Efficacy and safety of administering oral misoprostol by titration compared to vaginal misoprostol and dinoprostone for cervical ripening and induction of labour: study protocol for a randomised clinical trial.

BACKGROUND: Among the various methods available, the administration of prostaglandins is the most effective for inducing labour in women with an unfavourable cervix. Recent studies have compared treatment with various titrated doses of oral misoprostol with vaginal misoprostol or dinoprostone, indicating that the use of an escalating dose of an oral misoprostol solution is associated with a lower rate of caesarean sections and a better safety profile. The objective of this study is to assess which of these three therapeutic options (oral or vaginal misoprostol or vaginal dinoprostone) achieves the highest rate of vaginal delivery within the first 24 h of drug administration. METHODS: An open-label randomised controlled trial will be conducted in Araba University Hospital (Spain). Women at ≥41 weeks of pregnancy requiring elective induction of labour who meet the selection criteria will be randomly allocated to one of three groups: 1) vaginal dinoprostone (delivered via a controlled-release vaginal insert containing 10 mg of dinoprostone, for up to 24 h); 2) vaginal misoprostol (25 µg of vaginal misoprostol every 4 h up to a maximum of 24 h); and 3) oral misoprostol (titrated doses of 20 to 60 µg of misoprostol following a 3 h on + 1 h off regimen up to a maximum of 24 h). Both intention-to-treat analysis and per-protocol analysis will be performed. DISCUSSION: The proposed study seeks to gather evidence on which of these three therapeutic options achieves the highest rate of vaginal delivery with the best safety profile, to enable obstetricians to use the most effective and safe option for their patients. TRIAL REGISTRATION: NCT02902653 Available at: https://clinicaltrials.gov/show/NCT02902653 (7th September 2016).

The feasibility of home monitoring of young people with cystic fibrosis: Results from CLIMB-CF.

BACKGROUND: CF is traditionally assessed in clinic. It is unclear if home monitoring of young people with CF is feasible or acceptable. The COVID-19 pandemic has made home monitoring more of a necessity. We report the results of CLIMB-CF, exploring home monitoring's feasibility and potential obstacles. METHODS: We designed a mobile app and enrolled participants with CF aged 2-17 years and their parents for six months. They were asked to complete a variety of measures either daily or twice a week. During the study, participants and their parents completed questionnaires exploring depression, anxiety and quality of life. At the end of the study parents and participants completed acceptability questionnaires. RESULTS: 148 participants were recruited, 4 withdrew prior to starting the study. 82 participants were female with median (IQR) age 7.9 (5.2-12 years). Median data completeness was 40.1% (13.6-69.9%) for the whole cohort; when assessed by age participants aged ≥ 12 years contributed significantly less (15.6% [9.8-30%]). Data completeness decreased over time. There was no significant difference between parental depression and anxiety scores at the start and the end of the study nor in CFQ-R respiratory domain scores for participants ≥ 14 years. The majority of participants did not feel the introduction of home monitoring impacted their daily lives. CONCLUSIONS: Most participants felt home monitoring did not negatively impact their lives and it did not increase depression, anxiety or decrease quality of life. However, uptake was variable, and not well sustained. The teenage years pose a particular challenge and further work is required.

Haploidentical IL-15/41BBL activated and expanded natural killer cell infusion therapy after salvage chemotherapy in children with relapsed and refractory leukemia.

Primary refractory or relapsed pediatric leukemia yield significant morbidity and mortality, with long-term survival rates <40%. Here we present a post-hoc analysis assessing safety and efficacy of infusing activated and expanded Natural Killer cells (NKAE) from haploidentical donors in patients from 2 clinical trials. In total, 18 children, adolescents and young adults with relapse or refractory acute leukemia were treated with two cycles of rescue chemotherapy followed by fresh NKAE cells infusions and low doses of IL-2. The overall response rate, complete remission achievement at the end of the study, was 72% (13 of 18). We infused 52 NKAE cell products containing a median of 6.76 × 106 NK cells/kg (0.7-34.16) and 0.49 × 106 T cells/kg (0-11). All infusions were well tolerated with no graft versus host disease nor other serious adverse events. Among the 14 patients who completed treatment, 4 of them are alive and leukemia-free more than 750 days post-transplant. We conclude that infusion of fresh NKAE cell therapy is feasible and safe in heavily pretreated pediatric population, and should be further investigated in advanced-phase clinical trials as well as a consolidation therapy to decrease relapse in patients with high-risk leukemia. TRIALS REGISTRATION: Registered at www.clinicaltrials.gov as NCT01944982 and NCT02074657.

