Showing papers by "Gideon Koren published in 1996"

Chemotherapy With Focal Therapy Can Cure Intraocular Retinoblastoma Without Radiotherapy

Abstract: Background: External beam radiotherapy is standard treatment for medium and large, or visually threatening, intraocular retinoblastoma but markedly increases the risk of cosmetic deformities and second malignant neoplasms in children with germline RB1 mutations. Large tumors and those with vitreous seeds do poorly despite radiotherapy. Chemotherapy traditionally is ineffective for intraocular retinoblastoma, perhaps because many retinoblastomas overexpress the multidrug resistance protein, P-glycoprotein. Objective: To avoid radiotherapy in the management of intraocular retinoblastoma by using chemotherapy and focal therapy. Interventions: We shrank retinoblastomas in 40 eyes of 31 patients that conventionally should be enucleated or receive radiotherapy by using chemotherapy (ie, vincristine-teniposide, 8 eyes; additional carboplatin, 32 eyes) combined with the administration of cyclosporine, a known multidrug—resistance-reversal agent. We then consolidated these responses to chemotherapy by subsequent 532- and 1064-nm laser therapy and cryotherapy. Results: At the median follow-up of 2/8 years (range, 1/10-43/4 years), the results of treatment were excellent. The actuarial relapse-free rate was 89% in patients not previously treated (91% for 28 eyes) and 67% in patients treated after relapse from previous therapy (70% for 12 eyes). For the eyes with the worst prognosis (ie, vitreous seeds), the relapse-free rate was 88%, better than previously reported. Cyclosporine is nontoxic and did not enhance the expected toxic effects of chemotherapy. Most eyes required laser therapy, cryotherapy, or both for consolidation of tumor control. Conclusions: This pilot study suggests that most retinoblastomas are curable by combining chemotherapy with cyclosporine therapy, laser therapy, and cryotherapy, without requiring external beam radiotherapy. We propose a randomized trial to clarify the role of cyclosporine.

Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation.

Abstract: Chemotherapy without radiation has not controlled most intraocular retinoblastoma, perhaps because of the common high expression of multidrug resistance P-glycoprotein that we found in retinoblastoma. Cyclosporin blocks P-glycoprotein-induced efflux of vincristine and teniposide in vitro, and possibly modulates responses to carboplatin. To avoid eye irradiation in bilateral retinoblastoma patients with RB1 germline mutations, which incurs a high second malignancy rate, we added cyclosporin A to a vincristine-teniposide-carboplatin protocol and consolidated chemotherapy responses with focal therapy. We scored patients requiring irradiation, enucleation, or focal ablation of central vision as failures. In 21 study patients, the overall relapse-free rate at a median follow-up of 3.3 years was 76%, with a rate of 92% for newly diagnosed and 50% for previously treated, relapsed retinoblastoma. Our results for the most unfavorable tumors with vitreous seeds (86% at 3.5 years) are better than published success rates of irradiation for similar tumors, or irradiation with the same chemotherapy without cyclosporin (45% at 2. 6 years). These results also exceeded our historic success rate with similar chemotherapy without cyclosporin, focal therapy, and/or radiation in 19 equivalently poor-risk patients (relapse-free rate 37% at a median follow-up of 5.6 years, P = 0.032), 16 of whom were previously untreated (relapse-free rate also 37%, P = 0.012). A better outcome occurred with higher cyclosporin blood levels and projected tissue exposure. Cyclosporin did not enhance the usual chemotoxicity. This clinical study suggests that cyclosporin improves the long-term response of retinoblastoma to chemotherapy, possibly by more than one mechanism.

