Typical values of z-resolution for different Digital Breast Tomosynthesis systems evaluated in a multicenter study.

PURPOSE: The aim of the present study, conducted by a working group of the Italian Association of Medical Physics (AIFM), was to define typical z-resolution values for different digital breast tomosynthesis (DBT) models to be used as a reference for quality control (QC). Currently, there are no typical values published in internationally agreed QC protocols. METHODS: To characterize the z-resolution of the DBT models, the full width at half maximum (FWHM) of the artifact spread function (ASF), a technical parameter that quantifies the signal intensity of a detail along reconstructed planes, was analyzed. Five different commercial phantoms, CIRS Model 011, CIRS Model 015, Modular DBT phantom, Pixmam 3-D, and Tomophan, were evaluated on reconstructed DBT images and 82 DBT systems (6 vendors, 9 models) in use at 39 centers in Italy were involved. RESULTS: The ASF was found to be dependent on the detail size, the DBT angular acquisition range, the reconstruction algorithm and applied image processing. In particular, a progressively greater signal spread was observed as the detail size increased and the acquisition angle decreased. However, a clear correlation between signal spread and angular range width was not observed due to the different signal reconstruction and image processing strategies implemented in the algorithms developed by the vendors studied. CONCLUSIONS: The analysis led to the identification of typical z-resolution values for different DBT model-phantom configurations that could be used as a reference during a QC program.

Antibodies and B cells recognising citrullinated proteins display a broad cross-reactivity towards other post-translational modifications.

OBJECTIVE: Autoantibodies against antigens carrying distinct post-translational modifications (PTMs), such as citrulline, homocitrulline or acetyllysine, are hallmarks of rheumatoid arthritis (RA). The relation between these anti-modified protein antibody (AMPA)-classes is poorly understood as is the ability of different PTM-antigens to activate B-cell receptors (BCRs) directed against citrullinated proteins (CP). Insights into the nature of PTMs able to activate such B cells are pivotal to understand the 'evolution' of the autoimmune response conceivable underlying the disease. Here, we investigated the cross-reactivity of monoclonal AMPA and the ability of different types of PTM-antigens to activate CP-reactive BCRs. METHODS: BCR sequences from B cells isolated using citrullinated or acetylated antigens were used to produce monoclonal antibodies (mAb) followed by a detailed analysis of their cross-reactivity towards PTM-antigens. Ramos B-cell transfectants expressing CP-reactive IgG BCRs were generated and their activation on stimulation with PTM-antigens investigated. RESULTS: Most mAbs were highly cross-reactive towards multiple PTMs, while no reactivity was observed to the unmodified controls. B cells carrying CP-reactive BCRs showed activation on stimulation with various types of PTM-antigens. CONCLUSIONS: Our study illustrates that AMPA exhibit a high cross-reactivity towards at least two PTMs indicating that their recognition pattern is not confined to one type of modification. Furthermore, our data show that CP-reactive B cells are not only activated by citrullinated, but also by carbamylated and/or acetylated antigens. These data are vital for the understanding of the breach of B-cell tolerance against PTM-antigens and the possible contribution of these antigens to RA-pathogenesis.

Population genetic structure of Attalea vitrivir Zona (Arecaceae) in fragmented areas of southeast Brazil.

Attalea vitrivir Zona (synonym Orbignya oleifera) is one of the six species of Arecaceae known as "babassu". This species is used to make cosmetics, food, and detergents due to the high concentration of oil in the seeds. It is found only in fragmented areas of southern Bahia State and northern Minas Gerais State, southeast Brazil, and this fragmentation has affected both its ecological and genetic characteristics. We evaluated the genetic diversity and population genetic structure of A. vitrivir in six areas of two different regions at the extremes of its geographical range, in order to gain a better understanding of the factors that affect the distribution and partitioning of its diversity. Nine inter simple sequence repeat (ISSR) markers amplified 74 polymorphic bands, resulting in large diversity values (Shannon diversity index, 0.37-0.47; intrapopulation genetic diversity, 0.25-0.34). Analysis of molecular variance (AMOVA) revealed considerable differentiation between sampling sites (30.03%) and regions (12.08%), although most of the diversity was observed within sampling sites (69%). Further differentiation between sampling sites was noted more in the northern region than in the southern region, highlighting the genetic connectivity between the sampling sites within Rio Pandeiros Environmental Protection Area (southern region). The identification of two distinct genetic clusters (K = 2) corresponded to the northern and southern regions, and corroborated the AMOVA results. We suggest that the northern area, outside Rio Pandeiros Environmental Protection Area, must be included in future management plans for this species.