Massive localized lymphedema: additional locations and association with hypothyroidism.

We report the second series of a new entity called "massive localized lymphedema in morbidly obese patients" (MLL), recently described in medical literature. Our 6 cases present additional locations as well as an association with hypothyroidism. Huge masses, of longstanding duration ranging from 9 months to 8 years, afflicted the thigh, popliteal fossa, scrotum, suprapubic and inguinal region, and abdomen of morbidly obese adults. Although clinical impressions were generally of a benign process, including lipoma and recurrent cellulitis, the possibility of a malignant neoplasm could not be eliminated. Poorly defined and non-encapsulated, these skin and subcutaneous lesions were most remarkable for their sheer size, measuring 50.6 cm in mean diameter (range, 38-75 cm) and weighing a mean of 6764.5 g (range, 2,060-12,000 g) The overlying skin exhibited the induration and peau d'orange characteristic of chronic lymphedema. Grossly and histologically, a prominent marbled appearance, rendered by fibrous bands intersecting lobules of adipose tissue, simulated sclerosing well differentiated liposarcoma. However, the absence of atypical stromal cells, atypical adipocytes, and lipoblasts precluded the diagnosis of well differentiated liposarcoma. Instead, reactive features, encompassing lymphatic vascular ectasia, mononuclear cell infiltrates, fibrosis, and edema between the collagen fibers, as well as ischemic changes including infarction and fat necrosis, established the diagnosis of MLL. Although the pathogenesis of MLL may be as simple as obstruction of efferent lymphatic flow by a massive abdominal pannus and/or prior surgery, the presence of hypothyroidism in 2 of our patients suggests an alternative pathogenesis. Recognition of this entity by both clinicians and pathologists should avert a misdiagnosis as a low-grade liposarcoma.

Treatment options for localized recurrence of prostate cancer following radiation therapy.

Patients with radioresistant clinically localized prostate cancer may be treated by various means. Although androgen ablation is relatively noninvasive, it cannot be considered a curative option. We believe that a subset of patients with locally recurrent prostate cancer without subclinical metastatic disease exists and would benefit from maximally aggressive local therapy. Salvage surgery may offer long-term cancer control, particularly when the tumor is organ-confined, but is a technically challenging operation with a high incidence of postoperative incontinence. Cryoablation of the prostate for postirradiation recurrence may offer a less invasive alternative to radical surgery, but its long-term efficacy remains to be fully determined. Each therapeutic option has its characteristic attendant morbidity and the choice of therapy for local recurrence should be made with informed consent after frank discussion between physician and patient. We propose the treatment algorithm shown in Figure 1 for the management of patients with suspected recurrence after radiation therapy with the caveat that individual therapeutic strategies must be patterned around individual patient needs.

Morfología de la placenta en recién nacidos con defecto congénito / Morphology of the placenta in newborns with congenital defects

El objetivo del estudio fue comparar el índice de madurez placentaria y las alteraciones histopatológicas en placentas de recién nacidos/óbitos con y sin defecto congénito (DC). Se realizó un estudio tipo casos y controles. Se incluyeron n=25 casos yn=50 controles sin DC. Los casos se clasificaron de acuerdo a la presencia de DC aislado (n=17) omúltiple (n=8). Se incluyeron recién nacidos/óbitos (RN) con una edad gestacional (EG) > 20 semanas. Se excluyeron embarazos gemelares. Se recolectó información sobre las características clínicas del producto y de la madre, antropometría del RN y su evaluación de APGAR. Se examinó la placenta, macroscópica y microscópicamente, para determinar la presencia y extensión de alteraciones histopatológicas. Se determinó el índice de madurez placentaria (IMP), calculado dividiendo el número de membranas vásculo sinciciales en 1 mm2 entre el grosor de las mismas (µ). El IMP (media ±DE) fue de 27.77±14 en el grupo de controles, 30.31±12 en el grupo de casos aislados y 16.76± 1 en el grupo de DC múltiple (p<0.05).El resto de las variables evaluadas no mostraron diferencias significativas entre grupos. En conclusión este trabajo muestra una menor madurez placentaria asociada con la presencia de DC múltiple.