Excretion of fluoxetine and its metabolite, norfluoxetine, in human breast milk

Abstract: A study was conducted to measure breast milk concentrations of fluoxetine and its active metabolite, norfluoxetine, excreted in breast milk in a cohort of nursing women using fluoxetine, and to estimate infant dose from nursing. The study included 10 women nursing 11 infants (median age, 185 days). The mean fluoxetine dose was 0.39 mg/kg/day. Each patient manually collected 3 to 6 milk samples throughout a dosing interval. Concentrations of fluoxetine and norfluoxetine in milk were measured by gas-liquid chromatography. Mothers reported whether they observed adverse effects in their infants. The average infant doses of fluoxetine and norfluoxetine, as estimated for an exclusively breast-fed infant ingesting 1000 mL of milk per day, were 0.077 mg (SD = 0.054 mg) and 0.084 mg (SD = 0.043 mg), respectively. The total dose of fluoxetine and norfluoxetine (expressed as fluoxetine equivalents) was 0.165 mg (SD = 0.092 mg), which was equivalent to 10.8% (SD = 2.2%) of the maternal dose, adjusted on a mg/kg basis in a 4-kg infant. No adverse events were reported by mothers in their infants. Approximately one tenth of the adult therapeutic dose of fluoxetine is excreted in breast milk. Although short-term adverse effects in the infant from exposure through nursing were not reported in this cohort, future studies that assess the potential long-term consequences are needed.

Validation of Self-Reported Smoking by Analysis of Hair for Nicotine and Cotinine

Abstract: Evidence suggesting the use of self-reports as an index of systemic exposure to cigarette smoke in selected study populations is highly inaccurate. In order to assess the use of hair analysis as a biochemical marker of cigarette smoking, we compared measurements of nicotine and cotinine in the hair and plasma of 36 volunteers whose reports of smoking were deemed to be reliable. A significant correlation was observed between the number of cigarettes smoked and hair measurements of nicotine (r = 0.48, p = 0.004) and cotinine (r = 0.57, p = 0.0008). In addition, a good correlation was found between the reported number of cigarettes smoked and plasma nicotine, plasma cotinine, and carboxyhemoglobin levels. These results suggest that hair analysis is a reliable noninvasive method of determining human exposure to cigarette smoke and is comparable to blood analysis.

Safety of first trimester exposure to histamine H2 blockers. A prospective cohort study.

Abstract: The objective of this study was to examine whether H2 blockers represent a major teratogenic risk. This prospective cohort study was done at the Motherisk Program, a Teratology Information Service, Toronto, Canada. The subjects included 178 women who contacted Motherisk about gestational H2-blocker use, and 178 controls matched for maternal age, smoking, and heavy alcohol consumption. The main outcome measures were primary--major malformations, and secondary--pregnancy outcome, method of delivery, gestational age, prematurity, birthweight, small for gestational age infants, neonatal health problems, and developmental milestones. No increase in major malformations was found following first trimester exposure to H2 blockers [2.1% vs 3.5% (controls), mean difference (95% CI) -1.4% (-5.2, +2.4)]. No other aspects of pregnancy outcome or neonatal health differed between groups. This study suggests that H2-blocker exposure during the first trimester does not represent a major teratogenic risk.

Nicotine and cotinine in maternal and neonatal hair as markers of gestational smoking.

