Improved Measurement of Solar Neutrinos from the Carbon-Nitrogen-Oxygen Cycle by Borexino and Its Implications for the Standard Solar Model.

We present an improved measurement of the carbon-nitrogen-oxygen (CNO) solar neutrino interaction rate at Earth obtained with the complete Borexino Phase-III dataset. The measured rate, R_{CNO}=6.7_{-0.8}^{+2.0} counts/(day×100 tonnes), allows us to exclude the absence of the CNO signal with about 7σ C.L. The correspondent CNO neutrino flux is 6.6_{-0.9}^{+2.0}×10^{8} cm^{-2} s^{-1}, taking into account the neutrino flavor conversion. We use the new CNO measurement to evaluate the C and N abundances in the Sun with respect to the H abundance for the first time with solar neutrinos. Our result of N_{CN}=(5.78_{-1.00}^{+1.86})×10^{-4} displays a ∼2σ tension with the "low-metallicity" spectroscopic photospheric measurements. Furthermore, our result used together with the ^{7}Be and ^{8}B solar neutrino fluxes, also measured by Borexino, permits us to disfavor at 3.1σ C.L. the "low-metallicity" standard solar model B16-AGSS09met as an alternative to the "high-metallicity" standard solar model B16-GS98.

First Directional Measurement of Sub-MeV Solar Neutrinos with Borexino.

We report the measurement of sub-MeV solar neutrinos through the use of their associated Cherenkov radiation, performed with the Borexino detector at the Laboratori Nazionali del Gran Sasso. The measurement is achieved using a novel technique that correlates individual photon hits of events to the known position of the Sun. In an energy window between 0.54 to 0.74 MeV, selected using the dominant scintillation light, we have measured 10 887_{-2103}^{+2386}(stat)±947(syst) (68% confidence interval) solar neutrinos out of 19 904 total events. This corresponds to a ^{7}Be neutrino interaction rate of 51.6_{-12.5}^{+13.9} counts/(day·100 ton), which is in agreement with the standard solar model predictions and the previous spectroscopic results of Borexino. The no-neutrino hypothesis can be excluded with >5σ confidence level. For the first time, we have demonstrated the possibility of utilizing the directional Cherenkov information for sub-MeV solar neutrinos, in a large-scale, high light yield liquid scintillator detector. This measurement provides an experimental proof of principle for future hybrid event reconstruction using both Cherenkov and scintillation signatures simultaneously.

Test of Electric Charge Conservation with Borexino.

Borexino is a liquid scintillation detector located deep underground at the Laboratori Nazionali del Gran Sasso (LNGS, Italy). Thanks to the unmatched radio purity of the scintillator, and to the well understood detector response at low energy, a new limit on the stability of the electron for decay into a neutrino and a single monoenergetic photon was obtained. This new bound, τ≥6.6×10^{28} yr at 90% C.L., is 2 orders of magnitude better than the previous limit.

First evidence of pep solar neutrinos by direct detection in Borexino.

We observed, for the first time, solar neutrinos in the 1.0-1.5 MeV energy range. We determined the rate of pep solar neutrino interactions in Borexino to be 3.1±0.6{stat}±0.3{syst} counts/(day·100 ton). Assuming the pep neutrino flux predicted by the standard solar model, we obtained a constraint on the CNO solar neutrino interaction rate of <7.9 counts/(day·100 ton) (95% C.L.). The absence of the solar neutrino signal is disfavored at 99.97% C.L., while the absence of the pep signal is disfavored at 98% C.L. The necessary sensitivity was achieved by adopting data analysis techniques for the rejection of cosmogenic {11}C, the dominant background in the 1-2 MeV region. Assuming the Mikheyev-Smirnov-Wolfenstein large mixing angle solution to solar neutrino oscillations, these values correspond to solar neutrino fluxes of (1.6±0.3)×10{8} cm{-2} s^{-1} and <7.7×10{8} cm{-2} s{-1} (95% C.L.), respectively, in agreement with both the high and low metallicity standard solar models. These results represent the first direct evidence of the pep neutrino signal and the strongest constraint of the CNO solar neutrino flux to date.

Precision measurement of the (7)Be solar neutrino interaction rate in Borexino.

The rate of neutrino-electron elastic scattering interactions from 862 keV (7)Be solar neutrinos in Borexino is determined to be 46.0±1.5(stat)(-1.6)(+1.5)(syst) counts/(day·100 ton). This corresponds to a ν(e)-equivalent (7)Be solar neutrino flux of (3.10±0.15)×10(9) cm(-2) s(-1) and, under the assumption of ν(e) transition to other active neutrino flavours, yields an electron neutrino survival probability of 0.51±0.07 at 862 keV. The no flavor change hypothesis is ruled out at 5.0 σ. A global solar neutrino analysis with free fluxes determines Φ(pp)=6.06(-0.06)(+0.02)×10(10) cm(-2) s(-1) and Φ(CNO)<1.3×10(9) cm(-2) s(-1) (95% C.L.). These results significantly improve the precision with which the Mikheyev-Smirnov-Wolfenstein large mixing angle neutrino oscillation model is experimentally tested at low energy.

