Hz filter; time gain compensation, 73; pulse repetition frequency, 6.6). ROC analyses and t tests were performed. RESULTS. The mean (± SD) PI values in the prepubertal, pubertal, and CPP groups were 6.3 ± 1.4, 3.4 ± 1.1, and 4.1 ± 1.5, respectively (p < 0.001). The best PI cutoff value to distinguish pubertal from prepubertal girls was 4.6 (sensitivity, 83%; specificity, 94%; positive predictive value, 95%; negative predictive value, 80%; accuracy, 87%). ROC AUC values for LH peak (cutoff value, 5 mU/mL) and for spectral Doppler US PI plus longitudinal uterine diameter (i.e., the combination of a PI of 4.6 with a longitudinal uterine diameter of 35 mm) were 0.9272 and 0.9439, respectively (p = 0.7925). The negative predictive values for LH peak and for PI plus longitudinal uterine diameter were 89% and 88%, respectively. CONCLUSION. A PI greater than 4.6 at spectral Doppler US combined with a longitudinal uterine diameter less than 35 mm allows noninvasive exclusion of female precocious puberty with comparable accuracy and lower costs compared to examination of LH peak after GnRH stimulation. Therefore, PI plus longitudinal uterine diameter might be used as a noninvasive first-line test to exclude precocious puberty and thereby avoid further investigations.

Clinical and immunologic responses in melanoma patients vaccinated with MAGE-A3-genetically modified lymphocytes.

Cancer vaccines have recently been shown to induce some clinical benefits. The relationship between clinical activity and anti-vaccine T cell responses is somewhat controversial. Indeed, in many trials it has been documented that the induction of vaccine-specific T cells exceeds the clinical responses observed. Here, we evaluate immunological and clinical responses in 23 MAGE-A3(+) melanoma patients treated with autologous lymphocytes genetically engineered to express the tumor antigen MAGE-A3 and the viral gene product thymidine kinase of the herpes simplex virus (HSV-TK). HSV-TK was used as safety system in case of adverse events and as tracer antigen to monitor the immune competence of treated patients. The increase of anti-TK and anti-MAGE-A3 T-cells after vaccination was observed in 90 and 27% of patients, respectively. Among 19 patients with measurable disease, we observed a disease control rate of 26.3%, with one objective clinical response, and four durable, stable diseases. Three patients out of five with no evidence of disease (NED) at the time of vaccination remained NED after 73+, 70+ and 50+ months. Notably, we report that only patients experiencing MAGE-A3-specific immune responses showed a clinical benefit. Additionally, we report that responder and non-responder patients activate and expand T cells against the tracer antigen TK in a similar way, suggesting that local rather than systemic immune suppression might be involved in limiting clinically relevant antitumor immune responses.

Feasibility of safe ultra-high (EQD(2)>100 Gy) dose escalation on dominant intra-prostatic lesions (DILs) by Helical Tomotheraphy.

PURPOSE: to verify the possibility of using Helical Tomotherapy to safely escalate dose to single or multiple highly radioresistant dominant intra-prostatic lesions (DILs) as assessed by functional magnetic resonance imaging (MRI). MATERIAL: in seven intermediate/high risk patients, T2WI, T1WI and DWI MRI imaging showed evidence of one DIL in four patients and two DILs in three patients in the peripheral zone of the prostate. The planning strategy was to deliver median doses of 80, 90, 100 and 120 Gy to PTVDIL while delivering 71.4 Gy/28 fractions (EQD(2)=75 Gy) to the remaining portion of PTV. A higher priority was assigned to rectal constraints relative to DIL coverage. Rectal NTCP calculations were performed using the most recently available model data. RESULTS: the median dose to DIL could safely be escalated to at least 100 Gy (EQD(2,α/ß=10)=113 Gy) without violating safe constraints for the organs at risk. Typical rectal NTCP values were around or below 1-3% for G3 toxicity and 5-7% for G2-G3 toxicity. For the 100 Gy DIL dose boost strategy, mean D95% of DIL and PTVDIL were 98.8 Gy and 86.7 Gy, respectively. The constraints for bladder, urethra and femoral heads were always respected. CONCLUSIONS: IGRT by Helical Tomotherapy may permit the safe escalation of EQD(2,α/ß=10) to at least 113 Gy to DILs without significantly increasing rectal NTCP compared to plans without dose escalation. A Phase I-II clinical study is warranted.

Apparent diffusion coefficient in the evaluation of side-specific extracapsular extension in prostate cancer: Development and external validation of a nomogram of clinical use.

OBJECTIVES: The aim of this study is to develop a nomogram of clinical utility based on apparent diffusion coefficient (ADC) from diffusion-weighted imaging to predict extracapsular extension (ECE), and to validate externally its clinical utility. MATERIALS AND METHODS: A total of 101 men (70 for the creation and 31 for external validation of the nomogram) underwent 1.5T multiparametric magnetic resonance imaging followed by radical prostatectomy at 2 different institutions. ADC values were assessed for normal and pathological tissue. Clinical and pathological variables were investigated by univariate and multivariate logistic regression analyses on 70 patients and logistic regression coefficients were used to develop our nomogram. Receiver operating characteristic curve analysis was performed to determine the optimal ADC cut off for ECE. The nomogram was then externally validated on 31 patients at another institution. RESULTS: At univariate analysis, the following variables were associated with ECE: pathological ADC and Gleason at biopsy (P<0.001) along with tumor volume and ECE at imaging (P = 0.003). At multivariate analysis, pathological ADC (P = 0.027), tumor volume (P = 0.011), and biopsy Gleason (P = 0.040) maintained their independent predictor status and were included in our nomogram together with normal ADC and ECE at imaging. Our nomogram showed a significant higher sensitivity (88%) than T2-weighted imaging (54%; P = 0.010). External validation resulted in an overall accuracy of 81%. CONCLUSIONS: ADC represents a potential imaging biomarker to predict side-specific ECE in patients with prostate cancer. Our nomogram could improve the current diagnostic pathway and possibly the therapeutic approach for this disease.