Abstract: Objectif : Etablir le degre d'exposition foetale a la fumee de cigarettes, qui ne peut etre extrapole avec certitude d'apres les seules donnees maternelles. Les auteurs ont donc mesure la concentration de nicotine et de cotinine dans les cheveux de meres et de leurs nouveau-nes et etudie les correlations entre ces mesures, les antecedents maternels et les mesures d'evaluation de la grossesse. Conception : Etude prospective de 94 paires de meres et de nouveau-nes. Contexte : Pouponniere de deux hopitaux de Toronto. Sujets : Quatre-vingt-treize meres avec tabagisme actif ou passif ou sans tabagisme, et leurs nouveau-nes (y compris un couple de jumeaux). Interventions : Les specimens de cheveux obtenus des meres et des nouveau-nes peu apres la naissance ont ete analyses par essai radio-immunologique. Principale mesure des resultats : Chez les meres, des donnees demographiques, l'anamnese obstetricale, les maladies, l'anamnese medicamenteuse et le tabagisme ont ete etudies. Chez les nouveau-nes, des donnees demographiques, l'âge de grossesse, le mode d'accouchement, le poids, la circonference de la tete, la longueur, la presence de meconium, les mesures de reanimation, les interventions speciales requises et les malformations congenitales ont ete analyses. Chez les meres et les nouveau-nes, la concentration en nicotine et cotinine dans les cheveux a ete mesuree. Resultats : Les nouveau-nes de meres avec tabagisme actif avaient plus de resultats defavorables que les autres nouveau-nes, y compris le faible poids a la naissance, une plus petite circonference de la tete, une longueur corporelle plus courte et un taux de complications perinatales plus eleve. Ces differences etaient significatives sur le plan statistique. Des differences significatives ont aussi ete observees quant a la concentration de cotinine extraite des cheveux des meres et des nouveau-nes selon qu'il s'agissait de sujets avec tabagisme actif ou passif ou de sujets non fumeurs. En presence de tabagisme maternel et chez d'autres membres de la famille, la concentration de nicotine et de cotinine dans les cheveux des nouveau-nes etait trois fois plus elevee que chez les nouveau-nes dont la mere etait la seule a fumer a la maison. Conclusions : La concentration de nicotine et de cotinine dans les cheveux est un fort marqueur biologique du degre d'exposition intra-uterine a la fumee de cigarettes.

ab-Plane Anisotropy of Transport Properties in Unidirectionally Twinned YBa2Cu3O7- delta Films.

Abstract: A unidirectionally twinned, {ital c} oriented YBa{sub 2}Cu{sub 3}O{sub 7{minus}{delta}} film was prepared on a (001) NdGaO{sub 3} substrate. In the normal state between 100 and 300K, the unidirectional twin plane lattice induces a strong anisotropy of {rho}{sub {ital ab}}, leading to a temperature independent ratio of 6 between the resisitivities across and along the twin boundaries. At 77K, the self-field critical current parallel to twin planes is 1.2{times}10{sup 6} A/cm{sup 2}, a value which is 25 times higher than along the perpendicular direction. This shows that, at this temperature, twin boundaries control the critical current values in YBCO films by either channeling or pinning effects. {copyright} {ital 1996 The American Physical Society.}

Outpatient Treatment of Croup With Nebulized Dexamethasone

Abstract: Purpose: To determine if treating children who have acute, moderate croup with nebulized dexamethasone sodium phosphate in the emergency department results in clinical improvement by 4 hours and a decrease in the hospitalization rate. Design: Randomized, double-blind, placebocontrolled trial. Setting: Emergency department, children's hospital. Patients: Fifty-five children with croup who were in moderate respiratory distress after treatment with mist for 30 minutes who met inclusion and exclusion criteria. Measurements: Croup score, respiratory rate, heart rate, and oxygen saturation were assessed by one of us (D.W.J. or S.S.) before treatment and 2 and 4 hours after treatment. A staff pediatrician or senior pediatric resident, also "blind" to treatment, decided on admission to or discharge from the hospital. The differences between groups for change in croup score and hospitalization rate after treatment were analyzed. Results: Evaluation of the croup scores disclosed a significant improvement in the dexamethasone-treated group compared with the placebo group at 4 hours (P=.005, Mann-WhitneyU). However, the hospitalization rate was not statistically different at the end of treatment (33% vs 52%,P=.28) or after 24 hours (48% vs 60%,P=.56, Yates corrected χ2). Our study has 80% power to detect a two-thirds reduction in hospitalization rate. Two patients with neutropenia treated with dexamethasone had a clinical course consistent with bacterial tracheitis. Conclusions: Treatment of moderate croup with nebulized dexamethasone results in clinical improvement within 4 hours. We did not show a decrease in hospitalization rates, although our sample size was only large enough to detect a 67% reduction in the rate of hospitalization. Given the infectious complications and the absence of evidence for a sustained clinical effect, we do not recommend that patients with croup be treated with nebulized dexamethasone. (Arch Pediatr Adolesc Med. 1996;150:349-355)

Hepatotoxicity of 6-mercaptopurine in childhood acute lymphocytic leukemia: pharmacokinetic characteristics.

