Final safety and efficacy results from the CPX-351 early access program for older patients with high-risk or secondary acute myeloid leukemia.

CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic 5:1 molar drug ratio, achieved superior efficacy compared with conventional chemotherapy in older adults with newly diagnosed, high-risk/secondary acute myeloid leukemia (AML) in phase 2 and 3 studies. Prior to CPX-351 commercialization, an expanded access program (EAP) provided CPX-351 access for this population in the United States. In this phase 4, single-arm, open-label study (NCT02533115), 52 patients were treated with CPX-351 for 1-2 induction cycles and ≤4 consolidation cycles. The primary endpoint was safety. The most common serious adverse events were febrile neutropenia (19%), pneumonia (10%), and infection (8%). The 30- and 60-d mortality rates were 0% and 6%, respectively. Remission was achieved by 44% of patients; 90% of patients were alive at study completion. Overall, these results support outcomes from prior studies and the use of CPX-351 in older adults with newly diagnosed, high-risk/secondary AML.

Computer-assisted analysis in organic synthesis.

The planning of alternative routes for the synthesis of complex organic molecules has been facilitated by the formulation of guiding strategies that can be applied to a broad range of problems. Analysis of organic synthesis can be carried out in the retrosynthetic direction, opposite to the actual process of chemical synthesis, or bidirectionally, that is, as a combined retrosynthetic and synthetic search. An interactive computer program is described which utilizes the general strategies of retrosynthetic analysis and an appropriate database to generate pathways of chemical intermediates for chemical synthesis of a particular target structure. Computer graphics and standard chemical structures are used for man-machine communication.

Cytochrome P450-catalyzed hydroxylation of taxa-4(5),11(12)-diene to taxa-4(20),11(12)-dien-5alpha-ol: the first oxygenation step in taxol biosynthesis.

BACKGROUND: The structural complexity of taxol dictates continued reliance on biological production methods, which may be improved by a detailed understanding of taxol biosynthesis, especially the rate-limiting steps. The biosynthesis of taxol involves the cyclization of the common isoprenoid intermediate geranylgeranyl diphosphate to taxa-4(5), 11(2)-diene followed by extensive, largely oxidative, modification of this diterpene olefin. We set out to define the first oxygenation step in taxol biosynthesis. RESULTS: Microsomal enzymes from Taxus stem and cultured cells were used to define the first hydroxylation of taxadiene. We confirmed the structure of the reaction product (taxa-4(20), 11(12)-dien-5alpha-ol) by synthesizing this compound. The responsible biological catalyst was characterized as a cytochrome P450 (heme thiolate protein). In vivo studies confirmed that taxadienol is a biosynthetic intermediate and indicated that the hydroxylation step that produces this product is slow relative to subsequent metabolic transformations. CONCLUSIONS: The structure of the first oxygenated intermediate on the taxol pathway establishes that the hydroxylation reaction proceeds with an unusual double bond migration that limits the mechanistic possibilities for subsequent elaboration of the oxetane moiety of taxol. The reaction is catalyzed by a cytochrome P450, suggesting that the seven remaining oxygenation steps in taxol biosynthesis may involve similar catalysts. Because the first oxygenation step is slow relative to subsequent metabolic transformations, it may be possible to speed taxol biosynthesis by isolating and manipulating the gene for the taxadiene-5-hydroxylase that catalyzes this reaction.

Mycotic aortic aneurysm. A complication of Campylobacter fetus septicemia.

The first surviving case, to our knowledge, of a Campylobacter fetus mycotic aortic aneurysm is reported. Bacteremia and an ileofemoral thrombophlebitis preceded the development of the infected aneurysm, reconfirming the vascular tropism of this organism. The clinical similarity with infections caused by Salmonella choleraesuis is illustrated by this case. The full recovery of our patient attests to the efficacy of extralanatomic bypass combined with long-term antibiotic therapy in the treatment of aortic mycotic aneurysm. Because of frequent changes in nomenclature and insufficient emphasis on speciation of the various campylobacters, pathogenesis and optimal antimicrobial therapy for systemic C fetus infections have not yet been adequately defined.

Pulsed Doppler echocardiography: principles and applications.

A new recording and display system is described for use with pulsed Doppler blood flow velocity detectors in the diagnosis of valvular and septal defects. The principles of the pulsed Doppler device are described along with the methods used to analyze and display the Doppler shifted signal from flow jets resulting from various valve defects. An M-mode display is combined with blood flow display to provide a convenient record of the clinical procedure. Examples of aortic stenosis, aortic insufficiency, mitral stenosis and regurgitation are presented along with signals from other valves.