The objective of the study was to compare the placental maturity index (PMI) and pathohistological alterations of placentas from newborn/stillborns (NB) with or without congenital defects (CD). A case control study was carried out. N=25 CD cases and n=50 controls without CD were included. Cases were classified according to the presence of simple (n=17) or multiple (n=8) CD. Newborn/stillborns with gestational age >20 weeks were included. Twin pregnancies were excluded. We collected information on clinical characteristics of the NB and the mother, NB anthropometry and APGAR score. The placenta was macro and microscopically examined to determine the presence and extension of histological alterations. The PMI was obtained by dividing the number of vasculo-syncytial membranes in 1 mm2, by their thickness (µ). The PMI (Mean ± SD) was 27.77 ± 14 in the control group, 30.31 ± 12 in the group diagnosed with simple CD, and 16.76 ± 1 in the group diagnosed with multiple CD (p<0.05. The rest of the assessed variables did not show significant difference between groups. In conclusion, this work shows a lower placental maturity associated with the presence of multiple CD.

Defectos del tubo neural y de labio y paladar hendido: un estudio morfológico / Neural tube defects, cleft lip and palate: a morphological study

El objetivo del trabajo fue realizar una evaluación morfológica externa de recién nacidos (RN) y lactantes con diagnóstico de defectos de tubo neural (DTN) y labio hendido c/s paladar hendido (LH c/s PH) para determinar el tipo de defecto, ubicación, extensión, clasificación y evaluar la proporción de RN con retardo del crecimiento intauterino (RCIU) y lactantes desnutridos. Estudio descriptivo. Se estudiaron 36 niños desde su nacimiento hasta los 12 meses de edad; 20 con DTN y 16 con LH c/s PH. El estudio se realizó en cinco hospitales de la ciudad de Chihuahua, México. Se hizo una evaluación morfológica externa y antropometría de los niños. Los DTN se clasificaron como lesiones abiertas y cerradas, como defectos altos o bajos, según el modelo de sitios múltiples y por la CIE-10. Los LH c/s PH se clasificaron como unilaterales o bilaterales, completos e incompletos y como aislados o múltiples. Se determinó RCIU en los RN y desnutrición en los lactantes. El análisis estadístico se realizó con el paquete STATA 8.0 para Windows. Se estudiaron 20 casos de DTN; 3 lactantes y 17 RN. De LH c/s PH fueron 8 lactantes y 8 RN. En cuanto a los DTN, 60 por ciento fueron mielomeningocele y correspondían a lesiones abiertas. El 85 por ciento se localizaron a nivel alto. En el modelo de cierres múltiples, el Z1 fue el 80 por ciento. Los LH c/s PH más frecuentes fueron aquellos con hendidura completa (50 por ciento). El 35 por ciento de los RN con DTN tuvieron RCIU y el 67 por ciento de los lactantes presentaron desnutrición. Es importante conocer los mecanismos del desarrollo de las anomalías congénitas ya que esto permite precisar el momento en que ocurrió la falla y permite estudiar los factores predisponentes, con lo cual se puede ofrecer asesoramiento genético para una posible prevención.

The objective of this study was to perform an external morphological evaluation of newborn (NB) and lactating children (LC) with diagnosis of neural tube defects (NTD) and cleft lip c/s palate (CL/s PH) to determine the type of defect, location, extent, classification and assess the proportion of infants with intrauterine growth retardation (IUGR) and malnourished infants. A descriptive study in 36 children from birth to 12 months of age , 20 with NTD and 16 with LH c / s PH was carried out. The study was conducted in five hospitals in the city of Chihuahua, Mexico. An external morphological assessment and anthropometry of children were performed. The DTN lesions were classified as open and closed, as defects high or low, depending on the model of multiple sites and ICD-10. The LH c / s PH were classified as unilateral or bilateral, complete or incomplete, and as isolated or multiple. IUGR was determined in the RN and malnutrition in infants. A statistic analysis was made with STATA 8.0 for Windows. We studied 20 cases of NTDs, 3 LCs and 17 RN. LH c/s PH were 8 LC and 8 RN. The DTN, 60 percent were myelomeningocele and corresponded to open lesions. Eighty five percent were located at high level. In the model of multiple closures, the Z1 was 80 percent. The LH c/s PH were more frequent with complete cleft (50 percent). The 35 percent of newborns with NTD had IUGR and 67 percent of LC had malnutrition. It is important to understand the mechanisms of development of congenital anomalies as this allows to specify the time the fault occurred and to study the underlying diseases to offer genetic counseling for possible prevention.

