Association of location of BRCA1 and BRCA2 mutations with benefit from olaparib and bevacizumab maintenance in high-grade ovarian cancer: phase III PAOLA-1/ENGOT-ov25 trial subgroup exploratory analysis.

BACKGROUND: In the phase III PAOLA-1 study, the addition of maintenance olaparib to bevacizumab in patients with newly diagnosed high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for homologous recombination deficiency-positive tumors, including those with a BRCA mutation (BRCAm). The magnitude of benefit from olaparib and bevacizumab according to the location of mutation in BRCA1/BRCA2 remains to be explored. PATIENTS AND METHODS: Patients with advanced-stage HGOC responding after platinum-based chemotherapy + bevacizumab received maintenance therapy bevacizumab (15 mg/kg q3w for 15 months) + either olaparib (300 mg b.i.d. for 24 months) or placebo. PFS was analyzed in the subgroup of patients with BRCA1m/BRCA2m according to mutation location in the functional domains of BRCA1 [Really Interesting Gene (RING), DNA-binding domain (DBD), or C-terminal domain of BRCA1 (BRCT)] and BRCA2 [RAD51-binding domain (RAD51-BD); DBD]. RESULTS: From 806 randomized patients, 159 harbored BRCA1m (19.7%) and 74 BRCA2m (9.2%). BRCA1m in RING, DBD, and BRCT domains was detected in 18, 40, and 33 patients, and BRCA2m in RAD51-BD and DBD in 36 and 13 patients, respectively. After a median follow-up of 25.5 months, benefit from maintenance olaparib + bevacizumab was observed irrespective of location of BRCAm. The benefit was particularly high for those with BRCA1m located in the DBD, with 24-month PFS estimated to be 89% and 15% [olaparib + bevacizumab versus placebo + bevacizumab hazard ratio = 0.08 (95% confidence interval 0.02-0.28); interaction P = 0.03]. In BRCA2m patients, 24-month PFS rates for those with mutations located in the DBD were 90% and 100% (olaparib + bevacizumab versus placebo + bevacizumab), respectively. CONCLUSIONS: Advanced-stage BRCA-mutated HGOC patients reported PFS benefit from maintenance olaparib and bevacizumab regardless of mutation location. The benefit is particularly high for patients with mutations located in the DBD of BRCA1. Mutations located in the DBD of BRCA2 are also associated with excellent outcome.

The impact of olaparib dose reduction and treatment interruption on treatment outcome in the SOLO2/ENGOT-ov21 platinum-sensitive recurrent ovarian cancer.

BACKGROUND: Maintenance treatment with poly (ADP-ribose) polymerase (PARP) inhibitor is now the standard of care in patients with BRCA-mutated platinum-sensitive recurrent ovarian cancer following response to chemotherapy. In the SOLO2 trial, adverse event (AE)-associated olaparib interruption, dose reduction, and discontinuation occurred in 50%, 28%, and 17% of patients, respectively. We used data from the SOLO2 trial to evaluate the impact of dose alterations on survival outcomes and identified baseline characteristics associated with dose alteration. PATIENTS AND METHODS: We computed relative dose intensity (RDI) defined as the received dose as a percentage of the standard dose (300 mg twice a day) during the first 12 weeks on treatment. Patients were categorized into RDI >98%, RDI 90%-98%, and RDI <90%. The association between RDI categories with progression-free survival (PFS) and overall survival (OS) were examined using a 12-week landmark Cox regression analysis. Logistic regression analysis was used to correlate baseline factors with RDI at 12 weeks. RESULTS: In patients on olaparib included in the landmark analysis (n = 185), the mean 12-week RDI was 91.4%. There was no significant difference across 12-week RDI >98% (n = 110), 90%-98% (n = 29), and <90% (n = 45) categories for PFS (median, 14.2 versus 19.3 versus 34.4 months; P = 0.37) and OS (median, 49.7 versus 49.5 versus 54.1 months; P = 0.84). Risk of RDI ≤90% increased with baseline performance status 1 [odds ratio (OR): 2.54; 95% confidence interval (CI): 1.11-5.82] any nausea (OR: 3.17; 95% CI: 0.9-11.23), and with body weight ≤70 kg (OR: 1.86; 95% CI: 0.92-3.76). CONCLUSIONS: Dose reduction and interruption for the management of olaparib-associated AEs during the first 12 weeks did not impact on PFS and OS. When counselling patients requiring dose reductions or interruptions due to AEs, the results of this study will help assure patients that their outcomes will not be adversely affected.

