Folic Acid Prophylaxis Research Articles

Anencephaly: A case report and the crucial role of folic acid supplementation and early diagnosis

Anencephaly is a congenital malformation caused by neural tube failure, which can be managed through folic acid intake during pregnancy. Diagnosis is typically prenatal, and termination of pregnancy is often recommended. A newborn born at Kolwezi paediatric clinic was born with a visible congenital malformation. The mother had a low socio-economic background and was 41 years old. An ultrasound scan revealed a progressing pregnancy at 30 weeks gestation with polyhydramnios. No antenatal care monitoring or folic acid prophylaxis was implemented during the periconceptional period and throughout the pregnancy. Anencephaly diagnosis was confirmed, and the newborn died five minutes post-birth. Preventive folic acid treatment has shown a decrease in neural tube defects, and first-trimester ultrasound scans can help identify life-incompatible congenital malformations. Advocating for legislative measures and genetic counselling is crucial to educate parents on recurrence risks and the advantages of folic acid supplementation before subsequent pregnancies.

Identification of immune-related biomarkers in embryos with neural tube defects via a bioinformatics analysis.

BackgroundNeural tube defects (NTDs) are one of the most common types of birth defects. Oral folic acid (FA) prophylaxis is currently available, but the pathogenesis of NTDs is not fully understood. We conducted this study to examine the role of the immune landscape of NTDs and identify novel diagnostic and therapeutic biomarkers.MethodsWe downloaded the GSE33111 data set of 12 NTD embryos and 12 healthy embryos in the same period of fetal development from the Gene Expression Omnibus (GEO) database. We compared the healthy embryos and NTD embryos to identify the differentially expressed genes (DEGs). We also performed a functional enrichment analysis of the DEGs using the clusterProfiler package. We extracted the top 10 ranked genes as hub immune-related biomarkers. We then used receiver operating characteristic (ROC) curves to determine the expression levels of the hub immune-related genes and the accuracy of the diagnosis of NTDs. Finally, we analyzed the immune landscape of the NTD embryos and healthy embryos via a single-sample gene set enrichment analysis (ssGSEA).ResultsA total of 611 DEGs were identified by the differential analysis, including 95 immune genes. The functional enrichment analysis indicated that Epstein-Barr virus infection, antigen processing and presentation, inflammatory bowel disease, and type I diabetes mellitus were associated with NTDs. The results of the expression level analysis showed that the hub immune-related genes were more highly expressed in the NTD embryos than the healthy embryos. Additionally, the ROC curve analysis also indicated that the expression levels of the 10 hub immune-related genes were highly accurate in the diagnosis of NTDs [area under the curve (AUC) range, 0.708–0.812]. The immune infiltration analysis demonstrated that 20 of the 28 immune cell types were more highly infiltrated in the NTD embryos than the healthy embryos.ConclusionsImmune-related genes are important regulators of the occurrence and development of NTDs.

Patient safety in the treatment of rheumatic diseases : Laboratory monitoring in methotrexate treatment

HintergrundMethotrexat (MTX) ist das das am häufigsten verordnete krankheitsmodifizierende Antirheumatikum. Ein regelmäßiges Labormonitoring wird empfohlen, um Nebenwirkungen wie Hepatotoxizität und Myelotoxizität sowie MTX-Toxizität-begünstigende Zustände wie eingeschränkte Nierenfunktion früh zu erkennen. Zudem wird eine prophylaktische Folsäuregabe empfohlen. Diese Arbeit untersucht, ob die empfohlene Kontrolluntersuchungen und Folsäureverordnungen während der MTX-Therapie durchgeführt werden.Material und MethodenAbrechnungsdaten der gesetzlichen Krankenkassen vom 01.01.2009 bis 31.12.2013 wurden analysiert. Aus der Forschungsdatenbank des InGef (Institut für angewandte Gesundheitsforschung Berlin, früher Health Risk Institute) wurden 40.087 Erwachsene mit einer kodierten rheumatischen Erkrankung (ICD-10-Codes M05–M18), ohne Karzinomdiagnose und ohne MTX-Verordnung ≥ 12 Monate vor Erstverordnung extrahiert. Es wurde analysiert, ob Laborkontrollen entsprechend den Handlungsempfehlungen, eine jährliche rheumatologische Betreuung sowie die Verordnung von Folsäure erfolgten.ErgebnisseEs begannen 12.451 Patienten eine neue MTX-Therapie im Beobachtungszeitraum. Das Blutbild, die Leberwerte und die Nierenfunktion wurden bei 42–46 % und der Urinstatus bei 14 % der Patienten wie empfohlen untersucht; 84 % befanden sich in regelmäßiger rheumatologischer Betreuung, und 74 % bekamen eine Folsäureprophylaxe. Möglicherweise MTX-assoziierte schwerwiegende Komplikationen wurden in 0,7 bis 3,5 Fällen/1000 Personenjahre beobachtet.DiskussionKontrolluntersuchungen bei MTX-Therapie werden seltener als empfohlen durchgeführt. Möglicherweise MTX-assoziierte Komplikationen sind aus der Praxisperspektive sehr selten. Einerseits sind Maßnahmen für die bessere Koordination der Kontrolluntersuchungen erforderlich. Andererseits müssen der Nutzen des Monitorings und die Abstände der Monitoringintervalle durch empirische Untersuchungen besser belegt werden.Zusatzmaterial onlineDie Online-Version dieses Beitrags (10.1007/s00393-021-00976-7) enthält eine Übersicht über die GOP-Ziffern und deren Bedeutung. Beitrag und Zusatzmaterial stehen Ihnen auf www.springermedizin.de zur Verfügung. Bitte geben Sie dort den Beitragstitel in die Suche ein, das Zusatzmaterial finden Sie beim Beitrag unter „Ergänzende Inhalte“.

