Phase II study of weekly plitidepsin as second-line therapy for small cell lung cancer.

OBJECTIVE: To evaluate the antitumor activity and safety profile of plitidepsin administered as a 1h weekly intravenous (i.v.) infusion of 3.2mg/m(2) to patients with small cell lung cancer (SCLC) who relapsed or progressed after one line of chemotherapy. PATIENTS AND METHODS: This was a multicenter, open-label, single-arm, exploratory, phase II clinical trial. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. Objective response rate (primary efficacy endpoint) was evaluated according to response evaluation criteria in solid tumors (RECIST). The rate of stable disease (SD) lasting for at least 6 months and time-to-event variables were secondary endpoints of efficacy. Toxicity was assessed using National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. RESULTS: Twenty pretreated SCLC patients (median age, 60 years) with extensive (n=13) or limited-stage disease (n=7) received a total of 24 treatment cycles (median, one cycle per patient; range, 1-2). Objective tumor responses were not observed and only one of the 17 evaluable patients had SD. With a median follow-up of 11.8 months, the progression-free survival and the median overall survival were 1.3 months and 4.8 months, respectively. The most troubling or common toxicities were fatigue, muscle weakness, lymphopenia, anemia (no patients showed neutropenia), and asymptomatic, non-cumulative increase of transaminases levels and alkaline phosphatase. CONCLUSION: This clinical trial shows that a cycle of 1h weekly i.v. infusion of plitidepsin (3.2mg/m(2)) was generally well tolerated other than fatigue and muscle weakness in patients with pretreated SCLC. One patient died due to multi-organ failure. The absence of antitumor activity found here precludes further studies of this plitidepsin schedule as second-line single-agent treatment of SCLC.

Incidence of second sarcomas: a cancer registry-based study.

BACKGROUND: In high-quality cancer registration systems, about one in eight incident cancers are second primary cancers. This is due to a combination of careful diagnostic ascertainment, shared genetic determinants, shared exposure to environmental factors and consequences of treatment for first cancer. METHODS: We used data derived from the Swiss population-based cancer Registries of Vaud and Neuchâtel, including 885,000 inhabitants. RESULTS: Among 107,238 (52% males) first cancers occurring between 1976 and 2010, a total of 126 second sarcomas were observed through active and passive follow-up versus 68.2 expected, corresponding to a standardized incidence ratio (SIR) of 1.85 (95 % CI 1.5-2.2). Significant excess sarcoma risks were observed after skin melanoma (SIR = 3.0), breast cancer (2.2), corpus uteri (2.7), testicular (7.5), thyroid cancer (4.2), Hodgkin lymphoma (5.7) and leukemias (4.0). For breast cancer, the SIR was 3.4 ≥5 years after sarcoma diagnosis. CONCLUSIONS: The common denominator of these neoplasms is the utilization of radiotherapy in their management. Some sarcomas following breast cancer may be due to shared genetic components (i.e., in the Li-Fraumeni syndrome), as well as possibly to shared environmental factors, with sarcomas, including overweight, selected dietary and reproductive factors which are, however, too little defined for any quantitative risk assessment.

Hyperglycemia-induced abnormalities in rat and human corneas: the potential of second harmonic generation microscopy.

BACKGROUND: Second Harmonic Generation (SHG) microscopy recently appeared as an efficient optical imaging technique to probe unstained collagen-rich tissues like cornea. Moreover, corneal remodeling occurs in many diseases and precise characterization requires overcoming the limitations of conventional techniques. In this work, we focus on diabetes, which affects hundreds of million people worldwide and most often leads to diabetic retinopathy, with no early diagnostic tool. This study then aims to establish the potential of SHG microscopy for in situ detection and characterization of hyperglycemia-induced abnormalities in the Descemet's membrane, in the posterior cornea. METHODOLOGY/PRINCIPAL FINDINGS: We studied corneas from age-matched control and Goto-Kakizaki rats, a spontaneous model of type 2 diabetes, and corneas from human donors with type 2 diabetes and without any diabetes. SHG imaging was compared to confocal microscopy, to histology characterization using conventional staining and transmitted light microscopy and to transmission electron microscopy. SHG imaging revealed collagen deposits in the Descemet's membrane of unstained corneas in a unique way compared to these gold standard techniques in ophthalmology. It provided background-free images of the three-dimensional interwoven distribution of the collagen deposits, with improved contrast compared to confocal microscopy. It also provided structural capability in intact corneas because of its high specificity to fibrillar collagen, with substantially larger field of view than transmission electron microscopy. Moreover, in vivo SHG imaging was demonstrated in Goto-Kakizaki rats. CONCLUSIONS/SIGNIFICANCE: Our study shows unambiguously the high potential of SHG microscopy for three-dimensional characterization of structural abnormalities in unstained corneas. Furthermore, our demonstration of in vivo SHG imaging opens the way to long-term dynamical studies. This method should be easily generalized to other structural remodeling of the cornea and SHG microscopy should prove to be invaluable for in vivo corneal pathological studies.