A modified acidic approach for DNA extraction from plant species containing high levels of secondary metabolites.

Purified genomic DNA can be difficult to obtain from some plant species because of the presence of impurities such as polysaccharides, which are often co-extracted with DNA. In this study, we developed a fast, simple, and low-cost protocol for extracting DNA from plants containing high levels of secondary metabolites. This protocol does not require the use of volatile toxic reagents such as mercaptoethanol, chloroform, or phenol and allows the extraction of high-quality DNA from wild and cultivated tropical species.

Development and characterization of microsatellite markers for Lychnophora pinaster: a study for the conservation of a native medicinal plant.

Lychnophora pinaster Mart. (Asteraceae) is a Brazilian medicinal plant, extensively employed in popular medicine as an anti-inflammatory, analgesic and healing agent. Thirteen polymorphic microsatellite markers were developed and optimized for L. pinaster from an enriched genomic library. The markers were used to analyse 37 plants from two native populations, generating an average number of 6.6 alleles per polymorphic locus. These loci are important tools for future studies of population genetics.

Isolation and characterization of microsatellite markers for Casearia sylvestris Sw. (Salicaceae), a neotropical medicinal tree.

Casearia sylvestris Sw. is a widespread neotropical tree utilized in popular medicine. Recent research ranked Casearia as one of the most promising genus in the search of drugs against cancer. Despite its wide distribution and pharmacological importance, no microsatellite markers have yet been developed for this genus. In this study, we provide 10 polymorphic microsatellite loci specifically designed for C. sylvestris, used to analyse 90 individuals distributed in two populations from São Paulo state, Brazil. On average, 12.3 alleles per locus were identified, showing the ability of the markers to detect microsatellite polymorphism in this species.

Impact of chemotherapy dose-density on radiotherapy dose-intensity after breast conserving surgery.

PURPOSE: To evaluate if chemotherapy (CT) dose-intensification jeopardizes radiotherapy (RT) dose-intensity (DI). PATIENTS AND METHODS: From 1992 to 1997, 247 stage I-II breast cancer patients, treated with conserving surgery, were treated at the National Cancer Institute of Genoa in a randomized study comparing the same CEF regimen delivered every two weeks (CEF14) or three weeks (CEF21). RT was applied to the residual breast at a total dose of 50 Gy in five weeks. Allowance was made for treatment at 2.3 Gy per fraction in order to compensate for gaps (hypofractionation). Radiotherapy DI was expressed as the average total dose received each week, i.e., 'weekly dose-rate' (WDR). The effect of various tumour, treatment and patient-related factors on the endpoint (a delivered WDR of RT < 9.5 Gy) was investigated by univariate analysis. Factors found to have P-value < or = 0.20 were entered in multivariate analysis. RESULTS: All but three patients (244 of 247, 98.8%) received a cumulative total dose of RT within +/- 10% of that planned. Moreover, most of them (197 of 247, 79.8%) received an average WDR of > or = 9.5 Gy/wk. With univariate analysis the probability of WDR < 9.5 Gy/wk significantly correlated with age, menopausal status, concomitant administration of RT and CT, and white blood cell toxicity. Moreover, a positive effect on WDR was found in patients treated at 2.3 Gy per fraction. The type of treatment (CEF14 vs. CEF21) did not affect the probability of WDR < 9.5 Gy/wk. With multivariate analysis, age (< or = 55 vs. > 55 years, RR = 3.99, 95% CI: 1.89-8.42, P = 0.0003), RT fractionation (conventional vs. hypofractionation, RR = 0.32, 95% CI: 0.15-0.68, P = 0.017) and WBC toxicity (none vs. some, RR = 1.54, 95% CI: 1.06-2.22, P = 0.027) were independent predictors of WDR < 9.5 Gy. Regarding the CT-RT overlap, patients receiving more than two cycles of chemotherapy during radiotherapy had an increased risk of RT delay compared to other patients (RR = 3.74, 95% CI: 1.44-9.48, P = 0.0063). CONCLUSIONS: There is no evidence of a direct effect of CT dose-density on dose-intensity of RT. However, the concomitant use of CT and RT reduces the possibility of giving a full dose-intensity of RT.