Acute Thoracic Syndrome in Sickle Cell Children at the Pediatrics Department of Donka National Hospital

Introduction: Acute thoracic syndrome is the appearance of a new pulmonary infiltrate on radiology associated with fever, desaturation or respiratory signs. It is the second leading cause of hospitalization and the first cause of death in sickle cell patients. It is an acute pulmonary complication whose pathophysiological mechanisms are still poorly understood. This study aims to study the epidemiological, clinical, therapeutic and evolutionary aspects of Acute Chest Syndrome in children at the Pediatrics Department of Donka National Hospital. Method: This is a prospective study of descriptive type for a period of 6 months from February 19 to August 19, 2019 on patients with sickle cell disease who developed an ATS in the pediatrics department of Donka National Hospital. Epidemiological, clinical, therapeutic and evolutionary data were studied and proportionate data were calculated. Results: The frequency of ATS was 39%. The mean age of our patients was 9.83 years with the extremes of 4 and 16 years. The age group from 6 to 10 years with a frequency of 66.7% was the most affected. Fever was the main clinical manifestation, followed by hepatomegaly. All our patients were homozygous SS and undergoing folic acid prophylaxis. 96% of our patients did not receive any specific vaccine. Antibiotic therapy, hyperhydration and analgesics were administered to all our patients. 96% of our patients were transfused with red blood cell concentrate. 96% of our patients were transfused with packed red blood cells. 96% of our patients were transfused with packed red blood cells and 96% of them had a favorable outcome. Conclusion: ATS is an acute complication of sickle cell disease responsible for significant mortality and morbidity in the pediatric population. Its treatment is symptomatic and must be started early. Emphasis must be placed on prevention to prevent or limit its occurrence.

Risk factors for abdominal wall defects.

In the last decades, the prevalence of gastroschisis (GS) has increased worldwide. The purpose of this study was to identify maternal risk factors explaining the described gain and to identify differences between GS and omphalocele (OC). A case-control design was used to compare GS (n = 36) and OC (n = 18) mothers to control group (CG; n = 30) matched for maternal age. Specialized questionnaires and mothers' prenatal records were used, and participants completed a structured interview. Focus was on medical history, changing nutrition, drug consumption, and external risk factors. The local ethics committee approved this study. GS mothers were significantly younger (mean 23.00; median 24; SD ±5) than OC (P = 0.007; mean 28.61; median 28, 19-41; SD ±5.1) and CG (P = 0.001; mean 30.77; median 31, SD ±6.2). Mothers with abdominal wall defects (AWD) ingested antibiotics more often (P = 0.008) than CG. Socioeconomic characteristics, for example, level of profession, of GS mothers was significantly lower than OC (P = 0.039) and CG (P = 0.05) mothers, and their cohabitation time was shorter (P < 0.05; mean 35 month/median 24 month, SD ±35.8). Incidence of OC significantly increased after hormonal treatment (P = 0.022) and invasive prenatal diagnostics (P < 0.05) compared to GS. GS mothers took folic acid prophylaxis less often than OC (P = 0.02). Smoking, illicit drugs, and external risks like herbicides showed no influence, but GS mothers drink significantly more often alcohol (P = 0.05). We confirmed an increased risk for GS if several factors such as young maternal age, short cohabitation time, and usage of antibiotics coincide with alcohol consumption and associated immune diseases. OC increased after hormonal treatment and invasive prenatal diagnostics.

