Chemotherapy-induced gut microbiome disruption, inflammation, and cognitive decline in female patients with breast cancer.

Chemotherapy is notorious for causing behavioral side effects (e.g., cognitive decline). Notably, the gut microbiome has recently been reported to communicate with the brain to affect behavior, including cognition. Thus, the aim of this clinical longitudinal observational study was to determine whether chemotherapy-induced disruption of the gut microbial community structure relates to cognitive decline and circulating inflammatory signals. Fecal samples, blood, and cognitive measures were collected from 77 patients with breast cancer before, during, and after chemotherapy. Chemotherapy altered the gut microbiome community structure and increased circulating TNF-α. Both the chemotherapy-induced changes in microbial relative abundance and decreased microbial diversity were related to elevated circulating pro-inflammatory cytokines TNF-α and IL-6. Participants reported subjective cognitive decline during chemotherapy, which was not related to changes in the gut microbiome or inflammatory markers. In contrast, a decrease in overall objective cognition was related to a decrease in microbial diversity, independent of circulating cytokines. Stratification of subjects, via a reliable change index based on 4 objective cognitive tests, identified objective cognitive decline in 35% of the subjects. Based on a differential microbial abundance analysis, those characterized by cognitive decline had unique taxonomic shifts (Faecalibacterium, Bacteroides, Fusicatenibacter, Erysipelotrichaceae UCG-003, and Subdoligranulum) over chemotherapy treatment compared to those without cognitive decline. Taken together, gut microbiome change was associated with cognitive decline during chemotherapy, independent of chemotherapy-induced inflammation. These results suggest that microbiome-related strategies may be useful for predicting and preventing behavioral side effects of chemotherapy.

Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer.

BACKGROUND: The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician's choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes. PATIENTS AND METHODS: Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline. RESULTS: Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations. CONCLUSIONS: SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.

Lung protective ventilatory strategies in very low birth weight infants.

Respiratory distress syndrome (RDS) is the most common respiratory diagnosis in preterm infants. Surfactant therapy and mechanical ventilation using conventional or high-frequency ventilation have been the standard of care in the management of RDS. Bronchopulmonary dysplasia (BPD) continues to remain as a major morbidity in very low birth weight infants despite these treatments. There is no significant difference in pulmonary outcome when an optimal lung volume strategy is used with conventional or high-frequency ventilation. Lung injury is directly related to the duration of invasive ventilation via the endotracheal tube. Studies using noninvasive ventilation, such as nasal continuous positive airway pressure and noninvasive positive pressure ventilation, have shown to decrease postextubation failures as well as a trend toward reduced risk of BPD. Lung protective ventilatory strategy may involve noninvasive ventilation as a primary therapy or following surfactant administration in very preterm infants with RDS. Initial steps in the management of preterm infants may also include sustained inflation to establish functional residual capacity, followed by noninvasive ventilation to minimize lung injury and subsequent development of BPD.

Validation of noninvasive hemoglobin measurement by pulse co-oximeter in newborn infants.

OBJECTIVE: To describe the accuracy of noninvasive hemoglobin (Hb) obtained with pulse co-oximeter (SpHb) compared with total Hb (tHb) from laboratory co-oximeter in neonates. STUDY DESIGN: Neonates with birth weight (BW) <3000 g admitted to LAC+USC Medical Center neonatal intensive care unit were included. SpHb was recorded using Masimo Radical-7 and compared with tHb. A total of three data sets were obtained for each patient. Regression analysis and Bland-Altman analysis were performed. RESULT: Sixty-one patients (mean±s.d., BW 1177±610 g and gestational age 28.7±3.9 weeks) were enrolled. The mean tHb value was 13.9±2.0 g dl(-1) and the mean SpHb was 14.0±2.0 g dl(-1). There was a moderately positive correlation between SpHb and tHb (r=0.66, P<0.001) with a bias and precision of -0.09±1.67 g dl(-1). Data from a subgroup of infants with gestational age ⩽32 weeks (52/61 patients) were analyzed, and the correlation coefficient was moderately positive (r=0.69, P<0.001) with a bias and precision of -0.23±1.60 g dl(-1). CONCLUSION: Our results suggest that noninvasive SpHb may be considered as an adjunct to invasive tHb measurements in newborn infants <3000 g especially in preterm infants ⩽32 weeks of gestation.

Effects of early dexamethasone therapy on pulmonary mechanics and chronic lung disease in very low birth weight infants: a randomized, controlled trial.