Abstract: Treatment with 6-mercaptopurine (6MP) is associated with adverse gastrointestinal (GI) and hepatic effects. Four patients, ages 6.9 +/- 2.6 (mean +/- S.D.) years, with acute lymphocytic leukemia (ALL) on maintenance chemotherapy including 6MP, developed nausea, vomiting, abdominal pain, elevated liver enzymes, and hyperbilirubinemia after 1.4 +/- 1.0 (range 0.5-2) years. Liver biopsy in 1 patient was suggestive of drug-induced intrahepatic cholestatis. Symptoms resolved and liver function returned to normal after discontinuation of 6MP. Pharmacokinetic data of the symptomatic patients were compared with those of 25 ALL patients on the same protocol but without GI symptoms or hepatotoxicity. Levels of 6-thioguanine nucleotides (6-TGN) and the methylated metabolites of 6MP in red blood cells of the patients with hepatotoxicity, were not significantly different when compared to patients without hepatotoxicity, suggesting similar absorption of 6MP in both groups. Time to achieve peak 6MP levels was significantly longer in the symptomatic patients compared to the asymptomatic patients (P = 0.005). Peak levels and standardized concentration versus time curve (AUC) per 1 mg of 6MP per m2 of body surface area were significantly lower in the patients with hepatotoxicity (P = 0.016; P = 0.037, respectively). A significant correlation between peak 6MP levels and standardized AUC (r = 0.729, P < 0.0001) was found. These results suggest accumulation of 6MP and its metabolites in the liver of the patients with GI symptoms, leading to hepatotoxicity.

Microwave power dependence of yba2cu3o7 thin-film josephson edge junctions

Abstract: Using a stripline resonator technique, we measured the dependence on microwave current of the impedance of fabricated superconductor/normal‐metal/superconductor Josephson junctions in YBa2Cu3O7 thin films. The results are compared with predictions of a resistively shunted junction model that yields good agreement at low and intermediate values of the microwave current. At high currents deviations from the model predictions are observed, which we propose are due to flux penetration into the junction. The results are consistent with previously proposed explanations of the rf power dependence of the high‐Tc materials.

The safety of astemizole in pregnancy

Abstract: Since the introduction of nonsedating selective H1 antagonists, they have been largely used by women of reproductive age for the treatment of seasonal allergic rhinitis, conjunctivitis, chronic urticaria, and other allergic conditions. However, because of tack of human studies on the reproductive safety of these compounds, their manufacturers either cannot support their use in pregnancy, through the product monographs, 1 or label them as relatively safe even when no data exist to support such statements. The issue of documenting pregnancy outcome after exposure to new drugs is even more complex if one considers that over 50% of all pregnancies are unplanned, and therefore it may not be sufficient to advise women "not to use a compound in pregnancy." Astemizole is a potent long-acting selective H1 blocker antihistamine, which does not produce the typical central nervous system depression and drowsiness. In animal studies, doses that were 200to 800-fold the recommended human dose per kilogram did not induce teratogenic effects? We report on the first prospective, controlled, observational study of women who took astemizole during the first trimester of pregnancy and their offspring.

The pharmacokinetics of extended release felodipine in children

Abstract: Felodipine ER (extended release), a dihydropyridine calcium channel blocker, effectively lowers elevated blood pressure in adults [I] and children [2]. Once a day dosing, reduced fluctuation in plasma concentration, and improved compliance with felodipine ER would be beneficial in the treatment of hypertension in childhood. However, no kinetic data are available in the pediatric age group to guide the dosing regimen. To that end we studied felodipine ER steady state pharmacokinetics in children.