Treating Pediatric Hydrocephalus at the Neurosurgery Education and Development Institute: The Reality in the Zanzibar Archipelago, Tanzania

Pediatric hydrocephalus is a health burden for East African countries, with an estimated incidence of 6000 new cases per year. The objective of this study is to describe the epidemiology and surgical outcomes of patients treated for pediatric hydrocephalus in the single neurosurgical center of Zanzibar. From December 2016 to December 2017, we prospectively collected data on all patients admitted with the diagnosis of hydrocephalus. Information was gathered regarding demographics, maternal health, preoperative imaging, surgical procedures, and postsurgical complications. We collected data on 63 patients. Average age was 203 days, and gender was 49.2% female and 50.8% male. All mothers of patients attended an antenatal clinic for routine screening during pregnancy. Folic acid prophylaxis was used by 9.5% of the mothers during pregnancy. At the first visit, 46.0% of patients presented with signs of infection, 20.6% with congenital abnormalities, and 20.6% with seizures. Regarding etiology of hydrocephalus, 22.2% of all cases were uncertain; 20.6% were associated with neural tube defects; 39.7% were postinfectious hydrocephalus; 3.2% were aqueduct stenosis; 4.8% were associated with brain tumor; and 9.6% were malformative. We performed 7 endoscopic third ventriculostomies and placed 40 ventriculoperitoneal shunts. The complication rate at follow-up was 12.5%. It seems that hydrocephalus in Zanzibar has similar causes, progression, and complication rates to previous reports from other African hospitals. Further studies of postinfectious hydrocephalus need to be conducted because recent findings suggest that it is a potentially preventable cause of the disease.

Neural Tube Defects in Embryonic Life: Lessons Learned From 340 Early Pregnancy Failures.

The aim of this study was to evaluate the feasibility of sonographic assessment of the embryonic/fetal neural tube in nonviable pregnancies and to determine the defect incidence. Prospective analysis of transvaginally acquired 3-dimensional (3D) multiplanar and 3D surface-rendered volume sets of 340 cases of missed abortion between March 2010 and September 2015 was performed. Data regarding karyotype and postmortem examination as well as demographic features and the outcomes of subsequent pregnancies were evaluated. In 223 cases, an embryo/fetus was detected and considered suitable for further evaluation: in 37 of 223 (16.6%) embryos/fetuses, a neural tube defect was present: 27 of 37 cephaloceles, 5 of 37 anencephalies/exencepahlies, 3 of 37 spina bifidas, 1 of 37 caudal regression syndrome, and 1 of 37 iniencephaly. Additional alterations were not observed. In 7 of 37 cases karyotyping was carried out and showed no aneuploidy. Eight subsequent pregnancies had a favorable outcome, with 1 ending in an intrauterine fetal death during the 22nd week of gestation. Maternal folic acid supplementation was provided for all subsequent pregnancies. No neural tube defects occurred. Sonographic 3D evaluation of complete neural tube closure in embryonic/fetal demise is technically feasible and can be achieved in embryos with a crown-rump length greater than 8 mm. In 26 of 37 cases a defective closure site could be allocated to high-risk areas known for early embryonic demise. Regardless of the etiology of different neural tube defects, high-dose folic acid prophylaxis must be recommended in all cases. Sonographic evaluation of the neural tube, including 3D surface-rendered images, should be offered to every woman with a missed abortion because of the impact on subsequent pregnancies.

Orthopaedic Treatment for Patients with Myelomeningocele

Due to prenatal diagnostic and folic acid prophylaxis less children with myelomeningocele are now being born. But they become older and need increasingly more orthopaedic care. The orthopaedic care is aimed at the improvement or the preservation of function. In this review the current knowledge from the literature and our approach are presented. This is done in the context of the functional aspects within certain periods of life. Treatment Concept: In the first two years of life, the mobility of MMC children is supported by physiotherapy and orthoses irrespective of the level of the lesion. Afterwards, the optimal orthoses are chosen depending on the muscle power, emerging bone deformities, associated CNS malformation, shunt revisions, obesity and limitations in perception as well as the child's motivation. At school age, it is paramount to encourage independence. Orthotic treatment should be continued as long as the children benefit from it. Orthopaedic operations serve the orthosis fitting and the avoidance of pressure sores. Pathological fractures are common. They should be rapidly recognised in order to avoid further bony deformities. The aim of any orthopaedic treatment consists of the avoidance of musculoskeletal deformities in order to support the patient's self employment.

Anemia and Iron Deficiency in Pregnancy

Iron deficiency is still the world's most common nutritional deficiency, and generally, iron deficiency anemia is the most prevalent form of anemia. The major risk groups for iron deficiency include women of childbearing age, pregnant women, and lactating postpartum women. There exist plenty of studies attending and reconfirming this important issue. To combat this problem, different food iron fortification programmes have been implemented in some regions, iron supplementation guidelines have been elaborated in some countries, and iron therapy schemes involving both oral and intravenous administration have been proposed. But despite these efforts and the recommendations by the World Health Organization, the problem concerning iron deficiency and anemia is still unsolved in most parts of the world. Even in many industrialized countries, the topic of iron and pregnancy often stays unattended and there is a lack of consensus concerning guidelines in different countries. Other disorders, such as hemoglobinopathies, also contribute to the high prevalence of anemia worldwide. The prevalence of anemia is influenced by a variety of deficiencies (e.g., folate, vitamin B12, vitamin A, vitamin D, and vitamin C), infectious diseases, parasitic infestations, inflammatory diseases as well as malnutrition. As data for iron are quite profound, these are often scarce if we look on other vitamins and micronutrients, except for folic acid. As we know, periconceptional supplementation with folic acid has the potential to reduce the incidence of neural tube defects (e.g., spina bifida) dramatically. Unfortunately, folic acid prophylaxis is not commonly used for several reasons. By this special issue, our intention was to broaden the perspective on anemia in pregnancy and propose ways to solve the problems. We have chosen three articles concerning the prevention/treatment of iron deficiency anemia in pregnancy/postpartum including papers from Australia, Nigeria, and Denmark. Another Danish study focuses on the prevention of postpartum anemia through hemostatic sealing of the placental bed at caesarean section, thereby reducing perioperative blood losses. A paper from France and Lebanon evaluates the relationship between periconceptional folate deficiency and neural tube defects. A Chinese study addresses the supposed relationship between iron deficiency and postpartum depression. Together, these papers illustrate some of the many facets of the complexity of the prevention and treatment of anemia in pregnant and postpartum women. Alexander Krafft Laura Murray-Kolb Nils Milman