Recurrent transitional cell carcinoma in an ileal conduit treated by sandwich chemotherapy and surgical resection.

Recurrent transitional cell carcinoma in a ureteroileal conduit following radical cystectomy is rare. The prognosis for these patients is uniformly poor. We report on a patient with transitional cell carcinoma in an ileal conduit treated by chemotherapy and partial excision of the ileal conduit. He was without evidence of disease 4 1/2 years after completion of therapy.

Survival of men with clinically localized prostate cancer detected in the eighth decade of life.

We reviewed our experience with the management of men 70 to 79 years old with clinically localized prostate cancer to determine whether surgical candidates were likely to die of intercurrent disease soon after the disease was diagnosed. Of 101 men in the eighth decade of life who were surgical candidates by all criteria other than patient age 44 underwent radical prostatectomy, whereas 57 were managed by medical therapy including observation, radiation therapy and/or androgen deprivation. Five patients died in the surgical group at a median followup of 59 months, only 1 of whom died of intercurrent disease. Among 15 deaths in the medical group metastatic prostate cancer was the most common cause and all deaths from prostate cancer occurred more than 3 years after diagnosis. Survival for the surgical group was significantly better than that for the medical group during followup (p < 0.01 log-rank test). We conclude that men at our institution who underwent radical prostatectomy in the eighth decade of life did not frequently die of intercurrent disease, and experienced acceptable morbidity and mortality rates. We believe that men with localized prostate cancer should not be denied a radical operation based on age alone.

New approaches in the treatment of metastatic transitional-cell cancer of the bladder.

In recent years, chemotherapy of metastatic transitional-cell carcinoma of the bladder has advanced from the use of individual therapeutic agents, which has effected only rare responses, to the development of multi-agent regimens, which have greatly improved both partial and complete response rates, resulting in improved local care, palliation, and; perhaps, survival. However, because of the limited duration of response, frequent recurrences, and the significant proportion of patients with refractory disease, there have been only modest overall gains in long-term disease-free survival. These shortcomings have prompted investigation of alternative approaches to current combination chemotherapy regimens, including the use of hematopoietic growth factors and novel single-agent, multi-agent, and gene therapy protocols.

Ureteral entrapment in the sacroiliac joint in pelvic trauma.

We describe a case of unilateral entrapment of the ureter in the sacroiliac joint of a patient who sustained blunt abdominal trauma resulting in fractures of the public rami and sacroiliac joint and multiple bladder perforations. The entrapment was discovered intraoperatively and released by external traction and reduction of the pelvic fractures. No ureteric damage was observed, and reimplantation was not necessary. The importance of evaluating the upper tracts for potential injury in patients with fractures of the bony pelvis and concomitant bladder rupture is emphasized.

Improvement in organ blood flow by inhibition of thromboxane synthetase during experimental endotoxic shock in the rat.

Endotoxic shock is associated with increased metabolism of arachidonic acid to thromboxane (Tx) and prostaglandins. This investigation examined the effects of two structurally dissimilar inhibitors of (Tx) synthetase on Salmonella enteritidis endotoxin (LPS) (15 mg/kg)-induced alterations in cardiac output and organ blood flow in Long-Evans rats. An imidazole derivative, 7(1-imidazolyl) heptanoic acid (7-IHA), and sodium -(E)-3-[4-(3-pyridyl-methyl)phenyl]-2-methacrylate (OKY-1581) were injected intravenously at 30 and 5 mg/kg, respectively, 30 min before injection with endotoxin. Cardiovascular function was assessed 30 min post-LPS with Sr-85 labeled microspheres under light ether anesthesia. Injection of endotoxin caused a 60% decrease in cardiac output (34.0 +/- 2.7 ml/min/100 g body weight in control rats) and a 38.9% decrease in systolic arterial pressure. Both Tx synthetase inhibitors significantly (p less than 0.05) attenuated the decrease in cardiac output, although only 7-IHA improved blood pressure. Pretreatment with 7-IHA or OKY-1581 significantly (p less than 0.05) attenuated the LPS-induced decrease in renal perfusion. Lung nutrient blood flow (1.1 +/- 0.2 ml/min/g lung) decreased nearly 70% in shock. Both Tx synthetase inhibitors prevented this reduction. LPS shock resulted in approximately a 30% decrease in brain blood flow. 7-IHA significantly (p less than 0.05) improved flow, while OKY-1581 was without apparent effect. Splanchnic blood flow was likewise improved by 7-IHA and OKY-1581. Liver blood flow, 55% less than values of the control group in shock (p less than 0.05), was returned to values of the controls by both inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)