Cell kinetics analysis in patients affected by squamous cell carcinoma of the head and neck treated with primary surgery and adjuvant radiotherapy.

BACKGROUND: The increasing complexity of management strategies for patients with head and neck squamous cell carcinoma (HN-SCC) calls for the investigation of new objective prognostic parameters to subdivide patients according to the tumor's biological aggressiveness. METHODS: We evaluated in 35 HN-SCC patients the pretreatment cell kinetics parameters and DNA ploidy after in vivo infusion of bromodeoxyuridine and flow cytometric analysis. Patients were treated with radical surgery followed by conventional radiation therapy. Locoregional control data are available for follow-up times above five years. RESULTS: We found that the likelihood of locoregional control for patients with rapidly proliferating HN-SCC characterized by a short potential doubling time (Tpot <5 days) was significantly smaller than for HN-SCC patients with slow tumor proliferation (Tpot >5 days). Moreover, when patients were stratified according to DNA ploidy and Tpot value, we found that the locoregional failure rate for rapidly proliferating tumors was significantly higher for diploid HN-SCCs than for aneuploid HN-SCCs. CONCLUSION: The present data suggest that patients with resectable HN-SCC characterized by fast growth might have a worse prognosis after surgery and adjuvant conventional radiotherapy and might benefit from more aggressive radiotherapeutic modalities.

Meningite neutrofílica persistente em paciente com síndrome de imunodeficiência adquirida / Persistent neutrophilic meningitis in a patient with the acquired immunodeficiency syndrome

A meningite neutrofílica persistente é raramente diagnosticada e é caracterizada pelo predomínio neutrofílico na contagem diferencial do número de leucócitos nas amostras de líquido cefalorraquidiano retiradas após sete dias de tratamento adequado. O paciente aqui descrito é soropositivo para o HIV, apresentou febre e confusão mental durante 4 meses e pleocitose neutrofílica na análise liquórica por mais 5 meses. Foi tratado desde o início com tuberculostáticos. Durante três meses as reações imunológicas, as culturas e as pesquisas diretas foram negativas. No sexagésimo dia de internação, a pesquisa de bacilo álcool-ácido resistente (BAAR) no líquor foi positiva e a cultura confirmou a presença de Mycobacterium tuberculosis resistente à isoniazida. Vários fatores podem provocar esta evolução incomum. O comprometimento da imunidade celular, principalmente na liberação de citocinas pró-inflamatórias como a IL 8 e o FNT. O uso concomitante de medicações que poderiam alterar a concentração liquórica dos tuberculostáticos e o aparecimento crescente de cepas multirresistentes foram discutidos.

Persistent neutrophilic meningitis is rarely found and it is characterized by predominance of the number of neutrophils in samples of C SF (cerebrospinal fluid) from the patient after seven days of treatment. The above patient in HIV positive; he has developed fever and mental disorder for 4 months and has presented neutrophilic pleocytosis in analysis of CSF for more than 5 months. Since the beginning or the treatment he has taken antituberculous drugs and corticosteroids. For 3 months, the serologic evaluation, smears and cultures were negative. On the 60th day in hospital, the investigation of acid-fast bacilli in CSF was positive and culture confirmed the presence of Mycobacterium tuberculosis resistant to isoniazid. Several factors that may have caused this uncommon development were discussed: the disturbance of cell-mediated immunity, mainly in release of IL 8 and TNF, the simultaneous use of medicines that could alter the CSF concentration of antituberculous drugs, and the increasing number of multiresistant strains.