Detection of tissue abnormalities in normal mucosa surrounding colorectal cancer using an endocytoscopy system.

The endocytoscopy system is a novel diagnostic technique that provides extremely high-magnification imaging of the gastrointestinal mucosa. We are currently using a prototype Olympus endocytoscope for clinical research in gastrointestinal tumors. In one surgical specimen obtained after resection of a cancer of the transverse colon, focal abnormalities of colonic glands were detected 7 cm away from the primary tumor, within macroscopically normal mucosa. Our finding, which was confirmed by histopathological examination, suggests the need for further clinical investigation to assess whether endocytoscopy is able to identify premalignant changes in apparently normal mucosa. This could potentially be useful for accurate evaluation before planning minimally invasive therapy.

Healthy and tumoral tissue resistivity in wild-type and sparc-/- animal models.

Despite the technological improvement of radiologic, endoscopic and nuclear imaging, the accuracy of diagnostic procedures for tumors can be limited whenever a mass-forming lesion is identified. This is true also because bioptical sampling cannot be properly guided into the lesions so as to puncture neoplastic tissue and to avoid necrotic areas. Under these circumstances, invasive and expensive procedures are still required to obtain diagnosis which is mandatory to plan the most appropriate therapeutic strategy. In order to test if electrical impedance spectroscopy may be helpful in providing further evidence for cancer detection, resistivity measurements were taken on 22 mice, 11 wild-type and 11 sparc-/- (knock out for the protein SPARC: secreted protein acidic and rich in cysteine), bearing mammary carcinomas, by placing a needle-probe into tumor, peritumoral and contralateral healthy fat areas. Tumor resistivity was significantly lower than both peritumoral fat and contralateral fat tissues. Resistivity in sparc-/- mice was lower than wild-type animals. A significant frequency dependence of resistivity was present in tissues analyzed. We conclude that accurate measurements of resistivity may allow to discriminate between tissues with different pathological and/or structural characteristics. Therefore, resistivity measurements could be considered for in vivo detection and differential diagnosis of tumor masses.

Primary chemoradiation therapy with fluorouracil and cisplatin for cancer of the anus: results in 35 consecutive patients.

PURPOSE: This prospective phase II study was designed to test the activity and toxicity of a regimen of fluorouracil (5-FU) and cisplatin (CDDP) in combination with radiation therapy in the treatment of epidermoid cancer of the anal canal. PATIENTS AND METHODS: Thirty-five consecutive patients with untreated epidermoid cancer of the anal canal were candidates for chemoradiation therapy (CRT). Staging of cancer was as follows: T1, 26%; T2, 60%; T3, 14%; and N1, 2,3, 26%. No patient had distant metastases. The treatment protocol consisted of two to three cycles of chemotherapy starting on days 1 and 21 and concurrent radiotherapy at a daily dose of 1.8 Gy up to a total dose of 36 to 38 Gy in 4 weeks, delivered to the anal region, perineum, middle and lower pelvis, and inguinal and external iliac nodes. Radiotherapy was then delivered to the anoperineal region and metastatic inguinal nodes to a total dose of 18 to 24 Gy in 10 fractions. Chemotherapy consisted of 24-hour intravenous (IV) infusion of 5-FU 750 mg/m2 on days 1 to 4 and CDDP 100 mg/m2 by 60-minute IV infusion on day 1. RESULTS: All patients received two cycles of chemotherapy; the second was delayed in three patients because of leukopenia that was evident in 11 (31%). In eight patients, a third cycle was added. They all experienced nausea or vomiting; one patient showed signs of cardiotoxicity and one developed proctitis, dermatitis, and diarrhea (grade 3). Complete regression (CR) was assessed in 33 patients (94%); nine patients with metastatic lymph nodes also had CR. Two patients had a partial response (PR); both underwent abdominoperineal resection, which was not curative in one. Two patients (6%) had a local recurrence; in one, this was associated with hepatic metastases. One of these patients underwent surgery and is alive after about 4 years, while the other is undergoing chemotherapy. After a median follow-up duration of 37 months, 94% of patients are alive without evidence of disease and 86% are colostomy-free. CONCLUSION: This regimen is well tolerated; its toxicity does not exceed that observed with the combination of 5-FU and mitomycin (MMC). Compared with our previous experience based on the classic CRT (5-FU, MMC, and radiation), the objective response rate observed with this new combination was similar. However, the local recurrence rate, observed in patients treated with the new regimen, was lower (6% v 24%). According to more recent data from the literature, primary CRT is the elective indication in epidermoid cancer of the anus and replacement of MMC with CDDP seems an effective and logical evolution.