OBJECTIVE: To determine the changes in pulmonary mechanics before and during early dexamethasone therapy, and to evaluate the effect of dexamethasone on the duration of mechanical ventilation in very low birth weight (VLBW) ventilator-dependent infants at risk for chronic lung disease (CLD). METHODS: A prospective randomized trial was conducted. Forty-three patients (birth weight 600 to 1500 g, gestational age 24 to 32 weeks) who failed to be weaned from the respirator at 7 to 14 days of age were enrolled; 23 infants received a 7-day course of dexamethasone (0.5 mg/kg/day intravenously for 3 days, 0.25 mg/kg/day for 3 days, and 0.1 mg/kg/day for 1 day), and 20 patients were in the control group. At similar mean airway pressure (MAP) and fractional inspired oxygen concentration (FiO2), respiratory system mechanics were measured before and on days 2, 5, and 7 of the study. Airway pressure, flow and tidal volume (VT) were recorded and only mechanical breaths were analyzed. Respiratory compliance (Crs) and respiratory resistance (Rrs) were calculated by two factor least mean square analysis. RESULTS: Eighty-three percent of infants in the dexamethasone group and 90% in the control group received surfactant in the first 24 hours of life. There was a significant increase in Crs and VT in the dexamethasone group as compared with the control group (P < .001). No major changes in Rrs were observed. Dexamethasone therapy significantly decreased FiO2 and MAP P < .001) and facilitated successful weaning from mechanical ventilation. In addition to a shorter duration of mechanical ventilation (P < .01), the occurrence of CLD (FiO2 > 0.21 at 36 weeks of corrected gestational age, chest radiograph changes) was significantly decreased in the dexamethasone group (P < .01). Except for a transient increase in blood pressure and serum glucose, there were no significant differences in infection rates, intraventricular hemorrhage, or retinopathy of prematurity. Thirteen patients in the control group received dexamethasone at a later age. CONCLUSIONS: Our findings indicate that: 1) early dexamethasone therapy in VLBW infants markedly improves respiratory compliance and tidal volume, reduces FiO2 and MAP requirements, and facilitates extubation in these infants; 2) early dexamethasone therapy reduces the duration of mechanical ventilation and decreases CLD (at 28 days and 36 weeks) in a population of VLBW infants largely treated with surfactant.

Neonatal pulmonary mechanics and oxygenation after prophylactic amnioinfusion in labor: a randomized clinical trial.

OBJECTIVE: Amnioinfusion has been reported to improve the perinatal outcome of pregnancies complicated by decreased amniotic fluid volume, but detailed information on its possible adverse effects on neonatal pulmonary mechanics and oxygenation is not available. STUDY DESIGN: We evaluated 42 infants with birth weights of 2600 to 4320 g and gestational ages of 36 to 44 weeks, who were born to mothers enrolled in a prospective, randomized trial of amnioinfusion for oligohydramnios in labor. Maternal entry criteria were gestational age 36 weeks or older, estimated fetal weight more than 2500 g, oligohydramnios defined as an amniotic fluid index of 5 cm or less, and a normal fetal heart rate pattern. Evaluation of pulmonary mechanics and oxygen saturation (SaO2) was done with the infants breathing room air between birth and day 3 of life. Transpulmonary pressure, flow, and tidal volume were recorded simultaneously, and pulmonary resistance and lung compliance were calculated. SaO2 was measured for 30 minutes with the Nellcor N-200 oximeter and IBM computer oximetry software. RESULTS: Evaluation of the data revealed no significant difference between the two groups for tidal volume, lung compliance, pulmonary resistance, or work of breathing. There were no differences between the two groups in the number of desaturation episodes or in percent of desaturations to less than 90%, 85%, or 80% SaO2. CONCLUSION: Prior studies have shown amnioinfusion to improve perinatal outcome. Our findings demonstrate that amnioinfusion for oligohydramnios in labor does not adversely affect neonatal pulmonary mechanics or oxygenation.

Pulse oximetry in newborn infants with birth weights of 620 to 4285 grams receiving dopamine and dobutamine.