Hydrophilic, pro-drug analogues of T138067 are efficacious in controlling tumor growth in vivo and show a decreased ability to cross the blood brain barrier.

The novel anticancer compound T138067 is an irreversible inhibitor of tubulin polymerization. Amides 3-6 were synthesized using standard methodologies and determined to be significantly less lipophilic than T138067 based on logP calculations. Tubulin polymerization and [(3)H]-T138067 competition assays revealed that these amides are pro-drugs for parent aniline 2. Amides 3-5 showed no detectable signs of crossing the blood brain barrier, while amide 6 was found in extremely small amounts (12 ng/g of brain tissue). Aniline 2, which was formed in vivo from these amides, was found in significantly smaller amounts (approximately 20 to >5000 times) in the brain than when 2 was administered directly. The in vivo efficacy of amide 6 approached that of T138067 and was better tolerated when administered to athymic nude mice bearing MX-1 human mammary tumor xenografts.

Inadvertent administration of positive end-distending pressure during nasal cannula flow.

In the clinical setting, nasal cannulas are frequently used to deliver supplemental oxygen to neonates and are not believed to affect the general respiratory status. In contrast, it was hypothesized that clinical changes associated with nasal cannula gas flow may be related in part to the generation of positive end-distending pressure. To test this hypothesis, alterations in esophageal pressure were quantified as an indication of end-distending pressure and thoracoabdominal motion was quantified as an indication of breathing patterns in 13 preterm infants at gas flow levels of 0.5, 1, and 2 L/min delivered by nasal cannula with an outer diameter of either 0.2 or 0.3 cm. Changes in esophageal pressure were assessed by esophageal balloon manometry. Ventilatory patterns were assessed from thoracoabdominal motion by using respiratory inductive plethysmography. Thoracoabdominal motion was quantitated as a phase angle (theta); larger values represent greater asynchrony. The 0.2-cm nasal cannula did not deliver pressure or alter thoracoabdominal motion at any flow. In contrast, the 0.3-cm nasal cannula delivered positive end-distending pressure as a function of increasing levels of gas flow (r = .92) and reduced thoracoabdominal motion asynchrony. The mean pressure generated at 2 L/min was 9.8 cm H2O. These data demonstrate that nasal cannula gas flow can deliver positive end-distending pressure to infants and significantly alter their breathing strategy. This finding raises important concerns about the indiscriminate therapeutic use, size selection, and safety of nasal cannulas for the routine delivery of oxygen in preterm infants.

Risks of coronary arteriography and bypass surgery in patients with left main coronary artery stenosis.

The risk of coronary arteriography is considerably increased in patients who have left main coronary artery stenosis (LMCAS). Among 1,060 patients undergoing coronary arteriography over a three-year period, 83 were found to have LMCAS and three of these patients died (3.6 percent) during or shortly after the arteriographic procedure. Bypass surgery, however, can now be carried out at a very low risk irrespective of the degree of coronary disease present--there was no hospital mortality in 74 patients with LMCAS undergoing bypass surgery at our institution during this period. In addition to careful attention to detail, techniques that can minimize the risk of both of these procedures in patients with LMCAS include invasive hemodynamic monitoring and various pharmacologic manipulations to prevent myocardial ischemia. In a small percentage of patients, rest angina may prove refractory to inhospital medical treatment, and intraaortic balloon pumping may be necessary to stabilize the conditions of these patients before proceeding with arteriography and myocardial revascularization.

Coexisting hypertrophic heart disease and mitral valve prolapse. A continuum of hereditary cardiac disease?

The finding at autopsy of typical pathologic features of hypertrophic heart disease (idiopathic hypertrophic subaortic stenosis, IHSS) and mitral valve prolapse (MVP) in a single patient prompted study of a number of close relatives of this patient. Several additional cases of IHSS or MVP were found. The HLA typing of this kindred revealed that four out of seven members tested had the Bw 35 antigen. Although the association might be due to chance, this kindred, together with prior reports of similar bizarre myocardial cellular disarray in HISS and MVP, suggest the hypothesis that in some instances, IHSS and MVP may represent a continuum of hereditary cardiac disorders.

Congestive heart failure and absent femoral pulses in newborns without coarctation of the aorta.