Final results of a randomized phase II trial of pemetrexed (P) + carboplatin (Cb) ± enzastaurin (E) versus docetaxel (D) + Cb as first-line treatment of patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC)

8037 Background: E is a selective, oral serine/threonine kinase inhibitor. The combination of PCb has shown clinical activity in two phase 2 trials of advanced NSCLC. A phase 3 trial among pts with stage IIIB/IV NSCLC showed that P + cisplatin provides similar efficacy with better tolerability than gemcitabine + cisplatin (Scagliotti, JCO, 2008). The toxicity profile observed with P + platinum doublets makes these regimens attractive for the integration of novel agents with different mechanisms of action. In the TAX 326 trial, D + cisplatin was associated with a median survival of 11.3 mos vs. 10.1 mos for vinorelbine + cisplatin (P=.04). The current open-label three- arm trial was designed to assess PCb ± E versus a control arm of DCb. Methods: Between 3/06 and 5/08, pts with stage IIIB (with pleural effusion) or IV NSCLC, ECOG PS of 0 or 1, and no prior systemic therapy were enrolled. Pts were equally randomized to 3 arms: (A) P 500 mg/m2 and Cb AUC 6 every 3 wks × 6 cycles with E given orally as a loading dose of 1200 mg or 1125 mg followed by 500 mg daily until disease progression; (B) The same regimen of PCb without E; or (C) D 75 mg/m2 and Cb AUC 6 every 3 wks × 6 cycles. Pts receiving P were administered folic acid, vitamin B12 and steroid prophylaxis. Pts on D also received steroid prophylaxis. Results: See table . Conclusions: First-line treatment with PCb was associated with a significantly longer overall survival than DCb in advanced or metastatic NSCLC. E did not add to the activity of the PCb doublet. PCbE, PCb, and DCb appeared to be well tolerated. Complete results for all patients in the study will be available at the time of the meeting. [Table: see text] [Table: see text]

A prospective evaluation of quality of life (QOL) in a phase II trial of pemetrexed (P) plus carboplatin (Cb) ± enzastaurin (E) versus docetaxel (D) plus Cb as first-line treatment of patients (pts) with advanced non-small cell lung cancer (NSCLC)

e19050 Background: E is a selective, oral serine/threonine kinase inhibitor. PCb has shown promising clinical activity in two phase 2 trials of advanced NSCLC. This open-label, three-arm trial was designed to assess PCb ± E versus a control arm of DCb. QOL may be an important consideration with the introduction of targeted agents such as E that have a different toxicity profile than traditional chemotherapeutic agents. Methods: Pts with Stage IIIB (with pleural effusion) or IV NSCLC, ECOG PS of 0 or 1, and no prior systemic therapy were enrolled. Pts were equally randomized to one of three arms: (A) P 500 mg/m2 and Cb AUC 6 every 3 wks X 6 cycles with E given orally as a loading dose of 1200 mg or 1125 mg followed by 500 mg daily until disease progression; (B) The same regimen of PCb without E; or (C) D 75 mg/m2 and Cb AUC 6 every 3 wks X 6 cycles. Pts receiving P were also administered folic acid, vitamin B12 and steroid prophylaxis. Pts on D also received steroid prophylaxis. The Functional Assessment of Cancer Therapy-Lung (FACT-L) Questionnaire and FACT-Taxane toxicity subscale were used to evaluate QOL at baseline and every 3 weeks up to 18 weeks during treatment. A best overall response of improved or worsened was defined as an increase or decrease from baseline to last patient visit of ≥ 0.5 standard deviations of baseline scores. Results: The intent-to-treat population of this study consisted of 218 randomized pts (PCE: 72, PC: 74, DC: 72). Baseline and ≥ 1 post-baseline score was obtained from 54 pts receiving PCE (75%), 62 pts receiving PC (84%), and 54 pts receiving DC (75%). QOL data are summarized in the table below. Conclusions: Across treatment groups, differences in mean scores were not statistically significant. In addition, differences in classification of improved, stable, or worsened were not statistically significant across treatment groups. [Table: see text] [Table: see text]