[Persistent neutrophilic meningitis in a patient with the acquired immunodeficiency syndrome]. / Meningite neutrofílica persistente em paciente com síndrome de imunodeficiência adquirida.

Persistent neutrophilic meningitis is rarely found and it is characterized by predominance of the number of neutrophils in samples of C SF (cerebrospinal fluid) from the patient after seven days of treatment. The above patient in HIV positive; he has developed fever and mental disorder for 4 months and has presented neutrophilic pleocytosis in analysis of CSF for more than 5 months. Since the beginning or the treatment he has taken antituberculous drugs and corticosteroids. For 3 months, the serologic evaluation, smears and cultures were negative. On the 60th day in hospital, the investigation of acid-fast bacilli in CSF was positive and culture confirmed the presence of Mycobacterium tuberculosis resistant to isoniazid. Several factors that may have caused this uncommon development were discussed: the disturbance of cell-mediated immunity, mainly in release of IL 8 and TNF, the simultaneous use of medicines that could alter the CSF concentration of antituberculous drugs, and the increasing number of multiresistant strains.

Measurement of ultrashort pulse durations by interferometric autocorrelation: influence of various parameters.

The interferometric autocorrelation technique for the measurement of ultrashort pulse durations is studied in detail. Effects of group velocity mismatch, group velocity dispersion, fundamental depletion, and pulse shape are carefully examined. A simple semianalytical calculation is developed that takes group velocity mismatch into account that can be used to predict the validity of this technique with real experimental parameters. A more complete calculation is also presented to analyze the effects of fundamental depletion or phase mismatch. Finally, the influence of the pulse shape is considered and a simple experimental procedure is proposed to determine whether a pulse is transform limited.

Concomitant administration of two standard regimens of chemotherapy and radiotherapy in advanced squamous carcinoma of the head and neck: a feasibility study.

BACKGROUND: In advanced squamous cell carcinoma of the head and neck, the superiority of a chemo-radiotherapy combination over radiotherapy alone has been strongly suggested. However, the best modality to combine the two treatments has still to be determinated. A pilot study was designed, testing a combination of two standard chemo- and radiotherapy regimens concomitantly administered. MATERIALS AND METHODS: 26 patients, with unresectable squamous cell carcinoma of the head and neck, were treated with three cycles of chemotherapy (cisplatin 20 mg/m2/day and fluorouracil 200 mg/m2/day as an intravenous bolus, for 5 consecutive days, every 21) simultaneously delivered with radiation (66-70 Gy/33-35 fractions/7 weeks). In order to reduce the mucoseal toxicity. observed in the first 15 patients, 1 week of pause was inserted after the third week of treatment in the subsequent 11 patients. RESULTS: Grade III-IV mucositis was detected in 40% of patients treated without pause after the third week of treatment and in 9% of those treated with. Complete responses were obtained in 13/26 patients (50%) and partial responses in 8/26 (31%). 1 stable disease, 3 early deaths (1 because of toxicity) and 1 lost before being evaluated were considered as treatment failures (19%). CONCLUSIONS: This concomitant chemo-radiotherapy approach showed a good antitumour activity but mucoseal toxicity is too high if no pause is planned during the treatment.

[Sulodexide in the prevention of post-mastectomy lymphedema]. / Il sulodexide nella prevenzione del linfedema post-mastectomia.

Post-mastectomy lymphedema of the upper limb, that can be noticed by 10 to 20 percent of patients with breast cancer, is usually related to some risk factors: use of radiotherapy on the axilla, obesity, venous outflow obstruction, delayed wound healing or infection. The most important contributing factor to postsurgical edema is the development of lymphangitis in the upper limb. Although literature contains numerous accounts on the use of pharmacological agents for the treatment of postmastectomy lymphedema, the results are not satisfactory in term of clinical response and side effects. In the present study we investigate tolerability and feasibility of the use of suledexide in patients, submitted to mastectomy for breast cancer, with an initial lymphedema of the limb omolateral to surgery or other risk factors for the development of a clinical remarkable lymphedema. Our results show that sulodexide is a very satisfactory therapy in term of lack of side effects and good compliance.