Preliminary Experience in Treatment of Papillary and Macular Retinoblastoma: Evaluation of Local Control and Local Complications After Treatment with Linear Accelerator-Based Stereotactic Radiotherapy with Micromultileaf Collimator as Second-Line or Salvage Treatment after chemotherapy.

PURPOSE: To determine the local control and complication rates for children with papillary and/or macular retinoblastoma progressing after chemotherapy and undergoing stereotactic radiotherapy (SRT) with a micromultileaf collimator. METHODS AND MATERIALS: Between 2004 and 2008, 11 children (15 eyes) with macular and/or papillary retinoblastoma were treated with SRT. The mean age was 19 months (range, 2-111). Of the 15 eyes, 7, 6, and 2 were classified as International Classification of Intraocular Retinoblastoma Group B, C, and E, respectively. The delivered dose of SRT was 50.4 Gy in 28 fractions using a dedicated micromultileaf collimator linear accelerator. RESULTS: The median follow-up was 20 months (range, 13-39). Local control was achieved in 13 eyes (87%). The actuarial 1- and 2-year local control rates were both 82%. SRT was well tolerated. Late adverse events were reported in 4 patients. Of the 4 patients, 2 had developed focal microangiopathy 20 months after SRT; 1 had developed a transient recurrence of retinal detachment; and 1 had developed bilateral cataracts. No optic neuropathy was observed. CONCLUSIONS: Linear accelerator-based SRT for papillary and/or macular retinoblastoma in children resulted in excellent tumor control rates with acceptable toxicity. Additional research regarding SRT and its intrinsic organ-at-risk sparing capability is justified in the framework of prospective trials.

Fonctions du plancher pelvien: de la phase expulsive à la consultation du post-partum [Pelvic floor functions: from the beginning of the second phase of labor to the postpartum consultation].

Vaginal delivery can cause lesions of the various pelvic structures responsible for the mechanisms of continence. These lesions may perhaps be prevented in the future by measuring pressure generated during childbirth. Tear of the anal sphincter during childbirth is a marker of a global impairment of the urinary, ano-rectal and sexual pelvic functions in the short and medium term. Persistence of a defect of the anal sphincter is frequent in spite of immediate suture. The correlation between these defects and ano-rectal incontinence are not established in our experience. The quality of the contraction of the sphincter complex and pubo-rectal sling seems to play a more important role in ano-rectal continence after a traumatic childbirth.

Playing Second Fiddle: Expert Advice and Decision-Making in Switzerland

This thesis concerns the role of scientific expertise in the decision-making process at the Swiss federal level of government. It aims to understand how institutional and issue-specific factors influence three things: the distribution of access to scientific expertise, its valuation by participants in policy for- mulation, and the consequence(s) its mobilization has on policy politics and design. The theoretical framework developed builds on the assumption that scientific expertise is a strategic resource. In order to effectively mobilize this resource, actors require financial and organizational resources, as well as the conviction that it can advance their instrumental interests within a particular action situation. Institutions of the political system allocate these financial and organizational resources, influence the supply of scientific expertise, and help shape the venue of its deployment. Issue structures, in turn, condition both interaction configurations and the way in which these are anticipated by actors. This affects the perceived utility of expertise mobilization, mediating its consequences. The findings of this study show that the ability to access and control scientific expertise is strongly concentrated in the hands of the federal administration. Civil society actors have weak capacities to mobilize it, and the autonomy of institutionalized advisory bodies is limited. Moreover, the production of scientific expertise is undergoing a process of professionalization which strengthens the position of the federal administration as the (main) mandating agent. Despite increased political polarization and less inclu- sive decision-making, scientific expertise remains anchored in the policy subsystem, rather than being used to legitimate policy through appeals to the wider population. Finally, the structure of a policy problem matters both for expertise mobilization and for the latter's impact on the policy process, be- cause it conditions conflict structures and their anticipation. Structured problems result in a greater overlap between the principal of expertise mobilization and its intended audience, thereby increasing the chance that expertise shapes policy design. Conversely, less structured problems, especially those that involve conflicts about values and goals, reduce the impact of expertise.

High constant incidence rates of second primary cancers of the head and neck: a pooled analysis of 13 cancer registries.