Genomic organization, expression of the human CBFA1 gene, and evidence for an alternative splicing event affecting protein function.

The Cbfa1 gene, which encodes the transcription factor Osf2/Cbfa1 required for osteoblast differentiation in mouse and human, is mutated in cleidocranial dysplasia, a skeletal dysplasia. We describe here the isolation of the full-length human OSF2/CBFA1 cDNAs, the genomic organization of the entire CBFA1 gene, its expression, and the existence of an alternative splicing event. Nucleotide sequence analysis of the human and mouse OSF2/CBFA1 cDNAs showed a 98% homology in the coding sequence and 96% in the 5' untranslated (UTR) sequence. Analysis of CBFA1 genomic clones revealed that the 5' UTR sequence of the human OSF2/CBFA1 cDNA lies 75 kb upstream of the originally described 5' end of the gene. The existence of two OSF2/CBFA1 cDNAs is due to an alternative splicing event around exon 8 that affects the transcriptional activity of the protein. Northern blot analysis demonstrates that the expression of the human OSF2/CBFA1 gene is restricted to osteoblastic cells.

Mitogenic response of osteoblast cells to prostate-specific antigen suggests an activation of latent TGF-beta and a proteolytic modulation of cell adhesion receptors.

During studies of mitogens in prostate, PSA quantities as low as 2.5 ng/mL caused cultured osteoblast cells to proliferate beyond controls (p = 0.05). Investigation of this novel mitogenicity suggested the use of several mechanisms by PSA, namely: 1) the activation of latent hTGF-beta in PC-3 conditioned medium, PSA treated conditioned medium stimulated DNA uptake in UMR-106 cells to 78% of acid treated conditioned medium, while DNA incorporation was less than controls with anti-hTGF-beta neutralizing IgG; and 2) the proteolytic modulation of cell surface receptors with temporary contact inhibition, PSA significantly stimulated cell detachment while hTGF-beta enhanced cell attachment of confluent Saos-2 cells above controls. Clinically, these results suggest that PSA may provide a mechanism for both tumor spread and the osteoblastic metastasis so common to prostate cancer.

Dissociation between bone resorption and bone formation in osteopenic transgenic mice.

Bone mass is maintained constant in vertebrates through bone remodeling (BR). BR is characterized by osteoclastic resorption of preexisting bone followed by de novo bone formation by osteoblasts. This sequence of events and the fact that bone mass remains constant in physiological situation lead to the assumption that resorption and formation are regulated by each other during BR. Recent evidence shows that cells of the osteoblastic lineage are involved in osteoclast differentiation. However, the existence of a functional link between the two activities, formation and resorption, has never been shown in vivo. To define the role of bone formation in the control of bone resorption, we generated an inducible osteoblast ablation mouse model. These mice developed a reversible osteopenia. Functional analyses showed that in the absence of bone formation, bone resorption continued to occur normally, leading to an osteoporosis of controllable severity, whose appearance could be prevented by an antiresorptive agent. This study establishes that bone formation and/or bone mass do not control the extent of bone resorption in vivo.

Prostate-specific antigenic domain of human prostate specific antigen identified with monoclonal antibodies.