Leukocytes recruited by tumor-derived HMGB1 sustain peritoneal carcinomatosis.

The factors that determine whether disseminated transformed cells in vivo yield neoplastic lesions have only been partially identified. We established an ad hoc model of peritoneal carcinomatosis by injecting colon carcinoma cells in mice. Tumor cells recruit inflammatory leukocytes, mostly macrophages, and generate neoplastic peritoneal lesions. Phagocyte depletion via clodronate treatment reduces neoplastic growth. Colon carcinoma cells release a prototypic damage-associated molecular pattern (DAMP)/alarmin, High Mobility Group Box1 (HMGB1), which attracts leukocytes. Exogenous HMGB1 accelerates leukocyte recruitment, macrophage infiltration, tumor growth and vascularization. Lentiviral-based HMGB1 knockdown or pharmacological interference with its extracellular impair macrophage recruitment and tumor growth. Our findings provide a preclinical proof of principle that strategies based on preventing HMGB1-driven recruitment of leukocytes could be used for treating peritoneal carcinomatosis.

Multicenter surveillance of women at high genetic breast cancer risk using mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging (the high breast cancer risk italian 1 study): final results.

OBJECTIVES: : To prospectively compare clinical breast examination, mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging (MRI) in a multicenter surveillance of high-risk women. MATERIALS AND METHODS: : We enrolled asymptomatic women aged ≥ 25: BRCA mutation carriers; first-degree relatives of BRCA mutation carriers, and women with strong family history of breast/ovarian cancer, including those with previous personal breast cancer. RESULTS: : A total of 18 centers enrolled 501 women and performed 1592 rounds (3.2 rounds/woman). Forty-nine screen-detected and 3 interval cancers were diagnosed: 44 invasive, 8 ductal carcinoma in situ; only 4 pT2 stage; 32 G3 grade. Of 39 patients explored for nodal status, 28 (72%) were negative. Incidence per year-woman resulted 3.3% overall, 2.1% <50, and 5.4% ≥ 50 years (P < 0.001), 4.3% in women with previous personal breast cancer and 2.5% in those without (P = 0.045). MRI was more sensitive (91%) than clinical breast examination (18%), mammography (50%), ultrasonography (52%), or mammography plus ultrasonography (63%) (P < 0.001). Specificity ranged 96% to 99%, positive predictive value 53% to 71%, positive likelihood ratio 24 to 52 (P not significant). MRI showed significantly better negative predictive value (99.6) and negative likelihood ratio (0.09) than those of the other modalities. At receiver operating characteristic analysis, the area under the curve of MRI (0.97) was significantly higher than that of mammography (0.83) or ultrasonography (0.82) and not significantly increased when MRI was combined with mammography and/or ultrasonography. Of 52 cancers, 16 (31%) were diagnosed only by MRI, 8 of 21 (38%) in women <50, and 8 of 31 (26%) in women ≥ 50 years of age. CONCLUSION: : MRI largely outperformed mammography, ultrasonography, and their combination for screening high-risk women below and over 50.

Integrated FDG PET/CT in patients with persistent ovarian cancer: correlation with histologic findings.

PURPOSE: To prospectively evaluate the accuracy of integrated positron emission tomography (PET) and computed tomography (CT) for depiction of persistent ovarian carcinoma after first-line treatment, with use of histologic findings as the reference standard. MATERIALS AND METHODS: Thirty-one women (mean age, 55.9 years) with ovarian carcinoma treated with primary cytoreductive surgery and followed up with platinum regimen chemotherapy were included. All 31 patients were scheduled for surgical second-look. Before surgical second-look, all patients underwent fluorodeoxyglucose (FDG) PET/CT. At PET/CT, three main categories of persistent disease were considered for data analysis: lymph nodal lesion, peritoneal lesion, and pelvic lesion. In all patients, imaging findings were compared with results of histologic examination after surgical second-look to determine the diagnostic accuracy of PET/CT in the evaluation of disease status. The kappa statistic (Cohen kappa) was used for statistical analysis. RESULTS: Seventeen (55%) of 31 patients had persistent tumor at histologic analysis after surgical second-look, and fourteen (45%) had no histologically proved tumor. The total number of lesions that was positive for tumor cells at histologic analysis was 41 (lymph nodes, n = 16; peritoneal lesions, n = 21; pelvic lesions, n = 4); maximum diameter of these lesions was 0.3-3.2 cm (mean, 1.7 cm). A correlation was found between PET/CT and histologic analysis (kappa = 0.48). The overall lesion-based sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of PET/CT were 78%, 75%, 77%, 89% and 57%, respectively. In the detection of a tumor, a size threshold could be set at 0.5 cm, as this was the largest diameter of a lesion missed at PET/CT. CONCLUSION: Integrated PET/CT depicts persistent ovarian carcinoma with a high positive predictive value.