SEOM clinical guideline in ovarian cancer (2020).

Despite remarkable advances in the knowledge of molecular biology and treatment, ovarian cancer remains the leading cause of death from gynecologic cancer. In the last decade, there have been important advances both in systemic and surgical treatment. However, there is no doubt that the incorporation of PARP inhibitors as maintenance after the response to platinum-based chemotherapy, first in recurrent disease and recently also in first line, will change the natural history of the disease.The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of ovarian cancer, and to provide evidence-based recommendations for clinical practice.

B Cell Lymphoma mimicking Rheumatoid Arthritis.

Non Hodking´s lymphoma (NHL) may involve bones but synovial involvement is uncommon. We describe a patient who presented with polyarthritis, sicca symptoms and rash suggestive of rheumatoid arthritis. An atypical skin rash prompted skin and synovial biopsies. A diagnosis of synovial and skin malignant large B-cell lymphoma anaplastic subtype was performed. Chemotherapy with dexamethasone, vincristine and rituximab was started. Following treatment the patient had complete resolution of cutaneous and articular lymphoma manifestations.

SEOM clinical guideline in ovarian cancer (2020)

Despite remarkable advances in the knowledge of molecular biology and treatment, ovarian cancer remains the leading cause of death from gynecologic cancer. In the last decade, there have been important advances both in systemic and surgical treatment. However, there is no doubt that the incorporation of PARP inhibitors as maintenance after the response to platinum-based chemotherapy, first in recurrent disease and recently also in first line, will change the natural history of the disease. The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of ovarian cancer, and to provide evidence-based recommendations for clinical practice (AU)

[Trends in the prevalence of pressure ulcers in an acute care tertiary hospital (2006-2013)]. / Evolución de la prevalencia de úlceras por presión en un hospital de agudos de tercer nivel (2006-2013).

OBJECTIVES: To analyse the trends in pressure ulcer prevalence from 2006 to 2013. To determine the main risk factors associated with pressure ulcers. METHOD: A descriptive study analysing the prevalence in a series of pressure ulcers collected in the study on the prevalence of nosocomial infections in Spain from 2006 to 2013 in the Clinical University Hospital of Zaragoza. RESULTS: The mean prevalence among the 5,354 patients included over the period of study was 4.5% (95% CI=3.9-5.0%). No significant difference in its trend or distribution of pressure ulcers was observed over the several years of the study. Prevalence increased up to 5.0% (95% CI=4.4-5.6%) when short-stay patients (less than 24 hours) and those admitted into low risk units (Paediatrics, Psychiatry and Obstetrics) were removed from the study, but there was still no significant differences in its yearly trend or distribution (p>0.05). Age, length of stay, presence of coma, in-dwelling urethral catheters, malnutrition, infection, and admission unit were risk factors associated with pressure ulcer prevalence in the logistic regression. CONCLUSIONS: Age, length of stay, coma, in-dwelling urethral catheters, malnutrition, infection, and admission unit were independent risk markers for patients with pressure ulcers. No particular trend of pressure ulcer prevalence could be determined to demonstrate any effects from the different strategies of improvement implemented during the period of study, although this fact could be due to the limitations of data used in the study.

Effect of Er:YAG laser holes on osteoinduction in demineralized rat calvarial allografts.

