A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma.

BACKGROUND: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC. PATIENTS AND METHODS: Patients with mRCC and 2-3 prior lines of therapy were randomized 1 : 1 to CRLX101 + bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. RESULTS: In total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified. CONCLUSIONS: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned. CLINICAL TRIAL IDENTIFICATION: NCT02187302 (NIH).

Outcome of patients with metastatic renal cell carcinoma treated with targeted therapy without cytoreductive nephrectomy.

BACKGROUND: Cytoreductive nephrectomy (CN) became a standard procedure in metastatic renal cell carcinoma (mRCC) in the immunotherapy era. Historically, median overall survival (OS) of patients treated with interferon alpha (IFN-α) without CN was 7.8 months. Median OS in patients treated with targeted therapy (TT) without CN is unknown. PATIENTS AND METHODS: We retrospectively reviewed records of patients with mRCC who received TT without CN. Kaplan-Meier methods and Cox regression analysis were used to estimate median OS and identify poor prognostic factors. RESULTS: One hundred and eighty-eight patients were identified. Most patients had intermediate-risk (54.8%) or poor-risk (44.1%) disease. Median OS for all patients was 10.4 months [95% confidence interval (CI) 8.1-12.5]. By multivariable analysis, elevated baseline lactate dehydrogenase and corrected calcium, performance status of two or more, retroperitoneal nodal metastasis, thrombocytosis, current smoking, two or more metastatic sites, and lymphopenia were independent risk factors for inferior OS. Patients with four or more factors had increased risk of death (hazard ratio 8.83, 95% CI 5.02-15.5, P < 0.001) and 5.5-month median OS. Nineteen patients (10.0%) survived for 2+ years. CONCLUSIONS: These data highlight the improved OS of patients with mRCC treated with TT without CN, compared with historical IFN-α treatment, and may guide the design of trials investigating the role of CN in the TT era.

Detection and correction of a migration anomaly on a 310 genetic analyzer.

During STR analysis on the 310 Genetic Analyzer, retarded migration of GS500ROX size standards and alleles in some samples was observed. The contribution of reagents, capillary and performance optimized polymer POP 4 to the observed anomaly was experimentally eliminated. Variation in electrophoresis temperature between 55 degrees C and 65 degrees C did not alter the rate of migration of GX500ROX size standard and sample alleles. An eroded connector for the cathode mounted on the heat plate assembly caused the abnormal migration. Hence, it is important to verify the mobility of all fragments in the size standard for each sample to avoid any erroneous allele calls by the automated data analysis software.

An appraisal of treatment guidelines for antepartum community-acquired pneumonia.

OBJECTIVE: The optimal strategy for the initial evaluation and management, including criteria for hospitalization, of pregnant women with pneumonia has not been defined. Our purpose was to evaluate a treatment protocol for antepartum pneumonia and to identify criteria for selection of women for potential outpatient treatment. STUDY DESIGN: A protocol based on British and American Thoracic Society guidelines was introduced and included prompt hospitalization and empiric initiation of erythromycin therapy. Maternal and neonatal outcomes were analyzed to assess the efficacy of the protocol. A second analysis involved the retrospective application of published guidelines to ascertain for which women outpatient management might have been appropriate. RESULTS: There were no maternal deaths among the 133 women studied, and in 14 (10%) women there was a misdiagnosis at admission. Erythromycin monotherapy was judged adequate in all but one of the 99 women so treated. Using a modified version of the American Thoracic Society guidelines, we project that only 25% of the women hospitalized with pneumonia could have been managed safely as outpatients. CONCLUSION: Most pregnant women with pneumonia respond well to monotherapy with erythromycin. Outpatient management may be a reasonable option for selected women.

Acute pancreatitis in pregnancy.

OBJECTIVE: Our purpose was to determine the cause and describe the natural history of acute pancreatitis complicating pregnancy and its effect on maternal and perinatal outcomes. STUDY DESIGN: Over the last decade we admitted 43 pregnant women with acute pancreatitis to our hospital. We reviewed presentation, diagnosis, management, and maternal and perinatal outcomes. RESULTS: The incidence of acute pancreatitis was one in 3333 pregnancies. The mean age of these 43 women was 24 years, 31 (72%) were multiparous, and pancreatitis was associated with biliary disease in 29 (68%). All had a favorable response to supportive therapy that included bowel rest, intravenous hydration, and antimicrobial therapy. Cholecystectomy was performed for persistent or recurrent biliary or pancreatic disease ante partum in eight women and post partum in another 12. Of 39 women who were delivered at our hospital, 32 were at term and their infants did well. The other six infants were delivered preterm; two were stillborn and another died after birth. One woman underwent a therapeutic abortion. CONCLUSIONS: Most pregnant women with acute pancreatitis have associated biliary tract disease. With prompt hospitalization, supportive care, and surgical intervention when indicated, maternal and fetal morbidity and mortality are not prohibitive. Fetal death and preterm delivery may result from severe disease.

The correlation between transperineal sonography and digital examination in the evaluation of the third-trimester cervix.