Two infants with thrombosis of the abdominal aorta are discussed. In each case the presentation was indistinguishable from that in coarctation of the aorta, with heart failure and absent femoral pulses. Surgery in one infant successfully relieved the obstruction. The diagnosis may not be suspected from the history. Aggressive management is indicated.

Comparison of gas and liquid ventilation: clinical, physiological, and histological correlates.

To differentiate the effects of gas and liquid ventilation on cardiopulmonary function during early development, we compared the clinical, physiological, and histological profiles of gas- and liquid-ventilated preterm lambs (n = 16; 108-116 days gestation). Immediately after cesarean section delivery, ventilation commenced using gas delivered by a volume ventilator (n = 9) or liquid perfluorochemical (n = 7) delivered by a mechanically assisted liquid ventilation system. Pulmonary gas exchange, acid-base status, vital signs, and respiratory compliance were assessed during the 3-h protocol; sections of the lungs were obtained for histological analyses when the animals were killed. Six of nine gas-ventilated lambs expired from respiratory failure before 3 h, with the remaining animals experiencing severe respiratory insufficiency, pneumothoraces, and cardiovascular deterioration. Six of seven liquid-ventilated lambs survived with good gas exchange and cardiovascular stability and without fluorothorax; one experienced ventricular fibrillation before 1 h and expired despite pulmonary stability. Respiratory compliance was significantly greater in the liquid- than in the gas-ventilated lambs. Histological analyses of gas-ventilated lungs demonstrated nonhomogeneous lung expansion, with thick-walled gas exchange spaces containing proteinaceous exudate, hemorrhage, and hyaline membranes. In contrast, liquid-ventilated lungs appeared clear, with thin-walled and uniformly expanded gas exchange spaces that were free of hyaline membranes and luminal debris. Morphometric analyses demonstrated that surface area and gas exchange index were greater in the liquid- than in the gas-ventilated lambs. These results indicate that elimination of surface active forces by liquid ventilation during early development provides more effective gas exchange with less barotrauma compared with gas ventilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Perfluorochemical rescue after surfactant treatment: effect of perflubron dose and ventilatory frequency.

To test the hypotheses that perfluorochemical (PFC) liquid rescue after natural surfactant (SF) treatment would improve pulmonary function and histology and that this profile would be influenced by PFC dose or ventilator strategy, anesthetized preterm lambs (n = 31) with respiratory distress were studied using nonpreoxygenated perflubron. All animals received SF at 1 h and were randomized at 2 h as follows and studied to 4 h postnatal age: 1) conventional mechanical gas ventilation (n = 8), 2) 30 ml/kg perflubron with gas ventilation [partial liquid ventilation (PLV)] at 60 breaths/min (n = 8), 3) 10 ml/kg perflubron with PLV at 60 breaths/min (n = 7), and 4) 10 ml/kg perflubron with PLV at 30 breaths/min (n = 8). All animals tolerated instillation without additional cardiopulmonary instability. All perflubron-rescued groups demonstrated sustained improvement in gas exchange, respiratory compliance, and reduction in pressure requirements relative to animals receiving SF alone. Improvement was directly related to perflubron dose and breathing frequency; peak inspiratory pressure required to achieve physiological gas exchange was lower in the higher-dose and -frequency groups, and mean airway pressure was lower in the lower-frequency group. Lung expansion was greater and evidence of barotrauma was less in the higher-dose and -frequency group; regional differences in expansion were not different as a function of dose but were greater in the lower-frequency group. Regional differences in lung perflubron content were reduced in the higher-dose and -frequency groups and greatest in the lower-dose and -frequency group. The results suggest that, whereas PLV of the SF-treated lung improves gas exchange and lung mechanics, the protective benefits of perflubron in the lung may depend on dose and ventilator strategy to optimize PFC distribution and minimize exposure of the alveolar-capillary membrane to a gas-liquid interface.

Catheterization of edematous uncircumcised penis.

Catheterization of a grossly edematous uncircumcised penis can be challenging if the prepuce cannot be retracted. Herein is described a technique in which an anoscope is used to visualize the meatus and facilitate placement of a Foley catheter. This simple technique can obviate the need for cystoscopy or suprapubic cystotomy.

Effect of nasal CPAP on thoracoabdominal motion in neonates with respiratory insufficiency.