Massive cortical autografts and allografts have been found to incorporate into host bone very slowly and thus are subject to complications such as fatigue fracture and infection. In order to understand and improve the process of osteogenesis in these types of bone grafts, a new experimental model was developed using bone discs from rat calvaria prepared by demineralization and drilling of 0.5 mm diameter holes with a pulsed, 2.94 microns wavelength Erbium:Yttrium-Aluminum-Garnet laser. Four types of bone discs were analyzed: untreated (Type I), demineralized (Type II), laser-ablated (Type III), and laser-ablated then demineralized (Type IV). The discs were transplanted into a subcutaneous site in adult Sprague-Dawley rats and followed for as long as 6 weeks. Histologic analysis of the discs at weekly intervals with use of hematoxylin and eosin staining confirmed the presence of new bone growth in Type-II and Type-IV discs. The amount of new bone growth in each disc was estimated by determining the mineral x-ray attenuation coefficient, which is proportional to mineral density, from digitized radiographs of the discs. The results showed that the processes of demineralization (P < 0.001) and laser ablation with demineralization (p < 0.05) were both significant in enhancing new bone growth in this model. This study demonstrated that osteoinduction can be fostered in cortical bone through the processes of demineralization and laser ablation. To the extent that laser ablation may allow maintenance of structural integrity while altering the surface geometry in such a way as to promote ingrowth of new bone, this experimental model represents an advance in understanding how osteogenesis in cortical bone grafts might be improved.

Glycoprotein biosynthesis at the time of palate fusion by rabbit palate and maxilla cultured in vitro.

The dynamics of glycoprotein biosynthesis in rabbit maxillary and palatal explants at the time of palatal fusion was studied using 3H-fucose and 14C-leucine as precursors. The results show that there is an increase in glycoprotein biosynthesis in the rabbit palate in vitro at a time commensurate with the onset of contact and adherence of the palatal shelves.

Risk of congenital anomalies in the vicinity of municipal solid waste incinerators.

BACKGROUND: Although municipal solid waste incineration (MSWI) has contributed to increase the overall environmental load of particulate matter containing dioxins and metals, evidence of health consequences to populations is sparse. AIMS: To assess at a regional level (in southeast France) the impact of these emissions on birth defect rates. METHODS: Communities with fewer than 50 000 inhabitants surrounding the 70 incinerators that operated at least one year from 1988 to 1997 were studied. Each exposed community (n = 194) was assigned an exposure index estimated from a Gaussian plume model. Poisson models and a reference population of the 2678 unexposed communities in the region were used to calculate relative risks for congenital malformations, adjusted for year of birth, maternal age, department of birth, population density, average family income, and when available, local road traffic. RESULTS: The rate of congenital anomalies was not significantly higher in exposed compared with unexposed communities. Some subgroups of major anomalies, specifically facial clefts and renal dysplasia, were more frequent in the exposed communities. Among exposed communities, a dose-response trend of risk with increasing exposure was observed for obstructive uropathies. Risks of cardiac anomalies, obstructive uropathies, and skin anomalies increased linearly with road traffic density. CONCLUSIONS: Although both incinerator emissions and road traffic may plausibly explain some of the excess risks observed, several alternative explanations, including exposure misclassification, ascertainment bias, and residual confounding cannot be excluded. Some of the effects observed, if real, might be attributable to old-technology MSWIs and the persistent pollution they have generated.

Maternal occupational risk factors for oral clefts. Occupational Exposure and Congenital Malformation Working Group.

OBJECTIVES: This study investigated the role of maternal exposures at work during pregnancy in the occurrence of oral clefts. METHODS: The occupational exposures of 851 women (100 mothers of babies with oral clefts and 751 mothers of healthy referents) who worked during the first trimester of pregnancy were studied. All the women were part of a multicenter European case-referent study conducted using 6 congenital malformation registers between 1989 and 1992. In each center, the mother's occupational history, obtained from an interview, was reviewed by industrial hygienists who were blinded to the subject's status and who assessed the presence of chemicals and the probability of exposure. Odds ratios (OR) were estimated by a multivariate analysis including maternal occupation or occupational exposures during the first trimester of pregnancy and possible confounding factors such as center of recruitment, maternal age, urbanization, socioeconomic status, and country of origin. RESULTS: After adjustment for confounding factors, cleft palate only was significantly associated with maternal occupation in services such as hairdressing [OR 5.1, 95% confidence interval (95% CI) 1.0-26.0] and housekeeping (OR 2.8, 95% CI 1.1-7.2). The analysis suggests that the following occupational exposures are associated with orofacial clefts: aliphatic aldehydes (OR 2.1, 95% CI 0.8-5.9) and glycol ethers (OR 1.7, 95% CI 0.9-3.3) for cleft lip with or without cleft palate and lead compounds (OR 4.0, 95% CI 1.3-12.2), biocides (OR 2.5, 95% CI 1.0-6.0), antineoplastic drugs (OR 5.0, 95% CI 0.8-34.0), trichloroethylene (OR 6.7, 95% CI 0.9-49.7), and aliphatic acids (OR 6.0, 95% CI 1.5-22.8) for cleft palate only. CONCLUSIONS: Due to the limited number of subjects, these results must be interpreted with caution. However, they point out some chemicals already known or suspected as reproductive toxins.