Sub-20-fs tunable pulses in the visible from an 82-MHz optical parametric oscillator.

We have produced pulses tunable in the 590-666-nm range, with durations down to 13 fs, using an 82-MHz Ti:sapphire second-harmonic-pumped, high-bandwidth, beta-barium borate optical parametric oscillator in a fused-silica prism group-delay-dispersion-compensated, six-mirror folded ring cavity.

Intensified chemotherapy with granulocyte-monocyte colony stimulating factor protection in advanced, relapsed squamous cell carcinoma of the head and neck. A phase I study.

BACKGROUND: The administration of granulocyte-monocyte colony stimulating factor (GM-CSF) should allow an increase in the doses of chemotherapy for patients with advanced cancers of the head and neck. PATIENTS AND METHODS: Eleven patients with histologically proven relapsed squamous cell carcinoma of the head and neck entered this Phase I study based on the combination of cisplatin (20 mg/m2/day for 5 days), escalating doses of 5-fluorouracil, both given by intravenous injection from day 1 to 5, and GM-CSF, 5 micrograms/kg from day 8 to day 19. RESULTS: The maximum tolerated 5-fluorouracil dosage was 300 mg/m2 i.v. bolus for 5 consecutive days q. 3 weeks. Thrombocytopenia was the limiting factor to further increase of 5-fluorouracil dosage. Moderate to severe stomatitis were quite rare despite the increased dose of the antimetabolite. GM-CSF was well tolerated: no significant local or systemic side effects attributable to this drug were recorded. CONCLUSIONS: Adding GM-CSF to the combination of cisplatin and 5-fluorouracil allowed to increase 5-fluorouracil dose up to 50% over the conventional dosage. Further increase of the dose was precluded by the development of severe thrombocytopenia.

Chemotherapy in head and neck cancer.

Chemotherapy has been used for many years as a palliative approach to advanced squamous cell carcinoma of the head and neck. Regimens employed have slowly evolved during this time, and the combination of cisplatin and 5-fluorouracil is still standard chemotherapy for such a tumour. However, clinical approaches to advanced squamous cell carcinoma of the head and neck are changing dramatically as physicians become increasingly familiar with multidisciplinary treatments. Integrating chemotherapy and radiotherapy, neo-adjuvant or adjuvant treatments and organ preservation are stimulating fields of investigation involving chemotherapy which definitely warrant further investigation.

Concomitant alpha-interferon and chemotherapy in advanced squamous cell carcinoma of the head and neck.

The combination of chemotherapy and interferons has been tested in several human tumors but, until now, no clinical data have been reported in head and neck cancer. At the Istituto Nazionale per la Ricerca sul Cancro of Genoa, 14 patients with previously treated SCC-HN underwent the following regimen: cisplatin, 20 mg/m2/day, 5-fluorouracil, 200 mg/m2/day i.v. bolus and recombinant interferon-alpha-2b (r-IFN-alpha-2b) (Intron-A, Shering-Plough), 3 MIU/day i.m., for 5 consecutive days. Recombinant IFN-alpha-2b was also administered, at the same dosage, 3 times per week during the 2 weeks interval among cycles. Grade III-IV hematological toxicity was recorded in 43% of patients. Increasing fatigue, anorexia, and flu-like symptoms were experienced by most patients. For these reasons 9 of 14 patients needed a chemotherapy delay and a r-IFN-alpha-2b discontinuation. Therefore, due to the heavy toxicity observed, accural was terminated early. The overall response rate was 54% (31% CR, 23% PR). Among the 5 patients who never delayed chemotherapy and discontinued r-IFN-alpha-2b, all but one responded. In conclusion, a synergistic activity between chemotherapy and r-IFN-alpha-2b in head and neck cancer cannot be excluded, but, in our opinion, further investigations should consider less aggressive regimens and/or more selected patients.

Oral lesions in children born to HIV-1 positive women.