Thoracoabdominal motion (TAM) profiles were determined in ten infants requiring nasal continuous positive airway pressure (CPAP) and supplemental oxygen, in order to assess the influence of CPAP on chest wall function in infants with respiratory insufficiency. (TAM) was quantitated by respiratory inductive plethysmography, measuring relative motion of the rib cage and abdomen. Baseline pulmonary function (without CPAP support) was assessed from simultaneous measurements of transpulmonary pressure, air flow, and tidal volume. Measurements of (TAM) were acquired at baseline and at nasal CPAP levels of 0, 3, 5, and 8 cm H2O, in randomized order. Without CPAP, relative paradoxical motion occurred, i.e., the rib cage collapsed inward instead of expanding outward early in inspiration. With CPAP, TAM resembled the pattern in preterm infants, without lung disease. We found that nasal CPAP lowers the phase angle in infants with respiratory insufficiency (P less than 0.003), indicating improved synchrony of TAM. In addition, the improvement with nasal CPAP was related to the severity of pulmonary compromise at baseline. We speculate that changes in TAM associated with nasal CPAP arise from an interaction between pulmonary mechanics and an enhanced stability of the chest wall. In this context, the greater synchrony of TAM is suggestive of an improved breathing strategy. This may be a noninvasively obtainable marker of an effective nasal CPAP level in infants with altered pulmonary and chest wall mechanics.

Cardiac surgery in the low-birth weight neonate. New approaches.

The LBW infant with congenital heart defects is likely to be at a higher risk for postoperative death and complications than their normal-sized counterparts because of the effects of prematurity and other organ system dysfunction. Current experience, however, does not suggest that waiting to obtain an arbitrary weight before surgery significantly improves outcome. Survival for low-weight infants undergoing complex repairs, such as those for interruption of the aortic arch and HLHS, is decreased compared with larger babies having the same operation at the same institution; however, the absolute survival rates are still quite acceptable. Weight alone should not be considered a contraindication to surgery for complex CHD. A careful investigation for the cause of the LBW must be undertaken (e.g., prematurity, infection, multiple congenital anomalies, and genetic abnormalities) and appropriate therapies initiated. The medical and surgical teams should collaborate to determine the optimal timing and type of surgery, with body weight being only of minor importance.

Effect of exchange transfusion with a red blood cell substitute on neonatal hemodynamics and organ blood flows.

The present study was designed to evaluate the effect of a perfluorocarbon erythrocyte substitute on hemodynamics in the newborn lamb. Isovolumic double volume exchange transfusions were performed with perfluorocarbon emulsion (FC-43) on lambs who were ventilated to maintain normal acid base status. Hematocrit, fluorocrit, viscosity, arterial gas tensions, mean arterial pressure, and heart rate were determined before (control) and after (exchange) exchange transfusion. A radiolabeled microsphere technique was used and cardiac output, organ blood flow, organ vascular resistance, and oxygen delivery were calculated. As the hematocrit and viscosity decreased and the fluorocrit increased, there was a significant increase in PaO2 as well as a significant decrease in A-a gradient and oxygen content. There was no significant change in the acid-base status or the hemodynamic profile (heart rate, stroke volume, cardiac output, and mean arterial pressure). Blood flow to the heart and brain showed a significant increase, whereas flow to the cortex of the kidney showed a significant decrease. There was no significant change in flow to the gastrointestinal tract. Organ vascular resistance in the brain significantly decreased, increased in the kidney, and showed no significant change in the heart and gastrointestinal tract. Oxygen delivery significantly decreased in all organs except the heart. These data suggest that perfluorocarbon emulsions can acutely maintain hemodynamic stability in the newborn lamb and that the intrinsic properties of perfluorocarbons allow for the preservation of adequate oxygenation and acid-base status.

Psychological aspects of parenting critically ill neonates.

This study was designed to objectively examine depression and distress levels in parents of ill versus parents of healthy neonates by utilizing two well-validated questionnaires, the Beck Depression Inventory (BDI) and Kellner Symptom Questionnaire (KSQ). In addition, morbidity of infants was assessed by the Minde-Whitelaw Neonatal Morbidity Scale, and parents completed a socioeconomic questionnaire. Analysis of mean BDI and KSQ scores revealed significant differences between parents of ill neonates and parents of healthy neonates in BDI, total KSQ scores, KSQ anxiety, and depression scale scores. Within these groups, respondents whose scores fell into moderate to severe ranges of distress on either questionnaire were referred for counseling. The BDI and KSQ can be tools for better understanding about distress levels in parents of ill and healthy neonates.