Ghrelin receptor modulates T helper cells during intestinal inflammation.

BACKGROUND: The orexigenic peptide ghrelin has anti-inflammatory properties in colitis, however, the mechanism of action and the immune cells targeted remain still to be elucidated. Here, we assessed the possible effect of ghrelin on T helper (Th) cells in a T cell transfer model of chronic colitis. METHODS: Disease was induced in the recombination activating gene 1 knockout mice (Rag1(-/-) ) by adoptive transfer of naïve Th cells from ghrelin receptor knockout mice (GRLN-R(-/-) ) or littermate wild-type (WT) mice. The course and severity of colitis was assessed by monitoring body weight, diarrhea score, histological analysis, gene expression, and flow cytometry analysis. The possible effects of ghrelin on Th cell proliferation, polarization, and apoptosis was examined in vitro. KEY RESULTS: Our data showed that Rag1(-/-) mice injected with GRLN-R(-/-) Th cells displayed increased severity of colitis compared to mice injected with WT Th cells. In addition, Rag1(-/-) mice injected with GRLN-R(-/-) Th cells had significantly higher intestinal inflammation and increased accumulation of Th1 and Th17 cells in the colon. In vitro, ghrelin directly affected proliferation of Th cells and induced apoptosis whereas it did not influence Th cell polarization. CONCLUSION & INFERENCES: Our observations suggest that ghrelin modulates Th effector cells in the gut controlling proliferation and inducing apoptosis. Our findings further support the use of ghrelin as a novel therapeutic option to treat intestinal inflammatory diseases.

Chromosome changes in benign prostatic hyperplasia and their significance in the origin of prostatic carcinoma.

Cytogenetic studies of benign prostatic hyperplasia (BHP) are scarce. We analyzed primary cell cultures obtained from biopsies of prostatic tissues from 10 patients (mean age: 60.7 years) with histologic diagnosis of BHP to compare the eventual chromosome changes with those reported in prostatic adenocarcinoma. Clonal chromosome abnormalities were noted in five of the 10 cases, with loss of Y chromosome in all. In one case, a clonal t(1;20) was observed with a -Y clone. Different numerical and structural sporadic abnormalities were evident in eight. Chromosome 1 was the chromosome most frequently involved in sporadic rearrangements. We concluded that -Y is a frequent nonrandom chromosome abnormality in BHP in this sample of patients. Immunohistochemical studies showed that loss of Y occurs in fibroblasts and not in epithelial cells; therefore, this anomaly is not related to cancer development.

Clonal chromosome changes in renal carcinoma do not correlate with clinical stages and histopathologic grades.

We analyzed the correlations between chromosome abnormalities and clinical and histopathologic characteristics in 77 cases of renal cell carcinoma (RCC). Chromosome changes such as +5,+7,+8,+10,+18,+X,+Y, and -Y have been excluded from the analysis because they also occur in nonneoplastic kidney tissue and cytogenetic analysis indicates that these anomalies are not involved in tumor progression. The most frequent specific chromosome abnormalities in this sample were 3p rearrangements, trisomy 17, and hyperdiploidy and were not related to tumor stage or grade or to development of distant metastases.

Clonal chromosome changes in non-neoplastic ureters.

Cytogenetic analysis was performed on 23 samples from non-neoplastic ureters. Clonal chromosome abnormalities were found in eight. They were: loss of Y chromosome, as a single abnormality (five cases) or associated with trisomy 10 and 20 (one case) or with trisomy 2 (one case); and duplication of Y chromosome (one case). Different numerical and structural sporadic abnormalities were found in nine cases. Immunohistochemical analysis and direct observation using the inverted microscope showed that the cells were mainly of the fibroblastic type. FISH analysis with chromosome 7 alpha-satellite probes failed to detect the presence of trisomy 7 in three epithelial cases tested.

Cytogenetic and interphase cytogenetic analyses reveal chromosome instability but no clonal trisomy 8 in Dupuytren contracture.

