Tolerance and efficacy of conformal radiotherapy for hepatocellular carcinoma in cirrhotic patients. Results of the French RTF1 phase II trial]

PURPOSE: While some patients presenting with hepatocellular carcinoma (HCC) benefit from curative therapies (transplantation, surgery, percutaneous ablation), others are only candidates for palliative options such as chemoembolization or symptomatic care. Although conventional external-beam radiotherapy of the liver is regarded as little efficient and potentially toxic in cirrhotic patients, 3-dimensional conformal radiotherapy (CRT), by decreasing the amount of normal liver included in the radiation portal, allows dose escalation to occur without increasing the risk of radiation-induced hepatitis. This trial was designed to assess the efficacy and tolerance of CRT for small-size HCC in cirrhotic patients. PATIENTS AND METHODS: Prospective phase II trial including stage A/B cirrhotic patients with small-size HCC not suitable for curative treatments; CRT consisted in a standard fractionation radiation, with a total dose of 66 Gy. RESULTS: Twenty-seven patients were included, 15 of whom had previously been treated for HCC; mean age was 68. Among the 23 assessable patients, 18 (78%) presented with complete response, 3 (13%) with partial response, and 2 with no response. Acute complications occurred in 24 patients, and were mainly acceptable (grade 1/2: 22 patients, grade 3/4: 11 patients, 4 (15%) of whom had clinical and/or hematological toxicities). Only 2 (9%) grade 3/4 clinical and/or hematological late toxicities are reported. CONCLUSION: CRT is a non-invasive curative technique highly suitable for small-size HCC in cirrhotic patients; further investigations are needed to compare it to the other available treatments, and to integrate it into the curative therapeutic algorithm of HCC.     

Prognostic significance of endometrial extension in carcinoma of the cervix

A retrospective analysis of 343 consecutive patients with histologically proven carcinoma of the cervix, treated at the Ottawa General Hospital, was undertaken to evaluate the prognostic significance of endometrial extension. All these patient had a D + C as part of their work-up. Sixty-seven patients had a (+) D + C: 34/150 (23%) in Stage IB, 21/106 (20%) in Stage II, and 12/87 (14%) in Stage III. Survival was closely related to the D + C findings in early stages. In Stage IB, the 5-year survival of D + C (-) patients was 90% vs 50% in D + C (+) patients (P less than 0.003) and in Stage II, the 5-year survival was 77% and 55%, respectively (P = 0.089). There was, however, no difference in survival in Stage III patients (35% vs 29%). Pelvic failures were similar in both groups, stage for stage, but those with a (+) D + C had a higher incidence of distant metastasis. In Stage IB, distant metastases were found in 8.5% (10/116) of D + C (-) patients compared to 38% (13/34) in D + C (+) patients (P less than 0.001) and in Stage II, in 18.5% (16/85 and 33% (7/21) of the patients (P = 0.126), respectively. There was no difference in Stage III patients (28% vs 25%). This study suggests that endometrial extension is a significant prognostic factor in early stages and is associated with a higher risk of distant metastases. Management of these high risk patients is discussed.     

L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition

Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a number of chronic disorders including asthma, chronic obstructive pulmonary disease (COPD) and cognitive disorders. This study delineates the preclinical profile of L-454,560, which is a potent, competitive and preferential inhibitor of PDE4A, 4B, and 4D with IC50 values of 1.6, 0.5 and 1.2 nM, respectively. In contrast to the exclusive binding of cilomilast and the preferential binding of roflumilast to the PDE4 holoenzyme state (Mg2+-bound form), L-454,560 binds to both the apo-(Mg2+-free) and holoenzyme states of PDE4. The intrinsic enzyme potency for PDE4 inhibition by L-454,560 also results in an effective blockade of LPS-induced TNFalpha formation in whole blood (IC50 = 161 nM) and is comparable to the human whole blood potency of roflumilast. The cytokine profile of inhibition of L-454,560 is mainly a Th1 profile with significant inhibition of IFNgamma and no detectable inhibition of IL-13 formation up to 1 microM. L-454,560 was also found to be efficacious in two models of airway hyper-reactivity, the ovalbumin (OVA) sensitized and challenged guinea pig and the ascaris sensitized sheep model. Furthermore, L-454560 was also effective in improving performance in the delayed matching to position (DMTP) version of the Morris watermaze, at a dose removed from that associated with potential emesis. Therefore, L-454,560 is a novel PDE4 inhibitor with an overall in vivo efficacy profile at least comparable to roflumilast and clearly superior to cilomilast.     