The reliability of pulse oximetry in neonates receiving inotropic drugs because of hypotension and microcirculatory perfusion failure has not been well documented. Signal loss of the pulse oximeter in adult patients receiving dopamine infusions has been reported. To evaluate the relationship between pulse oximeter oxygen saturation (SaO2) and co-oximeter directly measured oxygen saturation, we studied 30 infants in the first 4 days of life (birth weight 620 to 4285 gm, gestational age 26 to 43 weeks) receiving dopamine (30 patients) and dobutamine (10 infants). Infants had normal blood pressures at the time of the study. To minimize motion artifact a Nellcor N-200 (Nellcor Incorporated, Hayward, Calif.) oximeter with electrocardiographic synchronization was used. We compared pulse oximeter values with simultaneous arterial samples analyzed for oxygen saturation with an IL 282 co-oximeter (Instrumentation Laboratory, Inc., Lexington, Mass.). The values were corrected for spuriously elevated carboxyhemoglobin levels and fetal hemoglobin level was quantitatively measured. The partial pressure of oxygen at 90% hemoglobin saturation for each patient was calculated. The dosage of dopamine ranged from 4 to 28 micrograms/kg per minute and the dosage of dobutamine varied from 4 to 24 micrograms/kg per minute. Over a wide range of values for mean blood pressure (23 to 66 mm Hg), partial pressure of oxygen at 90% hemoglobin saturation (43.1 to 70.2 mm Hg), and oxygen saturation (SaO2 80% to 100%), linear regression analysis revealed a close correlation between pulse oximeter SaO2 and co-oximeter SaO2 values (r = 0.83, standard error of the estimate 2.2%, p < 0.0001). Our findings indicate that pulse oximetry can be used reliably for continuous oxygen monitoring in normotensive neonates with an SaO2 of 80% to 100% who are receiving dopamine and dobutamine.

Production and characterization of a monoclonal antibody to partially purified estrogen receptor from human breast tumor.

A hybridoma cell line that secretes monoclonal antibody, MAb-ER-Br-1-15-4-18 is established. The MAb is highly specific for estrogen receptor (ER) from human breast tumor cells. In order to raise the antibody, the ER was first isolated from human breast tumor. Mice were immunized with the partially purified ER and the fusion of the spleen cells from the mouse, showing the highest serum titer, with the cells of the NS-1 mouse myeloma line, produced hybrid cells which continuously secreted antibodies specific for ER. Three of the hybridoma cultures which tested strongly positive were cloned using limiting dilution method and one of the cell lines was selected for further study. The recovery of the MAb from the cell culture was done by ammonium sulfate precipitation followed by dialysis and then hydroxylapatite liquid chromatography using linear gradients. The purity of the antibody was checked by polyacrylamide gel electrophoresis. The MAb was isotyped and found to be IgG1. When checked against other antigens the MAb showed a minimal cross-reactivity to ER from rabbit uterus and none to ovalbumin or rat liver ferritin. Further experiments showed that the MAb recognized the ER bound to the hormone and ER in the nucleus of breast tumor cells.

Dexamethasone therapy in chronic lung disease.

Steroids have been used in the treatment of infants with chronic lung disease (CLD) for over a decade. Some studies have reported beneficial effects from long, tapering 42-day course of dexamethasone. Short term regimens have also shown beneficial effects on ventilator dependent infants with CLD. Although steroid therapy has been successful in infants with established CLD, more recently, dexamethasone therapy is being initiated in infants with RDS considered to be at risk for developing CLD. Some of the initial studies reported higher rates of infection, but more recent prospective data have not shown an increased incidence of sepsis in patients treated with steroids. Presently, early steroid therapy appears to be beneficial to minimize lung injury in infants treated with surfactant.

High frequency ventilation: basic concepts and clinical application.

High frequency ventilation (HFV) is a mode of therapy that improves gas exchange with pressure fluctuations much lower than that required for conventional ventilation. HFV is efficacious in the "rescue" management of infants with respiratory failure. Although each HFV system has functional characteristics that are design related, it now appears that when used with similar treatment strategies and within functional limitations, similar outcomes can be achieved. Ideally, the clinician or the operator should be familiar with the basic concepts of different high frequency ventilators to achieve maximal benefits from using these devices in infants with respiratory failure.

Accuracy of pulse oximeter readings from probe placement on newborn wrist and ankle.

OBJECTIVE: To compare the accuracy of pulse oximetry oxygen saturation (SpO(2)) measured on the wrist compared with the ipsilateral palm, and SpO(2) measured on the ankle compared with the ipsilateral sole. STUDY DESIGN: In this prospective observational study, neonates admitted to the neonatal intensive care unit were enrolled. We recorded SpO(2) (Masimo Radical-7 pulse oximeter) detected at the palm and ipsilateral wrist initially, then at 30 s, and at 1 min, and we repeated the same procedure over the sole and ipsilateral ankle. We recorded the time to obtain the SpO(2) readings from all these sites. Regression analysis was performed to determine the relationship between paired SpO(2) measurements. The mean difference (bias) and standard deviation of the paired SpO(2) differences (precision) were calculated (Bland-Altman plots). RESULT: A total of 150 patients (birth weight 2381±1020 g, gestational age 34.3±4.3 weeks, median postnatal age 3.5 days (25th-75th percentile 1-16 days)) were enrolled. There was a good correlation between SpO(2) measured at the palm versus the wrist (r=0.95, P<0.001 (right); r=0.97, P< 0.001 (left)) and between SpO(2) measured at the sole versus the ankle (r=0.92, P<0.001 (right); r=0.91, P<0.001 (left)). There was also a good agreement between paired SpO(2) measurements from these sites. The bias and precision for SpO(2) at the right palm and right wrist was 0.08±0.94% and for the left palm and left wrist 0.22±0.87%. Similarly, the bias and precision for SpO(2) at the right sole and right ankle was -0.03±0.93% and for the left sole and left ankle was -0.01±0.93%. CONCLUSION: Our results show that the wrist and ankle can be used as alternative sites to measure SpO(2) in newborn infants in place of the routinely used palm or sole.