The results of cytogenetic and FISH analysis performed in 26 cases of Dupuytren contracture are reported. Clonal or sporadic chromosome changes were found in 18 cases (69%). Clonal changes consisted of: +2, +16, -10, -Y, add(1)(p23), del(2)(q21), t(3;16)(p21;q24), add (3)(p24), del(18)(q21), t(Y;14)(p12;q24), +mar. The results differ from those obtained in normal palmar fascia used as control, in which -Y and +Y were the only clonal changes found in 2 of 11 analyzed cases (18%). No clonal trisomy 8 was found. FISH analysis performed in 11 cases (centromeric probe specific for chromosome 8) failed to show the presence of a cell population with +8. Clonal and sporadic structural changes were different from case to case and no clustering breakpoint was observed. The significance of the chromosome instability leading to clonal and sporadic chromosome changes not specific to Dupuytren contracture are discussed.

Pre-operative endoscopic ultrasonography can optimise the management of patients undergoing laparoscopic cholecystectomy with abnormal liver function tests as the sole risk factor for choledocholithiasis: a prospective study.

BACKGROUND: Pre-operative endosonography has been proposed as a cost-effective procedure in the management of patients who undergo laparoscopic cholecystectomy having an intermediate risk of common bile duct stones. We prospectively evaluated the impact of pre-operative endosonography on the management of patients facing laparoscopic cholecystectomy with abnormal liver function tests as the sole risk factor for choledocolithiasis. METHODS: Among 587 consecutive patients scheduled for laparoscopic cholecystectomy, 47 (8%) patients having one or more abnormal liver function tests but a normal appearance of common bile duct at abdominal ultrasound, underwent pre-operative endosonography. In patients with endosonography-detected common bile duct stones, a pre-operative endoscopic retrograde cholangiography was performed, or an intra-operative endoscopic retrograde cholangiography was scheduled. In all endosonography-negative patients, an intra-operative trans-cystic cholangiography was performed. RESULTS: Endosonography detected common bile duct stones in nine patients (19%) but only in five of them stones were radiologically confirmed (PPV 0.55). Endosonography-detected stones were confirmed in four of four (100%) patients in whom cholangiography was performed within 1 week, but only in one of five (20%) patients in whom radiology was further delayed (P < 0.05). In three of four cases (75%), stones detected at endosonography but not confirmed at X-rays, were smaller than 2.0 mm. Among 38 patients with negative endosonography, common bile duct stones were found in two patients (NPV 0.95), whereas unplanned endoscopic stone extraction was needed only in one patient (NPV 0.97). CONCLUSIONS: Pre-operative endosonography can spare unnecessary pre-operative endoscopic retrograde cholangiography as well as inappropriate scheduling of intra-operative endoscopic retrograde cholangiography in patients undergoing laparoscopic cholecystectomy with abnormal liver function tests. To maximise the impact of endosonography on the management of these patients, the procedure should be performed immediately before laparoscopic cholecystectomy.

Prevention and treatment of complications after endoscopic prostheses placement in tumors of the upper gastrointestinal tract.

Endoscopic intubation is a popular palliative method to resolve immediately malignant dysphagia. However, the complication rate is still high. Between 1978 and 1993, at the Division of Diagnostic and Surgical Endoscopy of Istituto Nazionale Tumori in Milan, 305 patients suffering from malignant dysphagia, were endoscopically treated by insertion of an endoprosthesis. We report the analysis of data regarding our complication rate, compared with the literature, and our experience in preventing managing complications related to this endoscopic procedure.

Endoscopic treatment of malignant dysphagia.

Palliative endoscopic treatment of dysphagia in patients with inoperable oesophageal cancer includes: dilation, Nd:YAG laser photocoagulation and intubation, used alone or in combination. Such procedures are usually performed on an outpatient basis and are associated with a low rate of morbidity and mortality. From 1978 to 1988, 476 patients (401 males, 75 females) were treated at the Endoscopy division of the National Cancer Institute of Milan for inoperable primary or recurrent malignancies of the oesophagus or cardia or for extra-oesophageal neoplasms causing dysphagia. Dilation was used in 172 cases, Nd:YAG laser photocoagulation in 90, prosthesis insertion in 72, dilation and laser in 97, and prosthesis and laser in 45. Functional improvement was reported in 75% of patients after dilation, in 89% after laser treatment, in 80% after intubation, in 80% after dilation and photocoagulation, and in 89% after laser and intubation. The median duration of dysphagia-free interval was 4 weeks in dilated patients, 6-8 weeks in photocoagulated patients and 20 weeks intubate patients. Overall median survival was 6.2 months. The complication rate was: 1.4% in dilation treatment, 1.4% in laser photocoagulation, and 8.8% in prosthesis intubation. Mortality related to endoscopic treatment was 2.1% (10/476 patients). Relief of dysphagia is one of the most important goals of palliative treatment in patients with inoperable oesophageal neoplasms. Moreover, endoscopic palliation improves the quality of life in the patients, with a low complication rate.