Schwangerschaft und Geburt bei Patientinnen mit Spina bifida

PURPOSE: In general fertility is not reduced in women with spina bifida. Hormonal contraception is more difficult, due to an increased risk of thrombosis in women with paraplegia. Thus pregnancies of women with spina bifida are possible. The literature does not provide any larger cohorts showing the evidence-based obstetrical management of such pregnancies. PATIENTS: We present five pregnancies in four women out of 180 patients of our spina bifida outpatient clinic. RESULTS: Only one of five pregnancies did not come to term and none of the five fetuses had a neural tube defect (appropriate folic acid prophylaxis was only taken in 3 pregnancies). The two mothers with shunted hydrocephalus experienced no complications with their shunting devices during pregnancy or labor. Urinary tract infections were a major problem only in one woman who had a single kidney and who had suffered from severe urinary tract infections before pregnancy. Intermittent catheterization was performed in three women during their pregnancies without complications. None of the women required antihypertensive drugs during pregnancy. All full-term newborns were born by cesarean section and experienced no peripartual problems. After birth the infants were cared for by their father (two children) or their grandparents. CONCLUSIONS: Before planning to become pregnant, genetic counseling should provide information on the risk of recurrence for neural tube defects (about 4 %). Folic acid prophylaxis was not taken regularly even in this high-risk group. The rate of abortions in pregnancies of mothers with spina bifida is not well documented in the literature due to a lack of larger cohorts. In our cohort the low rate of urological and shunt-related complications was remarkable. Care of pregnant women with spina bifida during pregnancy and labor must be given on an individual basis, because of the complexity of the problems (different mobility, the presence of a CSF-shunting valve, urological situation with neurogenic bladder and different methods of bladder emptying). Pregnancy and labor as well as postnatal care of the infant are new tasks for spina bifida outpatient clinics. New forms of cooperation with obstetrical departments will have to be established to solve the demanding medical and social problems.

Pemetrexed and carboplatin plus bevacizumab for advanced non-squamous non-small cell lung cancer (NSCLC): Preliminary results

7601 Background: Pemetrexed in combination with carboplatin has been shown to have promising activity and favorable toxicity profile in NSCLC. Bevacizumab has been shown to improve response rates and survival in pts with advanced non-squamous NSCLC when combined with carboplatin and paclitaxel. This study of pemetrexed and carboplatin plus bevacizumab was designed to evaluate the toxicity profile and to estimate the activity of the regimen in this pt population. Methods: Eligibility required that pts were chemotherapy-naive, had stage IIIB (effusion)/IV non-squamous NSCLC, PS 0–1, with no evidence of CNS metastases. Pts received pemetrexed 500 mg/m2 over 10 minutes, carboplatin AUC 6 over 30 minutes, and bevacizumab 15 mg/kg over 30–90 minutes on a 21-day cycle for 6 cycles. Pts with SD or PR received pemetrexed 500 mg/m2 and bevacizumab 15 mg/kg every 21 days until disease progression or toxicity. All pts received folic acid, vitamin B12 and steroid prophylaxis. Results: From 8/05 to 9/06, 39 pts (of planned 50) were enrolled: 20 M/19 F; median age 64 (range 41 - 80). One pt enrolled and subsequently refused treatment. Median number of cycles was 6 (range 1–22), and 25/38 (66%) completed at least 6 cycles of therapy. There was no grade 4 hematological toxicity. Grade 3 hematological toxicities were anemia (5%, N=2) and thrombocytopenia (3%, N=1). The most common grade 3/4 non-hematological toxicities included proteinuria (3%, N=1, gr 3), venous thrombosis (3%, N=1, gr 3), infection (3%, N=1, gr 4), and diverticulitis (11%: 8%, N=3, gr 3/3%, N=1, gr 4). 1 pt with diverticulitis experienced bowel perforation that required surgical intervention. The trial was temporally suspended and the group of pts with diverticulitis was analyzed separately. The only risk factor identified was previous history of diverticulitis. One CR, 20 PRs were observed for an overall response rate of 55% (95%, CI 43–75%). Conclusions: Treatment with pemetrexed and carboplatin plus bevacizumab in pts with advanced non-squamous NSCLC is feasible with an acceptable toxicity profile. The encouraging activity justifies further development of this regimen. However, pts with a prior history of diverticulitis should be excluded until this observation can be investigated further. No significant financial relationships to disclose.