Comparative study of the clinical efficacy of two different coumarin dosages in the management of arm lymphedema after treatment for breast cancer.

In a randomized, double-blind, parallel group study, we compared the clinical efficacy of coumarin 90 mg/day (Group A) with 135 mg/day (Group B) in 77 women (age 35-65 years) with lymphedema of the upper limb secondary to surgery and irradiation for treatment of breast cancer. During 12 months of coumarin therapy, the arm volume of lymphedema and a clinical score (degree of arm edema, heaviness, hardness, and neuralgia/dysesthesia) were determined. In both groups, the volume of arm lymphedema decreased (14.9% in Group A and 13.2% in Group B) (N.S.), the overall clinical score improved (12.9 +/- 4.3 to 5.7 +/- 3.5 in Group A and from 11.7 +/- 3.7 to 4.7 +/- 3.9 in Group B) (N.S.), and the overall efficacy of coumarin was similarly good or excellent (71.9% in Group A and 68.6% in Group B) (N.S.). Only mild to moderate side effects of drug therapy were recorded. Coumarin prevents a spontaneous trend toward an increase in arm lymphedema after treatment of breast cancer, decreases the severity of local symptoms, and overall improves the quality of life. No difference was found between the apparent benefits of coumarin at 90 mg/day compared with 135 mg/day.

Immunophenotypical characterization in Andalusian horse: variations with age and gender.

Assessment of lymphocyte subsets is an effective method for characterizing disorders such as leukemia, lymphomas, autoimmune and infectious diseases. In order to clinically interpret these parameters, normal reference values should be set, estimating age- and gender-related variations. This research aimed to: (1) characterize lymphocyte subpopulations in Andalusian horse, and (2) evaluate age and gender-related variations of lymphocyte subsets. Jugular blood samples were obtained from 159 animals, 77 males and 82 females, belonging to four age groups-1: 1-2 years (N=39; 21 males and 18 females), 2: 2-3 years (N=38; 16 males and 22 females), 3: 3-4 years (N=41; 19 males and 22 females) and 4: 4-7 years (N=41; 21 males and 20 females). T lymphocytes subsets were quantified by flow cytometry with monoclonal antibodies specific for CD2, CD4 and CD8 cell markers. B and NK cell counts were estimated by using a mathematical formula. No variations were found in T, B lymphocytes and NK cells between males and females. Animals of group 1 and 2 had a higher number of CD2, T, CD4+, CD8+, B lymphocytes and NK cells than animals of groups 3 and 4. The percentage of CD2 in group 1 was significantly lower than in group 4. The percentage of T and CD4+ lymphocytes in the group 1 were significantly higher than groups 2 and 3, respectively. Whereas the percentage of B cells calculated by flow cytometry was significantly lower in group 2 compared to group 4, the percentage of B cells calculated by a mathematical formula was higher in group 1. NK cells percentage was significantly lower in group 3 and 4 than in younger animals. In conclusion, in Andalusian horse, gender does not influence absolute numbers and percentages of T, B and NK. There is an age-related decline in absolute number of CD2, T, CD4+ and CD8+ lymphocytes, B lymphocytes and NK cells, with increasing percentage of CD2, T, CD4+ and B lymphocytes, and a decrease in NK with no differences in CD4/CD8 ratio. The decline of lymphocyte population numbers with age is a natural process in many animal species, and could be the origin for immune dysfunction observed in geriatric individuals.