With the use of five murine monoclonal antibodies (1A5, 2A4, 3F1, F5 and 3A12) and an antigen-affinity purified goat polyclonal IgG antibody, the presence of a prostate-specific antigenic domain in human prostate-specific antigen molecule was identified. The results were based upon a series of quantitative competitive inhibition assays of each 125I-labeled monoclonal antibody and polyclonal antibody binding to prostate-specific antigen by unlabeled monoclonal antibodies as inhibitors, and immunohistochemical examination of an extensive panel of human tissue specimens. A cluster of two epitopes that are spatially related or in close topographical proximity and represent a prostate-specific antigenic domain are defined by the monoclonal antibodies 1A5, 2A4, 3F1, and F5, 3A12, respectively.

Magnetic resonance imaging and magnetic resonance angiography before postchemotherapy retroperitoneal lymph node dissection.

OBJECTIVES: Retroperitoneal lymph node dissection (RPLND) after primary chemotherapy is an accepted therapeutic approach for metastatic nonseminomatous germ cell testicular cancer. Because of the intense desmoplastic reaction and adherence to venous and arterial walls, accurate imaging of the retroperitoneal vasculature and its relation to residual tumor is essential. We report our experience with magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), including the recently developed technique of bolus-contrast MRA, in patients undergoing postchemotherapy RPLND. METHODS: Eighteen patients underwent MRI of the retroperitoneal region before RPLND. In addition to routine sequences, MRA was performed in 10 patients, including 8 with a three-dimensional technique using bolus intravenous MR contrast. Results were compared with intraoperative and pathologic findings. RESULTS: MRI and MRA provided detailed information on retroperitoneal vasculature and its relation to tumor, including multiple renal vessels (n = 5), duplex inferior vena cava (n = 1), left retroaortic renal vein (n = 2), and common iliac vein thrombus (n = 1). In all cases, bolus-contrast MRA provided unique information on the location and number of renal and lumbar arteries, in addition to information on the aorta and the mesenteric and iliac vessels. The origin and number of renal arteries were accurately identified in all patients by bolus-contrast MRA; 2 patients had supernumerary renal arteries discovered at RPLND that had not been identified on non-bolus-contrast MRI. CONCLUSIONS: Bolus-contrast three-dimensional MRA provides unique information on renal and lumbar vessels. The potential benefit of avoiding vascular injury during dissection should be prospectively evaluated.

Combination chemotherapy for metastatic or locally advanced genitourinary squamous cell carcinoma: a phase II study of methotrexate, cisplatin and bleomycin.

PURPOSE: The prognosis of patients with advanced squamous cell carcinoma of genitourinary origin is poor. While single agent chemotherapy results mainly in partial responses of short duration, data on the efficacy of combination chemotherapy are extremely limited. We determined the response rate and toxicity of a combination of 3 of the most active agents, methotrexate, cisplatin and bleomycin, in patients with advanced genitourinary squamous cell carcinoma. MATERIALS AND METHODS: Patients with metastatic or locally advanced genitourinary squamous cell carcinoma were eligible for study. Treatment consisted of 200 mg./m.2 methotrexate on days 1, 15 and 22, and 20 mg./m.2 cisplatin and 10 mg./m.2 bleomycin on days 2 through 6 during a 28-day cycle. RESULTS: Of the 30 patients who enrolled in the trial 29 were evaluable for response. Objective response was achieved in 16 patients (55%, 95% confidence interval 36 to 72), 4 of whom achieved a complete response (14%). Median objective response duration was 4.7 months (range 1.9 to 39.5). Median survival of the entire group was 11.5 months (range 1.5 to 87.0). Of the patients 9 achieved disease-free status, including 6 following consolidation surgery or radiation therapy. Median survival of these 9 patients (34.4 months, range 9.6 to 87.0) was significantly greater (p = 0.0003) than that of patients who did not become disease-free (7.0 months, range 1.5 to 38.6). Grade III or IV hematological toxicity in 116 courses included neutropenia (13%) and thrombocytopenia (6%). Among 30 patients evaluable for toxicity serious nonhematological toxic effects included stomatitis (3%) and renal toxicity (7%). There was 1 death from neutropenic sepsis. CONCLUSIONS: Methotrexate, cisplatin and bleomycin combination chemotherapy for genitourinary squamous cell carcinoma results in a high but short lived overall response rate, and a low complete response rate with manageable toxicity. A multidisciplinary approach to achieve disease-free status may provide the best opportunity to effect survival and should be the focus of future trials.