Phase II trial of pemetrexed (P) and bevacizumab (B) in patients (pts) with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC): An interim analysis

6049 Background: P is a multi-targeted antifolate with single-agent activity in recurrent or metastatic HNSCC (RR 26%, Pivot et al. Br J Cancer 2001;85:649–55) and a preferable toxicity profile compared with cisplatin or the taxanes. B is a monoclonal antibody against the vascular endothelial growth factor that has been successfully incorporated in the treatment of other advanced solid tumors. Methods: Eligible pts had pathologically documented HNSCC, ECOG performance status 0–1, measurable disease, no history of bleeding diathesis or hemoptysis, and were not on anticoagulation. Pts had no prior systemic therapy for recurrent or metastatic HNSCC; chemotherapy as part of initial potentially curative therapy, but without P or B, was allowed if completed &gt;6 months earlier. Treatment consisted of P 500 mg/m2 and B 15 mg/Kg, both given intravenously every 21 days, until disease progression or intolerable toxicity. All patients received folic acid, vitamin B12, and corticosteroid prophylaxis. The primary endpoint was the time to progression (TTP) with a sample size of 40 pts (one stage design) with planned interim safety analysis after the first 6 and 12 pts. Results: 14 pts have been enrolled. Median age 64 years (35–84); male/female 13/1; PS 0/1: 7/7; prior chemotherapy: 8; primary site: oropharynx (7), larynx (4), oral cavity (3). Median number of cycles 5 (1–10). With a median follow up of 5.5 months, median TTP was 6 months (95% CI, 4–8). 11 pts were evaluable for response using RECIST. Best response was CR: 2, PR: 3, SD: 6, PD: 0, with ORR 45%. There were no grade 4 toxicities in 14 evaluable pts; 2 pts had grade 3 hemorrhagic events in the first cycle (1 tumor-related and 1 due to gastric ulcer post gastrostomy tube placement), and both discontinued treatment. 3 other pts had grade 1–2 hemorrhagic events. The relationship of these events to treatment was difficult to ascertain. Other grade 3 toxicities were stomatitis, dysphagia, and fatigue (all occurred in 1 pt). Conclusions: Preliminary results show that P plus B is a novel, highly active regimen that may represent a new treatment paradigm in HNSCC. However, bleeding complications were frequent in pts with susceptibility to such events. Study accrual continues. No significant financial relationships to disclose.

A phase II trial of pemetrexed (P) in patients (pts) with performance status (PS) 2 and 3 as first- and second-line treatment for advanced non-small cell lung cancer (NSCLC)

18149 P (Alimta) is approved as second-line therapy in pts with advanced NSCLC. In a phase III trial comparing P with docetaxel (D), median survival was 8.3 mos (P) vs 7.9 mos (D); P had a more favorable safety profile than D (Hanna, 2004). There are few data on pts with PS 3, and ASCO 2003 guidelines recommend that chemotherapy be reserved for pts with PS 0, 1 and possibly 2. Since P is well tolerated, PS3 pts may tolerate and benefit from it. In this trial, we treated 20 pts with stage IIIb/IV NSCLC and PS 2–3 who were chemo-naive or had received 1 prior regimen. Pts received P 500 mg/m2 IV D1 Q 3 wks. All pts received folic acid, vitamin B12 and dexamethasone prophylaxis. Serial blood samples were obtained to monitor inflammatory cytokines, and symptoms were monitored using the validated MDASI instrument. All pts were assessable for toxicity-symptoms, and 17 pts were evaluable for response (assessed after first cycle). Pt characteristics: 8 pts were PS 3 (4/8 first line) and 12 pts were PS 2 (6/12 first line). Median age was 69 for PS3 and 68 for PS2. 5/8 PS3 pts and 6/12 PS2 pts were men. 2/8 PS3 pts and 4/12 PS2 pts had stage IIIb. 4/8 PS3 pts and 6/12 PS2 pts were chemo-naive. Grade 3–4 toxicities for PS3/PS2 cohorts were: neutropenia 0/1 pt, anemia 1/2, fatigue 2/0, pneumonia 1/1, hypotension 1/1, neutropenic fever 0/1, atrial fibrillation 1/1. Response rates (RR) in PS3 pts were minor response (MR) 1/8, stable disease (SD) 5/8, progressive disease (PD) 2/8; RR in PS2 pts were partial response (PR) 1/12, MR 2/12, SD 3/12, PD 3/12, inevaluable 3/12. RR by line of therapy: first-line 6/10 SD, 2/10 PD, 2/10 inevaluable, and second-line, 1/10 PR, 2/10 MR, 3/10 SD, 3/10 PD, and 1/10 inevaluable. Reasons for PS3 pts coming off study were progression (4/8), constitutional toxicity (3/8), fatal pulmonary emboli (1/8); PS2 pts came off study due to progression (5/12), constitutional toxicity (2/12), and pneumonia (1/12). 4/12 PS2 pts are still on study. These preliminary data suggest that single-agent P is well-tolerated and has a promising RR in poor PS pts. Total planned accrual is 30 PS3 and 45 PS2 pts. Survival, symptom, cytokine data will be presented. [Table: see text]

Front line therapy with gemcitabine(G) administered immediately prior to pemetrexed (P) for patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC): Final report of a phase II clinical trial