Evolución de la prevalencia de úlceras por presión en un hospital de agudos de tercer nivel (2006-2013) / Trends in the prevalence of pressure ulcers in an acute care tertiary hospital (2006-2013)

Objetivos: Analizar la evolución de la prevalencia de úlceras por presión entre los años 2006 a 2013. Conocer los principales factores de riesgo asociados a las mismas. Método: Estudio descriptivo en el que se analizaron las series de prevalencia 2006-2013 de úlceras por presión del estudio de prevalencia de las infecciones nosocomiales en España del Hospital Clínico Universitario de Zaragoza. Resultados: La prevalencia media de úlceras por presión en los 5.354 pacientes del período de estudio fue de 4,5% (IC95% = 3,9-5,0%). No se encontraron diferencias significativas en la distribución ni en la tendencia a lo largo del período estudiado. La prevalencia aumentó al 5,0% (IC95% = 4,4-5,6% al eliminar de la muestra los pacientes con estancia inferior a 24 horas y los de servicios de bajo riego (Pediatría, Obstetricia y Psiquiatría), pero tampoco había diferencias en su distribución ni tendencia anual (p > 0,05). Los factores asociados a las úlceras fueron la edad, los días de ingreso, la presencia de coma, sonda urinaria, desnutrición, infección y el servicio de ingreso. Conclusiones: La edad, la estancia hospitalaria, la presencia de coma, desnutrición, infección, sonda urinaria y el ingreso en determinadas unidades constituyen marcadores independientes de riesgo de los pacientes con úlceras por presión. No se aprecia una tendencia en la prevalencia de úlceras por presión que sugiera algún efecto de las diferentes estrategias de intervención implantadas en el período de estudio, aunque esta ausencia de hallazgos podría ser debida a las limitaciones de los datos empleados (AU)

Objectives: To analyse the trends in pressure ulcer prevalence from 2006 to 2013. To determine the main risk factors associated with pressure ulcers. Method: A descriptive study analysing the prevalence in a series of pressure ulcers collected in the study on the prevalence of nosocomial infections in Spain from 2006 to 2013 in the Clinical University Hospital of Zaragoza. Results: The mean prevalence among the 5,354 patients included over the period of study was 4.5% (95% CI = 3.9-5.0%). No significant difference in its trend or distribution of pressure ulcers was observed over the several years of the study. Prevalence increased up to 5.0% (95% CI = 4.4-5.6%) when short-stay patients (less than 24 hours) and those admitted into low risk units (Paediatrics, Psychiatry and Obstetrics) were removed from the study, but there was still no significant differences in its yearly trend or distribution (p > 0.05). Age, length of stay, presence of coma, in-dwelling urethral catheters, malnutrition, infection, and admission unit were risk factors associated with pressure ulcer prevalence in the logistic regression. Conclusions: Age, length of stay, coma, in-dwelling urethral catheters, malnutrition, infection, and admission unit were independent risk markers for patients with pressure ulcers. No particular trend of pressure ulcer prevalence could be determined to demonstrate any effects from the different strategies of improvement implemented during the period of study, although this fact could be due to the limitations of data used in the study (AU)

The effect of hypervitaminosis A on rat palatal development.

Retinoic acid or retinyl acetate was administered to pregnant rats in doses sufficient to induce a 90% incidence of cleft palate. In another study, a delay in the reorientation of the palatal shelves was observed to be longer with the more potent teratogen, retinoic acid. On day 16 of gestation, 24 hours after final dosage with vitamin A, the synthesis of DNA and protein was studied in fetal carcass, mandible, and palate, and that of sulfated mucopolysaccharides (S-MPS) and glycoproteins (GP) in fetal head, mandible, and palate. Increases in DNA synthesis in fetal palate and in GP synthesis in fetal palate were found; thus, the mechanism of action of vitamin A in inducing cleft palates in rats may be caused by interference with the normal biochemical synthetic pattern of the palatal shelves.

Vitamin A induction of cleft palate.

Both retinoic acid and retinyl acetate, administered in high doses on days 13--15 of gestation, are capable of causing a 90 per cent incidence of cleft palate in Charles River rats. However, an attempt to develop as in vivo rabbit model system for the induction of clefts via hypervitaminosis A was unsuccessful. In the rat, the retinoic acid form of vitamin A is the more potent teratogen, inducing clefts at less than half the dose required to produce them with retinyl acetate. Histologic examination of fetal rat heads confirmed the biochemical evidence that retinoic acid is the more potent teratogen. Both forms of vitamin A prevented palatal shelf reorientation from occurring at the correct gestational age. The retinyl acetate treatment delayed the rotation for approximately 12 hours, the retinoic acid for at least 48 hours.