Scanty data are available on the incidence (i.e., the absolute risk) of second cancers of the head and neck (HN) and its pattern with age. We investigated this issue using data from a multicentric study of 13 population-based cancer registries from Europe, Canada, Australia and Singapore for the years 1943-2000. A total of 99,257 patients had a first primary HN cancer (15,985 tongue, 22,378 mouth, 20,758 pharyngeal, and 40,190 laryngeal cancer), contributing to 489,855 person-years of follow-up. A total of 1,294 of the patients (1.3%) were diagnosed with second HN cancers (342 tongue, 345 mouth, 418 pharynx and 189 larynx). Male incidence rates of first HN cancer steeply increased from 0.68/100,000 at age 30-34 to 46.2/100,000 at age 70-74, and leveled off at older age; female incidence increased from 0.50/100,000 at age 30-34 to 16.5/100,000 at age 80-84. However, age-specific incidence of second HN cancers after a first HN cancer in men was around 200-300/100,000 between age 40-44 and age 70-74 and tended to decline at subsequent ages (150/100,000 at age 80-84); in women, incidence of second HN cancers was around 200-300/100,000 between age 45-49 and 80-84. The patterns of age-specific incidence were consistent for different subsites of second HN cancer and sexes; moreover, they were similar for age-specific incidence of first primary HN cancer in patients who subsequently developed a second HN cancer. The incidence of second HN cancers does not increase with age, but remains constant, or if anything, decreases with advancing age.

Access of extracellular cations to their binding sites in Na,K-ATPase: role of the second extracellular loop of the alpha subunit.

Na,K-ATPase, the main active transport system for monovalent cations in animal cells, is responsible for maintaining Na(+) and K(+) gradients across the plasma membrane. During its transport cycle it binds three cytoplasmic Na(+) ions and releases them on the extracellular side of the membrane, and then binds two extracellular K(+) ions and releases them into the cytoplasm. The fourth, fifth, and sixth transmembrane helices of the alpha subunit of Na,K-ATPase are known to be involved in Na(+) and K(+) binding sites, but the gating mechanisms that control the access of these ions to their binding sites are not yet fully understood. We have focused on the second extracellular loop linking transmembrane segments 3 and 4 and attempted to determine its role in gating. We replaced 13 residues of this loop in the rat alpha1 subunit, from E314 to G326, by cysteine, and then studied the function of these mutants using electrophysiological techniques. We analyzed the results using a structural model obtained by homology with SERCA, and ab initio calculations for the second extracellular loop. Four mutants were markedly modified by the sulfhydryl reagent MTSET, and we investigated them in detail. The substituted cysteines were more readily accessible to MTSET in the E1 conformation for the Y315C, W317C, and I322C mutants. Mutations or derivatization of the substituted cysteines in the second extracellular loop resulted in major increases in the apparent affinity for extracellular K(+), and this was associated with a reduction in the maximum activity. The changes produced by the E314C mutation were reversed by MTSET treatment. In the W317C and I322C mutants, MTSET also induced a moderate shift of the E1/E2 equilibrium towards the E1(Na) conformation under Na/Na exchange conditions. These findings indicate that the second extracellular loop must be functionally linked to the gating mechanism that controls the access of K(+) to its binding site.

Paranasal sinuses in children: size evaluation of maxillary, sphenoid, and frontal sinuses by magnetic resonance imaging and proposal of volume index percentile curves.

Our objective was to establish the age-related 3D size of maxillary, sphenoid, and frontal sinuses. A total of 179 magnetic resonance imaging (MRI) of children under 17 years (76 females, 103 males) were included and sinuses were measured in the three axes. Maxillary sinuses measured at birth (mean+/-standard deviation) 7.3+/-2.7 mm length (or antero-posterior)/4.0+/-0.9 mm height (or cranio-caudal)/2.7+/-0.8 mm width (or transverse). At 16 years old, maxillary sinus measured 38.8+/-3.5 mm/36.3+/-6.2 mm/27.5+/-4.2 mm. Sphenoid sinus pneumatization starts in the third year of life after conversion from red to fatty marrow with mean values of 5.8+/-1.4 mm/8.0+/-2.3 mm/5.8+/-1.0 mm. Pneumatization progresses gradually to reach at 16 years 23.0+/-4.5 mm/22.6+/-5.8 mm/12.8+/-3.1 mm. Frontal sinuses present a wide variation in size and most of the time are not valuable with routine head MRI techniques. They are not aerated before the age of 6 years. Frontal sinuses dimensions at 16 years were 12.8+/-5.0 mm/21.9+/-8.4 mm/24.5+/-13.3 mm. A sinus volume index (SVI) of maxillary and sphenoid sinus was computed using a simplified ellipsoid volume formula, and a table with SVI according to age with percentile variations is proposed for easy clinical application. Percentile curves of maxillary and sphenoid sinuses are presented to provide a basis for objective determination of sinus size and volume during development. These data are applicable to other techniques such as conventional X-ray and CT scan.