A cohort of 69 children born to HIV-1 positive women was studied to evaluate types, prevalences and relationships to clinical stages of HIV-1-related oral lesions. In addition, relationships among C. albicans biotypes, clinical features of oral candidiasis and HIV-1 disease were investigated. C. albicans biotypes did not correlate with clinical features of oral lesions, disease stages and CD4+ lymphocyte count. Of 8 patients with recurrent oral candidiasis, 4 changed clinical features and 5 changed biotype. Our study pointed out the high frequency (28.9%) of oral lesions, especially caused by fungi and the importance of the examination of the oral cavity in children born to HIV-1 positive women.

Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy.

BACKGROUND: For patients with advanced, unresectable squamous-cell carcinoma of the head and neck, radiotherapy is the standard treatment but has poor results. We therefore designed a randomized trial to determine whether alternating chemotherapy with radiotherapy would improve the survival of such patients. METHODS: Patients in the trial had biopsy-confirmed unresectable, previously untreated Stage III or IV, squamous-cell carcinoma of the oral cavity, pharynx, or larynx. They were randomly assigned to chemotherapy consisting of four cycles of intravenous cisplatin (20 mg per square meter of body-surface area per day for five consecutive days) and fluorouracil (200 mg per square meter per day for five consecutive days) alternating with radiotherapy in three two-week courses (20 Gy per course; 2 Gy per day, five days per week), or to radiotherapy alone (up to 70 Gy; 2 Gy per day, five days per week). RESULTS: The 80 patients given chemotherapy alternating with radiotherapy and the 77 given radiotherapy alone were comparable in terms of age, sex, performance status, disease stage, and site of the primary tumor. Complete responses were obtained in 42 percent of the patients in the combined-therapy group and 22 percent of those in the radiotherapy group (P = 0.037). The median survival was 16.5 months in the combined-therapy group and 11.7 months in the radiotherapy group (P less than 0.05); the 3-year survival was 41 percent and 23 percent, respectively. Severe mucositis occurred in 19 percent of the patients in the combined-therapy group and 18 percent of those in the radiotherapy group. CONCLUSIONS: In patients with advanced unresectable squamous-cell carcinoma of the head and neck, chemotherapy alternating with radiotherapy increases the median survival and doubles the probability of survival for three years as compared with radiotherapy alone. However, since local disease cannot be controlled in over half the patients who receive the combined treatment and since almost two thirds die within three years, further improvements in management are necessary.

Combined chemotherapy and radiation therapy in advanced inoperable squamous cell carcinoma of the head and neck. The final report of a randomized trial.

Between 1983 and 1986, the National Institute for Cancer Research in Genoa and affiliated institutions conducted a randomized study to compare two different ways of combining chemotherapy (CT) and radiation therapy (RT). One hundred sixteen patients were randomized to receive neoadjuvant CT followed by definitive RT (treatment arm A) or alternating CT and RT. In treatment arm A, RT consisted of 70 Gy to the involved areas and 50 Gy to the uninvolved neck at 2 Gy/fraction, five fractions per week. In treatment arm B, RT consisted of 60 Gy to involved areas and 50 Gy to the uninvolved neck in three courses of 20 Gy each, 2 Gy/fraction, ten fractions/2 weeks alternated with four courses of CT. CT consisted of vinblastine 6 mg/m2 intravenously followed 6 hours later by bleomycin 30 IU intramuscularly, day 1; methotrexate 200 mg intravenously, day 2; leucovorin rescue, day 3. CT was repeated every 2 weeks up to four courses. The same CT was used in both treatment arms of the study. Fifty-five patients were entered in treatment arm A and 61 in treatment arm B. Complete responses were 7/48 and 19/57 in treatment arms A and B, respectively (P less than 0.03). Four-year progression-free survival was 4% in treatment arm A and 12% in treatment arm B (P less than 0.02), and four-year survival was 10% in A and 22% in B (P less than 0.02). Mucosal tolerance was significantly worse in treatment arm B (P less than 0.00004). The subgroup analysis shows the major improvement of alternating CT and RT in patients with the worst prognostic characteristics.