Efficacy of Deferiprone in the Treatment of Acute Iron Intoxication in Rats

Abstract: Background: Deferiprone [(1,2-dimethyl-3-hydroxypyrid-4-one) (L1)], is the first orally active iron chelating agent to reach clinical trials in patients with chronic iron overload. Its efficacy in preventing morbidity and mortality in acute iron poisoning has not been tested. Objective: To determine whether deferiprone can reduce the mortality of rats following toxic oral doses of iron. Methods: Rats were administered 612 mg/kg elemental iron by gavage, corresponding to the LDS8. A parallel group received the same oral dose of iron followed by deferiprone intraperitoneally at 400 mg/kg (loading dose), followed by additional intraperitoneal injections of 200 mg/kg, 100 mg/kg and 100 mg/kg of deferiprone at one hour intervals. Results: Coadministering deferiprone with the iron decreased mortality from 58% (11/19) to 15% (3/20) (p = 0.013). The administration of deferiprone was associated with urinary excretion of iron (which did not occur with iron alone) and the production of the red deferiprone-iron compl...

Folic acid and prevention of neural tube defects: a study of Canadian mothers of infants with spina bifida.

Abstract: Objectifs : Determiner le degre de propagation de l'information au sujet de la prevention des defauts de developpement du tube neural a l'aide de la consommation d'acide folique. L'etude a porte sur les meres d'enfants canadiens atteints a la naissance de spina-bifida, et qui sont devenues enceintes au moins 1 annee apres que l'effet preventif de l'acide folique sur le spina-bifida ait ete rendu public. L'etude avait pour objectif de determiner si ces meres connaissaient cette importante nouvelle et si elles avaient ingere suffisamment d'acide folique durant la periode entourant la conception. Conception : Un questionnaire alimentaire valide afin d'evaluer l'ingestion de folate. Contexte : L'Hopital des enfants malades, a Toronto, entre le 4 janv. et le 16 aout 1994. Sujets : Trente meres d'enfants sous traitement pour spina-bifida. Mesures des resultats : L'ingestion maternelle moyenne en folate, la connaissance des effets protecteurs de l'acide folique, ainsi que des informations demographiques et sur la sante. Resultats : L'ingestion maternelle moyenne en folate etait de 0,182 mg/jour (ecart type 0,076 mg/jour, fourchette 0,02 a 0,53 mg/jour), correspondant a moins de 50 % de la dose protectrice. Au moment de la conception, quatre (13 %) meres seulement connaissaient la relation entre l'etat nutritionnel en folate et les problemes de developpement du tube neural. Malgre cela, leur ingestion en acide folique s'avera insuffisante. En plus de demontrer l'echec des mesures de prevention primaire des defauts de developpement du tube neural, les donnees indiquent que les mesures de prevention secondaire a l'aide de tests diagnostiques durant la grossesse etaient insuffisantes. Conclusions : Dans un pays parmi les plus avances au monde, les nouvelles informations au sujet de la prevention des defauts de developpement du tube neural n'ont pas influence l'ingestion maternelle en folate. A moins que les aliments ne soient fortifies en folate, il ne sera pas possible de prevenir les defauts de developpement du tube neural survenant chez environ 400 a 800 enfants chaque annee au Canada.

Origin of the irreversibility line in thin YBa2Cu3O7- delta films with and without columnar defects.

Abstract: We report on measurements of the angular dependence of the irreversibility temperature {ital T}{sub irr}({theta}) in YBa{sub 2}Cu{sub 3}O{sub 7{minus}{delta}} thin films, defined by the onset of a third-harmonic signal and measured by a miniature Hall probe. From the functional form of {ital T}{sub irr}({theta}) we conclude that the origin of the irreversibility line in unirradiated films is a dynamic crossover from an unpinned to a pinned vortex liquid. In irradiated films the irreversibility temperature is determined by the trapping angle. {copyright} {ital 1996 The American Physical Society.}

The pharmacokinetics and pharmacodynamics of the oral iron chelator deferiprone (L1) in relation to hemoglobin levels.