7116 Background: P and G have well demonstrated, single-agent activity in pts with locally advanced or metastatic NSCLC. This phase II study was designed to determine the activity of the combination of PG when G was administered immediately prior to P on day 8 of a 21-day cycle. Methods: Pts with Stage IIIB/IV NSCLC were enrolled. Treatment was G 1250 mg/m2 on D 1 and 8, with P 500 mg/m2 on D 8, immediately following G. Treatment was repeated every 21 days for 6 cycles. Pts received folic acid, vitamin B12 and steroid prophylaxis. Results: 54 pts (32 M/22 F) were enrolled in the study. Median age was 65.0 (range = 43 - 87) years, ECOG PS 0: 1 = 35.2%: 57.4%; Stage IIIB (9.3%), Stage IV (90.7%); Histology: adeno (61.1%) squamous (18.5%), and large cell (5.6%). Median dose intensity was 83.2% for P and 82.2% for G. Grade 3 toxicities were neutropenia (12.0%), thrombocytopenia (8.0%), dyspnea (16.0%), febrile neutropenia (10.0%), anemia (4.0%), fatigue (18.0%), nausea (10.0%), vomiting (8.0%), and rash (2.0%). Grade 4 toxicities were neutropenia (28%), thrombocytopenia (4%), dyspnea (6%), anemia (0%), fatigue (4%), nausea (0%), vomiting (0%), rash (0%). Five patients (10%) experienced Grade 1 alopecia. Median TTPD was 4.4 months and survival was 10.6 months. There were 0 CR, 16 PR (35.6%), 16 SD (35.6%), and 12 PD (26.7%), for an overall best response rate of 35.6%. Conclusions: In this study, PG had a disease control rate (ORR + SD) of 71.1% in the front-line treatment of NSCLC, suggesting that this is an active doublet. Administering P on D 8 rather than D 1 did not seem to negatively impact the therapeutic index. [Table: see text]

A finalized phase II report of pemetrexed (P) plus gemcitabine (G) as front-line chemotherapy for patients with peritoneal mesothelioma (PM)

2050 Background: P in combination with cisplatin is approved for the treatment of malignant pleural mesothelioma. In an expanded access program, P ± cisplatin was shown to have activity in PM. P plus G are synergistic in preclinical models, but the activity of this combination in PM is unknown. The primary objective of this study was to determine time to disease progression in pts with PM receiving P plus G. Methods: Twenty pts were accrued. Treatment consisted of G 1250 mg/m2/30 minutes on D 1 and 8, and P 500mg/m2 /10 minutes on D 8, immediately before G. Treatment was repeated every 21 days for a total of 6 cycles or until progressive disease. All received folic acid, vitamin B12 and steroid prophylaxis. Results: Median age was 67.5 years (range: 46–79). Histology was epithelial:other = 14:6, M:F = 15:5, and ECOG PS 0:1:2 = 9:6:4. A total of 93 cycles (median 6) were administered. Patient-specific Grade 3/4 hematologic toxicity included neutropenia (60.0%), febrile neutopenia (10%; including one toxic death), anemia (5%), and thrombocytopenia (0%). Grade 3/4 nonhematologic events were fatigue (20.0%), constipation (10.0%), diarrhea (5.0%), peripheral neuropathy (5.0%), and dyspnea (5.0%). Median relative dose intensity was 94.5% for P and 82.9% for G respectively. Investigator-reported response rate was 15% (95% CI: 3.2–37.9%) with 1CR, 2PR, 7SD, 7PD, and 3 Unknown. Median time to progressive disease (MTTPD) and median survival (MS) were and 16.5 months (95% C: 6.6-TBD) and 19.1 months (95% CI: 6.6-TBD) respectively. Conclusions: P plus G is well tolerated in patients with PM. The clinical benefit rate (PR + SD) of 50%, MTTP and MS suggest that this non-platinum doublet can be a reasonable alternative to a platinum doublet in this disease. [Table: see text]

Initial results of a phase II study of biweekly pemetrexed and gemcitabine in patients with advanced NSCLC

7128 Background: Pemetrexed (P), a multi-targeted antifolate, is synergisitic with gemcitabine (G) in preclinical models. A phase I study examining a biweekly schedule established a recommended phase 2 dose of G 1500 mg/m2 followed by P 500mg/m2. Methods: Patients with Stage IIIB (with pleural effusion) or IV NSCLC, ECOG PS of 0 or 1, no prior systemic chemotherapy, immunotherapy, or biological therapy were enrolled. G was infused over 30 minutes, followed immediately by P given intravenously over 10 minutes once on day 1 every 14 days. Cycles were repeated until 12 treatments or progressive disease. All patients received folic acid, vitamin B12 and steroid prophylaxis. Results: Data on 53 patients (29 male, 24 female) are currently available. Median age: 64 (range: 35, 80), ECOG performance status 0:1 = 38%:60%, Stage IIIB:IV = 19%:81%. Three hundred twelve cycles of treatment were administered with 14 dose reductions (26.4%); median number of doses was 5 for both G and P, and median dose intensity was 98.05% for both G and P. Response data included 1 complete response (1.9%), 14 partial responses (26.4%), 24 stable diseases (45.3%), and 10 progressive diseases (18.9%), with a response rate of 28.3% (95% CI: 16.8–42.3%). Patient-based Grade 3/4 hematologic events included febrile neutropenia (9.4%), neutropenia (28.3%), and thrombocytopenia (1.9%). Grade 3/4 non-hematologic events included fatigue (22.6%), dyspnea (7.5%), dehydration (7.5%), diarrhea (5.7%), constipation (3.8%), and pneumonia (1.9%). Preliminary median survival was 7.8 months (95% CI: 6.0–10.8) with 43.4% patients censored and median TTPD was 4.6 months (95% CI: 2.8–6.1). Conclusion: Biweekly G and P appear to be well tolerated in advanced NSCLC. A clinical benefit rate (ORR + SD) of 73.6% indicates activity in patients with advanced NSCLC. The dose intensity for biweekly G and P is higher than a previously reported 6-cycle, 21-day regimen with median dose intensity of 83.2% for P and 82.2% for G (West, et al. Proc ASCO 2005; 7117). [Table: see text]