Fetal and maternal vitamin A levels in tissues of hypervitaminotic A rats and rabbits.

Pregnant rats and rabbits were given excess vitamin A, in the form of retinyl acetate or retinoic acid, for the 3-day period just prior to palatal closure in the fetuses. Twenty-four hours later, the various forms of vitamin A, and their levels, were determined in fetal liver and carcass and in maternal liver and serum by thin-layer chromatography. The predominant forms of vitamin A found in both fetal and maternal tissues were retinyl palmitate, retinol and retinoic acid. In both species, the tissues from the groups treated with retinoic acid contained levels of vitamin A similar to those found in control tissues. After retinyl acetate treatment in the rat, both of the maternal tissues studied had elevated vitamin A, whereas in the rabbit only maternal liver levels increased. In the groups treated with retinyl acetate, the ratio of the vitamin A levels in fetal liver: maternal serum reflected a species difference: the ratio was lower than the control value in the rabbit and higher than controls in the rat. Radiotracer studies in the rat, using either 3H-retinol or 14C-retinoic acid, demonstrated vitamin A transport across the placenta, with vitamin A concentrating in the fetal liver.

Descriptive epidemiological survey on a given day in all palliative care patients hospitalized in a French university hospital.

We conducted a descriptive study on a given day on all inpatients requiring palliative care in a French university hospital. In each department, a collaborative team made up of physicians and nurses identified and described the clinical signs, the treatment protocols, the social and family characteristics and the outcome for each patient using a standardized questionnaire. Study subjects were inpatients in the hospital and presented advanced or terminal-stage life-threatening conditions. Two-hundred-and-forty-five patients were included in the study. These patients represented 13% of the total number of inpatient beds available in the hospital on the day of the survey. Sixty-six per cent of study subjects suffered from physical discomfort and 80% suffered psychologically. Patients still received specific treatment for their condition in 45% of cases. Social problems were identified principally in medium- or long-term care department inpatients who made up 36% of the total inpatient population. A request for transfer to another care structure had been completed for 24% of patients. Assistance from the Palliative Care Unit's support team had been requested in 25% of cases, mainly to provide psychological support for the patient and the health care providers. These results have led us to reconsider the general organization of palliative care in the health care system.

Healing of bony defects in the irradiated and unirradiated rat mandible.

A model system of the irradiated rat mandible has been developed and used in conjunction with a non-spontaneously healing mandibular defect. The contribution of the tissue components in the healing of bony defects was studied using demineralized bone powder (DBP) prepared from unirradiated or in vivo irradiated rat long bones. Better bony fill of the defects occurred in the irradiated beds filled with unirradiated DBP than in the unirradiated beds containing irradiated DBP. This suggests that, at least in the early postirradiation period, the bed is not the limiting factor in healing of bony defects and the osteogenic components of bone in the DBP may be most affected by irradiation. In the irradiated bed, the defects grafted 2 weeks after irradiation healed better than those grafted at 4 weeks. Thus, the timing of surgery after irradiation also plays a role in the healing process, with early surgery producing better results.

The effects of phenytoin on rat development: an animal model system for fetal hydantoin syndrome.

An animal model system has been established which reproduces some of the features of the Fetal Hydantoin Syndrome. This pattern of altered growth and development includes growth retardation, craniofacial anomalies, distal phalangeal hypoplasia, and mental deficiency. Rats exposed in utero to phenytoin on gestational days 9, 11, and 13 exhibited fetal onset growth retardation, abnormalities of the craniofacial region and axial skeleton. In addition, the exposed offspring had significantly lower fetal weights, a shortened snout and a high-arched, irregular palate, and significant delays in skeletal maturation. These abnormalities resemble those reported for the Fetal Hydantoin Syndrome and provide a means to study the effect of phenytoin on the morphological and biochemical development of the fetus.