Abstract: Recently, we demonstrated that administration of the orally active iron chelating agent deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one (L1)) at 6-hour intervals results in significantly greater urinary iron excretion than that induced during administration of the drug at 12-hour intervals. That study was conducted in thalassemia patients, all of whom had received a packed red cell transfusion of 15 cc/kg. 72 hours prior to evaluation of urinary iron excretion, at a time when endogenous erythropoiesis would be expected to be at its lowest. In clinical practice however, thalassemia patients, suppression of endogenous erythropoiesis is not sustained between transfusions. We set out to determine the influence that administration of deferiprone has on urinary iron excretion at lower hemoglobin concentrations, immediately prior to transfusion. We hypothesized that hemoglobin levels will affect the ability of deferiprone to chelate iron. Ten regularly transfused patients with homozygous beta-thalassemia (HBT) aged mean +/- SD, 20.9 +/- 4.7, range 13 - 27 years, receiving long-term therapy with deferiprone, were treated with deferiprone 75 mg/kg/day, administered every 6 hours (or every 12 hours) for 72 hours immediately prior to a blood transfusion in the first month. One month later each patient received the other of the 2 dosing regimens for 72 hours immediately prior to transfusion. The deferiprone-induced 24-hour urinary iron excretion was similar during both dosing regimens; 0.56 +/- 0.45 mg/kg when L1 was given every 6 hours and 0.48 +/- 0.52 mg/kg when L1 was administered every 12 hours (p = 0.79). However, the calculated 24-hour area under the plasma concentration-time curve (AUC0-24) of deferiprone was significantly lower when deferiprone was administered at 6-hour intervals (6,762.8 +/- 1,601.6 mg*min/l), than that observed when deferiprone was administered every 12 hours (8,250.1 +/- 1,235.7 mg*min/l) (p = 0.04). The pharmacokinetics of deferiprone when administered immediately prior to transfusions are different from those following transfusions. More studies assessing total body iron excretion are needed to determine the contribution of the fecal route in iron excretion.

Oxygen-controlled transition from tunnel-like to a weak-link behavior in YBa2Cu3O7−δ/YBa2CoCu2Oy/YBa2Cu3O7−δ wedge-edge junctions

Abstract: Differential conductance measurements in YBa 2 Cu 3 O 7−δ /YBa 2 CoCu 2 O y /YBa 2 Cu 3 O 7−δ (YBCO/YBCoCO/YBCO) wedge-edge junctions are reported on. The properties of the junctions change dramatically with the oxygen concentration in the films. Junctions prepared in an oxygen-deficient atmosphere show differential conductance which increases with the bias voltage. This behavior is typical of high- T c tunnel junctions. In contrast, junctions prepared with fully oxygenated films show weak-link behavior where the differential conductance decreases with the bias voltage. In the tunnel-like type junctions a series of peaks is observed in the differential conductance versus voltage. We identify these peaks as due to Tomasch oscillations in the cover electrode along the c direction, yielding Δ c = 2.1 mV and a renormalized Fermi velocity v ′ F c = 2.4 × 10 7 cm/s.

Neurodevelopment of children exposed to fluoxetine(FL) in utero: A prospective longitudinal study

Abstract: Clinical Pharmacology & Therapeutics (1996) 59, 159–159; doi:10.1038/sj.clpt.1996.134