A qualitative analysis of women's short accounts of labour and birth in a Western Australian public tertiary hospital

This paper reports the findings of the postnatal qualitative arm of a larger study, which investigated women's prenatal and postnatal levels of childbirth fear. Women's expectations and experiences of labour and birth in a Western Australian public tertiary hospital were identified following thematic analysis of short written accounts from 141 participants who had given birth in the previous 6 to 14 weeks. Four major categories emerged to describe features and mediating factors in the trajectory of childbirth and the early puerperium. "Anticipating Labour and Birth," "Labour and Birth Depicted," "Mediating Factors and their Consequences," and "Evaluating, Resolving, and Looking Ahead" portray women's comparative reflections on expectations and realities of birth, on mediating influences, and on moving on from their experience. These findings will provide maternity care professionals with insight into the personal and environmental features of the childbirth setting which colours women's recollections. Being aware of what women value during labour and birth will reinforce the need for professionals to provide care using a mindful approach that considers the potential psychological, emotional, and behavioural implications of events.     

Management of premature rupture of membranes before 25 weeks

OBJECTIVES: The aim of our study was to define the benefits and risks related to expectant management in the midtrimester rupture of membranes and to assess the prognostic factors in order to give objective informations to parents facing these obstetrical situations. STUDY DESIGN: We conducted a retrospective study. The study population included 49 patients with premature rupture of membranes at 16-23 weeks' gestation during the period January 1998-June 2003. The main criterion for judgement was neonate survival. Statistical analysis included chi2-test for the qualitative variables and Student's test for the quantitative variables. The threshold for significance was 5%. RESULTS: Twenty couples out of 49 chose medical termination of pregnancy. Among the 29 other pregnancies, the mean latency period was 2.1 weeks. The mean gestational age at delivery was 23.2 weeks. Nineteen patients were delivered after 22 weeks. The main prognostic factors were the initial amniotic fluid index (2.9 cm versus 0.8 cm) (p=0.042) and gestational age at delivery (26.7 weeks versus 22.6 weeks) (p<0.001). About 2% of the pregnancies were complicated by maternal infection. Eighty-three percent of the survivors had neonatal respiratory distress syndrome. 41.2% of them presented sepsis. We observed no cases of severe intraventricular haemorrhage. The number of infants born after 24 weeks of gestation and still alive at 1 week was 12, representing 24% of pregnancies and 63% of the infants born after 24 weeks. CONCLUSION: Expectant management can be widely suggested to patients. However, termination of pregnancy is acceptable, in cases with a poor prognosis including anamnios and premature rupture of membranes before 21 weeks.     

Sialic acid concentration in the attached gingival tissue of rates realted to age and sex

Determination of N-acetylneuraminic acid concentration in the attached gingival tissue of rats related to the age and sex of the animals was carried out. The concentration of the sialic acid decreased with increasing age. Differences between male and female animals were noted.     

Vitamin D and Muscle Function: Is There a Threshold in the Relation?

ObjectivesFirst, to determine the association between serum 25 hydroxyvitamin D (25OHD) concentration and muscle mass, strength, and performance. Second, to explore if there is a threshold in the association.DesignCross-sectional, single-center study.SettingThe central part of the Netherlands (52° Northern latitude).ParticipantsA total of 802 independently living men and postmenopausal women 40 to 80 years of age.MeasurementsHealth-related and lifestyle factors, including physical activity, 25OHD concentration, lean mass, handgrip strength, knee extension strength, and physical performance were determined.ResultsOverall, higher 25OHD level was significantly associated with higher lean mass (22.6 g per nmol/L, 95% CI 7.3–37.9), handgrip strength (0.020 kg per nmol/L, 95% CI 0.001–0.038), and physical performance (0.006 points per nmol/L, 95% CI 0.001–0.012), after adjustment for various confounders. This association was most pronounced below a 25OHD level of 60 nmol/L, with lean mass increase 79.6 g per nmol/L (95% CI 40.8–118.4, P < .01), handgrip strength 0.09 kg per nmol/L (95% CI 0.045–0.141, P < .01), and physical performance 0.02 points per nmol/L (95% CI 0.005–0.032, P < .01), and these significant associations attenuated to null above this threshold.ConclusionIn middle-aged men and (postmenopausal) women, a higher 25OHD level was significantly associated with higher lean mass, muscle strength, and performance. These associations were most pronounced below 60 nmol/L and absent above 60 nmol/L, indicating a ceiling effect.     