Pemetrexed and carboplatin plus bevacizumab as first-line therapy for advanced non-squamous non-small cell lung cancer: preliminary safety results of a phase II trial

17111 Background: Bevacizumab is a novel antiangiogenic agent that has been shown to improve response rates and survival of patients with advanced non-squamous NSCLC when added to paclitaxel and carboplatin. Pemetrexed is a multitargeted antimetabolite that has shown activity in NSCLC as a single agent and when combined with carboplatin. Because the combination of pemetrexed and carboplatin has activity comparable to that of other standard platinum doublets and promising toxicity profile (Zinner, 2005), the addition of bevacizumab to this regimen is investigated. Methods: This single cohort, phase 2 study evaluates the safety and efficacy of the combination of pemetrexed and carboplatin plus bevacizumab in patients with untreated non-squamous NSCLC. Eligibility requires ECOG performance status 0–1, Stage IIIB (malignant effusion) or Stage IV non- squamous NSCLC, no evidence of CNS metastases, no anticoagulation. Treatment consists of pemetrexed 500 mg/m2 over 10 minutes, carboplatin AUC 6 over 30 minutes, and bevacizumab 15 mg/kg over 30–90 minutes. Treatment is repeated every 21 days for 6 cycles. For patients who have either stable disease or partial response, pemetrexed 500 mg/m2 and bevacizumab 15 mg/kg are continued every 21 days until progression of disease or toxicity. All patients receive folic acid, vitamin B12 and steroid prophylaxis. Tumor response is assessed using RECIST every 2 cycles during treatment with carboplatin and then every 3 cycles during treatment with pemetrexed and bevacizumab alone. Results: From 8/2005 to 12/2005, 10 (of planned 50) patients with Stage IIIB and IV non-squamous NSCLC have been enrolled and treated. Patient characteristics are: median age: 65 (48–71), 20% female, 80% male, 30% stage IIIB, 70% stage IV. Median number of cycles delivered is 5 (range 1–9). No patient has discontinued therapy secondary to progressive disease or toxicity to date. 6 patients are evaluable for response: 1 PR, 1 minor response (24% reduction), 4 SD. No grade 3/4 toxicities have been experienced. Conclusions: This is a highly tolerable and active regimen with little toxicity to date. Updated response and toxicity data will be forthcoming. Supported by Genentech Inc and Lilly Pharmaceuticals. [Table: see text]

Unzureichende Umsetzung der perikonzeptionellen Folsäureeinnahme zur Prävention von Neuralrohrdefekten

Einleitung: Die Neuralrohrdefektprophylaxe durch eine Folsäuresupplementation ist als wissenschaftlich fundierte Möglichkeit zu sehen, einer der schwersten und häufigsten angeborenen Fehlbildungen vorzubeugen. Untersuchungen des Fehlbildungsmonitorings Sachsen-Anhalt haben bereits 1998 gezeigt, dass die Empfehlungen deutscher Fachgesellschaften zu einer perikonzeptionellen Folsäureeinnahme nur unzureichend von Frauen im gebärfähigen Alter umgesetzt wurden. Methoden: Um der Fragestellung nachzugehen, ob sich die Kenntnisse über Folsäure und die Einnahmepraxis im Jahr 2000 verbessert haben, wurde eine retrospektive Wöchnerinnenbefragung (n = 1224) durchgeführt. Ergebnisse: Die Empfehlungen zur Folsäureprophylaxe kannten zum Zeitpunkt der Befragung 67 % der Frauen und 64 % der Wöchnerinnen, die Folsäure während der Schwangerschaft eingenommen haben. Bereits präkonzeptionell haben 4 % der Befragten die Folsäureeinnahme begonnen und mindestens bis zur achten Schwangerschaftswoche fortgeführt. Schlussfolgerung: Die Ergebnisse der Untersuchung zeigten auch im Jahr 2000, dass sich die Empfehlungen zur perikonzeptionellen Folsäureprophylaxe bei Frauen im gebärfähigen Alter noch nicht ausreichend durchgesetzt haben.