Fluoxetine Distribution in Human Milk

Abstract: To the Editor: The recent paper of Taddio et all presents some interesting data on the distribution of fluoxetine and norfluoxetine into human milk. They calculated that a 4-kg infant would be exposed to a mean of 10.8% (range, 6.3-13.9% as fluoxetine equivalents on a mg/kg basis] of the maternal dose. Calculation of infant exposure requires an accurate knowledge of the concentration of drug in the milk at steady-state (usually milkplasma ratio x concentration of drug in maternal plasma) and of the volume of milk consumed by the infant per day. Although Taddio et al had robust data on the milk concentrations of fluoxetine and norfluoxetine, their use of a mean intake of 1 L of milk/ day is too simplistic and unjustified. An extensive data set reported by Allen et a12 shows that milk production over the first 180 days of lactation varies from about 0.7-0.8 L/day, and is related to infant age. A more reliable approach is to use the widely accepted figure of 0.15 L/kg/day3 for infant milk intake. A 4-kg infant would thus consume 0.6 L of milk/day and could potentially absorb a mean of 0.10 mg of fluoxetine equivalentdday. This equates to 0.025 mg/kg/day, or 6.4% of the mean maternal intake of 0.39 mg/kg/day. Thus, in our view Taddio et a1 have grossly overestimated the calculated dose. Previously reported data for fluoxetine distribution in human milk are sparse and the data often less than optimal. Nevertheless, the dose calculations in a case reported by Burch and Wells4 gives an infant exposure of 3.4% of the weight-adjusted maternal dose, while similar calculations in the case reported by Isenberg5 gives an infant exposure of 3.3% of the weight-adjusted maternal dose (as fluoxetine equivalents). However, in both cases maternal body weight was not reported, and we have had to assume a value of 60 kg in the calculation. Although these data are lower than those calculated from Taddio's study, it is very clear that all such calculations are unreliable unless a full data set (with appropriately timed samples] is available and standard accepted milk intake values are used. In addition, exposure calculated in this way needs to be evaluated in light of infant drug clearance, which is likely to range from approximately 10% of the weight-adjusted maternal clearance for a very premature neonate to 33% at the normal 40 weeks gestation, and increasing to 100% at about 6 months of age.fi Thus, for very young infants fluoxetine exposure may be much larger than any of the above calculations suggest. Although most r epor t~ '*~*~ suggest that infants of mothers taking fluoxetine progress well and have no obvious drug-related problems, this is notoriously difficult to measure and there is one well-documented case of colic.' It should also be noted the in utero exposure to fluoxetine is likely to be an order of magnitude greater than post-birth exposure via milk, and a withdrawal syndrome has been reported in one infant.* We suggest that there is a need for more detailed and better designed studies of the distribution of fluoxetine and norfluoxetine and for recognition of the likelihood that symptoms in very young infants may sometimes result in part from in utero drug exposure.

Cancer in Pregnancy: Maternal and Fetal Risks: Fetal outcome following in utero exposure to cancer chemotherapy: the Toronto Study

Abstract: Cancer is the second leading cause of death among women during the reproductive years Its occurrence during pregnancy is rare with an incidence of 007% to 01% Over the years, significant advances have been made with current chemotherapeutic agents in increasing longevity and improving survival Cures and long-term remissions are obtained in diseases that previously were untreatable Oncologists, therefore, may be posed with a difficult challenge when a patient requires chemotherapy during pregnancy or becomes pregnant during the course of chemotherapy Although there are a variety of studies on the effects of chemotherapy during pregnancy on the fetus, review of the literature reveals that most reports are based on single cases cohorts with small sample sizes and cohorts that supply incomplete evaluation of the offspring Due to the rarity of chemotherapy use in pregnancy, it is unlikely that prospective studies will be undertaken We therefore performed an historical cohort study to evaluate the effects of chemotherapy during pregnancy on fetal outcome, among women treated in the Princess Margaret Hospital (PMH) in Toronto between 1958 and 1947 We hypothesized that babies exposed to chemotherapeutic agents during the first trimester, when organogenesis takes place, may be more likely to suffer from major malformations than babies not exposed to chemotherapy or those exposed at subsequent trimesters In addition, we hypothesized that suboptimal conditions in women with cancer receiving chemotherapy may increase the risk for spontaneous abortions, stillbirth, and lower birthweight for gestational age Methods Cases with cancer in pregnancy who received chemotherapy while pregnant were extracted from the Princess Margaret Hospital's data base