Evaluation of a Wastewater-Based Epidemiological Approach to Estimate the Prevalence of SARS-CoV-2 Infections and the Detection of Viral Variants in Disparate Oregon Communities at City and Neighborhood Scales

Background: Positive correlations have been reported between wastewater SARS-CoV-2 concentrations and a community’s burden of infection, disease or both. However, previous studies mostly compared wastewater to clinical case counts or nonrepresentative convenience samples, limiting their quantitative potential.Objectives: This study examined whether wastewater SARS-CoV-2 concentrations could provide better estimations for SARS-CoV-2 community prevalence than reported cases of COVID-19. In addition, this study tested whether wastewater-based epidemiology methods could identify neighborhood-level COVID-19 hotspots and SARS-CoV-2 variants.Methods: Community SARS-CoV-2 prevalence was estimated from eight randomized door-to-door nasal swab sampling events in six Oregon communities of disparate size, location, and demography over a 10-month period. Simultaneously, wastewater SARS-CoV-2 concentrations were quantified at each community’s wastewater treatment plant and from 22 Newport, Oregon, neighborhoods. SARS-CoV-2 RNA was sequenced from all positive wastewater and nasal swab samples. Clinically reported case counts were obtained from the Oregon Health Authority.Results: Estimated community SARS-CoV-2 prevalence ranged from 8 to 1,687/10,000 persons. Community wastewater SARS-CoV-2 concentrations ranged from 2.9 to 5.1log10 gene copies per liter. Wastewater SARS-CoV-2 concentrations were more highly correlated (Pearson’s r=0.96; R2=0.91) with community prevalence than were clinically reported cases of COVID-19 (Pearson’s r=0.85; R2=0.73). Monte Carlo simulations indicated that wastewater SARS-CoV-2 concentrations were significantly better than clinically reported cases at estimating prevalence (p<0.05). In addition, wastewater analyses determined neighborhood-level COVID-19 hot spots and identified SARS-CoV-2 variants (B.1 and B.1.399) at the neighborhood and city scales.Discussion: The greater reliability of wastewater SARS-CoV-2 concentrations over clinically reported case counts was likely due to systematic biases that affect reported case counts, including variations in access to testing and underreporting of asymptomatic cases. With these advantages, combined with scalability and low costs, wastewater-based epidemiology can be a key component in public health surveillance of COVID-19 and other communicable infections. https://doi.org/10.1289/{"type":"entrez-protein","attrs":{"text":"EHP10289","term_id":"372009674","term_text":"EHP10289"}}EHP10289     

A preliminary study for clinical pharmacokinetics of oral fluorine anticancer medicines using the commercial MRI system 19F-MRS

These preliminary studies of dynamic natural abundance 19F-magnetic resonance spectroscopy (19F-MRS) on 5-FU based medicines were performed in the human liver using commercial 1.5 T MRI equipment. A single tuned, custom-made circular shape surface coil with a diameter of 15 cm operating at 60 MHz was used for the 19F-MRS study. Localized proton shimming with a whole body coil was performed with adequate volume to include the observing area of the surface coil, and the line width of the water signal was less than 40 Hz. Very different spectroscopic appearance patterns of 5-FU were observed. We examined whether the pharmacokinetics in the liver of orally administered 1-hexylcarbamoyl-5-fluorouracil (HCFU) differ from those of orally administered 5'-deoxy-5-fluorouridine (5'-DFUR). This preliminary study suggested the 19F-MRS technique could be a useful method of evaluating in vivo the metabolism of 5-FU based medicines.