Herpes simplex encephalitis.

Herpes simplex encephalitis is a rapidly progressive disease in neonates and adults. Mortality is high, and there are severe neurologic sequelae in survivors. The reasons for centripetal transfer of virus to the brain are not fully understood. Prompt diagnosis followed by antiviral therapy with acyclovir significantly improves the prognosis. Controversy surrounds the need for brain biopsy before antiviral therapy is started.

Prone positioning decreases episodes of hypoxemia in extremely low birth weight infants (1000 grams or less) with chronic lung disease.

Extremely low birth weight infants with chronic lung disease (CLD) have frequent episodes of desaturation (hypoxemia). We quantified oxygenation and episodes of hypoxemia in 55 infants (birth weight < or = 1000 gm) with CLD in the supine versus prone position, for 1-hour time intervals. Oxygen saturation was measured with the Nellcor N-200 pulse oximeter and a computer program. Prone positioning increased oxygen saturation from 92.0% to 94.1% (p < 0.001) and significantly decreased episodes of hypoxemia to oxygen saturation levels of less than 90%, 85%, and 80% (p < 0.001). Our findings support prone positioning for the extremely low birth weight infant with CLD in an intensive care setting.

Dissecting aneurysm of the pulmonary artery in a case of unoperated patent ductus arteriosus.

A 54-year-old woman with unoperated patent ductus arteriosus developed fatal cardiac tamponade due to a dissecting aneurysm of the pulmonary artery causing haemopericardium. Histology of the pulmonary artery showed the presence of cystic medial necrosis. Previous reports of this condition are reviewed and the role of pulmonary hypertension causing secondary cystic medial necrosis is discussed.

Phaeochromocytoma and catecholamine induced cardiomyopathy presenting as heart failure.

Phaeochromocytoma is rare and usually presents as paroxysmal or sustained hypertension; none the less, it can also cause severe acute pulmonary oedema in normotensive individuals. Six patients with phaeochromocytoma presenting in Cornwall and West Devon between 1982 and 1986 are described. Five of them died of pulmonary oedema within 24 hours of the onset of symptoms. At necropsy all five had normal sized hearts and in the four hearts examined by histology there was evidence of catecholamine induced heart disease in the form of focal myocardial necrosis. The sixth patient presented with arterial spasms and pulmonary oedema. Surgical removal of the causative tumour was successful in this patient.

Aneurysm of the ductus arteriosus: a congenital lesion.

The objective of this study was to evaluate the clinical, radiological, and echocardiographic findings in 11 neonates with aneurysm of ductus arteriosus presented in our institutions between 1993 and 1996, and to postulate a new theory for the pathogenesis of this lesion. Medical records, radiographic studies, and echocardiograms were reviewed. All infants underwent follow-up echocardiograms every 2 to 3 days until the aneurysm spontaneously resolved or surgery was performed. The infants were predominantly term males; six had evidence of fetal distress, two were diagnosed prenatally by fetal echocardiogram, chest X ray evidenced mediastinal mass in six patients. The first echocardiogram showed structurally normal heart with an aneurysmal patent ductus arteriosus. In eight patients the aneurysm completely resolved by 5 to 10 days. One infant underwent surgical resection of the aneurysm after observation for 11 days with no change in size. Thrombosis of the aneurysm was noted in two patients; both underwent surgery. Increasing reports of ductal aneurysms in infants may reflect the availability of high-resolution echocardiography and more frequent use of echocardiography in the neonatal intensive care unit. Spontaneous resolution occurred in the majority of cases as in previous reports. We postulate that, at least in some cases, aneurysm of the ductus arteriosus is a congenital lesion that may represent poststenotic dilation of the ductus due to turbulent flow through a stenotic segment at its pulmonary artery end during fetal life. The presence of aneurysm of the ductus arteriosus should be excluded in selected cases of fetal distress, by fetal echocardiography.

Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn.

BACKGROUND: Although inhaled nitric oxide (iNO) causes selective pulmonary vasodilation and improves oxygenation in newborn infants with persistent pulmonary hypertension, its effects are variable. We hypothesized (1) that the response to iNO therapy is dependent on the primary disease associated with persistent pulmonary hypertension of the newborn (PPHN) and (2) that the combination of high-frequency oscillatory ventilation (HFOV) with iNO would be efficacious in patients for whom either therapy alone had failed. METHODS: To determine the relative roles of iNO and HFOV in the treatment of severe PPHN, we enrolled 205 neonates in a randomized, multicenter clinical trial. Patients were stratified by predominant disease category: respiratory distress syndrome (n = 70), meconium aspiration syndrome (n = 58), idiopathic PPHN or pulmonary hypoplasia (excluding congenital diaphragmatic hernia) ("other": n = 43), and congenital diaphragmatic hernia (n = 34); they were then randomly assigned to treatment with iNO and conventional ventilation or to HFOV without iNO. Treatment failure (partial pressure of arterial oxygen [PaO2] < 60 mm Hg) resulted in crossover to the alternative treatment; treatment failure after crossover led to combination treatment with HFOV plus iNO. Treatment response with the assigned therapy was defined as sustained PaO2 of 60 mm Hg or greater. RESULTS: Baseline oxygenation index and PaO2 were 48 +/- 2 and 41 +/- 1 mm Hg, respectively, during treatment with conventional ventilation. Ninety-eight patients were randomly assigned to initial treatment with HFOV, and 107 patients to iNO. Fifty-three patients (26%) recovered with the initially assigned therapy without crossover (30 with iNO [28%] and 23 with HFOV [23%]; p = 0.33). Within this group, survival was 100% and there were no differences in days of mechanical ventilation, air leak, or supplemental oxygen requirement at 28 days. Of patients whose initial treatment failed, crossover treatment with the alternate therapy was successful in 21% and 14% for iNO and HFOV, respectively (p = not significant). Of 125 patients in whom both treatment strategies failed, 32% responded to combination treatment with HFOV plus iNO. Overall, 123 patients (60%) responded to either treatment alone or combination therapy. By disease category, response rates for HFOV plus iNO in the group with respiratory syndrome and the group with meconium aspiration syndrome were better than for HFOV alone or iNO with conventional ventilation (p < 0.05). Marked differences in outcomes were noted among centers (percent death or treatment with extracorporeal membrane oxygenation = 29% to 75%). CONCLUSIONS: We conclude that treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN. Differences in responses are partly related to the specific disease associated with PPHN.

Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomised controlled trial.

BACKGROUND: Inhaled nitric oxide improves oxygenation and lessens the need for extracorporeal-membrane oxygenation in full-term neonates with hypoxaemic respiratory failure and persistent pulmonary hypertension, but potential adverse effects are intracranial haemorrhage and chronic lung disease. We investigated whether low-dose inhaled nitric oxide would improve survival in premature neonates with unresponsive severe hypoxaemic respiratory failure, and would not increase the frequency or severity of intracranial haemorrhage or chronic lung disease. METHODS: We did a double-blind, randomised controlled trial in 12 perinatal centres that provide tertiary care. 80 premature neonates (gestational age < or = 34 weeks) with severe hypoxaemic respiratory failure were randomly assigned inhaled nitric oxide (n=48) or no nitric oxide (n=32, controls). Our primary outcome was survival to discharge. Analysis was by intention to treat. We studied also the rate and severity of intracranial haemorrhage, pulmonary haemorrhage, duration of ventilation, and chronic lung disease at 36 weeks' postconceptional age. FINDINGS: The two groups did not differ for baseline characteristics or severity of disease. Inhaled nitric oxide improved oxygenation after 60 min (p=0.03). Survival at discharge was 52% in the inhaled-nitric-oxide group and 47% in controls (p=0.65). Causes of death were mainly related to extreme prematurity and were similar in the two groups. The two groups did not differ for adverse events or outcomes (intracranial haemorrhage grade 2-4, 28% inhaled nitric oxide and 33% control; pulmonary haemorrhage 13% and 9%; chronic lung disease 60% and 80%). INTERPRETATION: Low-dose inhaled nitric oxide improved oxygenation but did not improve survival in severely hypoxaemic premature neonates. Low-dose nitric oxide in the most critically ill premature neonates does not increase the risk of intracranial haemorrhage, and may decrease risk of chronic lung injury.