OBJECTIVE: To determine the correlation between transperineal or translabial ultrasound and digital examination of the cervix in the third trimester in women presenting to the obstetrical triage area complaining of uterine contractions and/or rupture of membranes. METHOD: One hundred women were evaluated initially with an ultrasound unit using a 5-MHz glove-covered curvilinear transducer applied to the perineum in the sagittal plane. Immediately after the ultrasound evaluation, another examiner assessed the cervix digitally, blinded to the sonographic results. Cervical dilatation, length, and station were assessed. RESULTS: Transperineal ultrasound correlated (P < .001) with digital cervical examination in the assessment of dilatation (Pearson correlation coefficient 0.87), length (Pearson correlation coefficient 0.80), and corrected station (Pearson correlation coefficient 0.69). CONCLUSION: There is a statistically significant correlation between the digital cervical examination and the sonographic assessment of cervical dilatation, length, and station by the transperineal approach.

Markers of acute and chronic asphyxia in infants with meconium-stained amniotic fluid.

OBJECTIVE: Cord blood pH, lactate, hypoxanthine, and erythropoietin levels have all been used as markers of either acute or chronic asphyxia. We sought to determine whether these index values were significantly different in infants with or without meconium-stained amniotic fluid. STUDY DESIGN: Fifty-six pregnant women in spontaneous labor at term were divided into two groups on the basis of the presence or absence of meconium-stained amniotic fluid. All meconium-stained fluid was centrifuged, and the volume percentage of particulate matter (i.e., meconium) was recorded. Umbilical artery blood and mixed arterial and venous cord blood were obtained at each delivery. Lactate, hypoxanthine, and erythropoietin levels were measured. Statistical analysis included Student t test and rank sum statistics where appropriate. Normal and Spearman correlation coefficients were also used. RESULTS: There were no significant differences in mean umbilical artery pH (7.26 +/- 0.06 vs 7.25 +/- 0.10), lactate levels (32.8 +/- 10 mg/dl vs 30.4 +/- 14.2 mg/dl), and hypoxanthine levels (13.4 +/- 6.7 mumol/L vs 14.0 +/- 6.0 mumol/L) in newborns with meconium (n = 28) compared with controls (n = 28). Erythropoietin levels were significantly greater in newborns with meconium (median 39.5 mIU/ml vs 26.8 mIU/ml, p = 0.039). There was no correlation between the amount of particulate matter and any marker of asphyxia. CONCLUSIONS: There was no correlation between markers of acute asphyxia (i.e., umbilical artery blood pH, lactate, or hypoxanthine) and meconium. However, erythropoietin levels were significantly elevated in newborns with meconium-stained amniotic fluid. This latter marker may better correlate with chronic asphyxia.

Infantile spasms associated with theophylline toxicity.

We report on a 6-month-old infant with asthma who developed spasms and hypsarrhythmia on the electroencephalogram (EEG) shortly after starting oral theophylline medication. Theophylline levels at that time were just above the upper normal range. The spasms stopped and the EEG normalized when theophylline was discontinued and nitrazepam therapy started. On follow-up over the next 3 years there was no recurrence of seizures and the child's neurodevelopment has been normal. Nitrazepam was stopped at 10 months and the waking and sleeping EEG were normal at 14 months. We believe that the infantile spasms were caused by theophylline.

Pneumonia complicating pregnancy.

OBJECTIVE: To determine the clinical course and perinatal outcomes of women with pneumonia complicating pregnancy. METHODS: Between 1989 and 1993, we admitted 71 pregnant women for treatment of community-acquired pneumonia. Exposure and outcome variables as well as characteristics of their clinical course were identified and analyzed. Two-sample Wilcoxon rank-sum and Fisher exact tests were used for statistical analyses. RESULTS: Five women had adverse pregnancy outcomes related to pneumonia: two maternal-fetal deaths, one preterm delivery, one fetal death, and one early abortion. Compared with women whose pregnancies went to term, these five women had a significantly lower mean oxygen pressure on admission (68 versus 83 mmHg). Other risk factors for adverse outcome included diffuse radiologic pulmonary involvement and current smoking of more than ten cigarettes per day. Neither illicit drug use nor anemia were risk factors. Although 31 of these 71 women had underlying chronic diseases, these were not associated with negative outcomes. CONCLUSIONS: Despite prompt hospitalization and treatment, antepartum pneumonia is potentially serious, even in young, otherwise healthy women. Although underlying maternal disease appears to be related to the development of antepartum pneumonia, we did not confirm previous reports that suggested its relation to adverse pregnancy outcome.

Thyrotoxic hypokalemic periodic paralysis following second-trimester prostaglandin-induced abortion.

BACKGROUND: Hypokalemic periodic paralysis with thyrotoxicosis has never been described in pregnancy or the puerperium. CASE: A 31-year-old Hispanic woman underwent three prostaglandin inductions for a second-trimester missed abortion. Her management was complicated by hyperthermia, nausea, vomiting, and diarrhea. She developed isolated proximal muscle paralysis and sensory loss on the first post-abortion day. Her serum potassium was 1.5 mEq/L. The serum free thyroxine index exceeded 25 and TSH was below 0.03 microIU/mL, leading to a diagnosis of thyrotoxic hypokalemic periodic paralysis. Oral and parenteral potassium repletion restored full neurologic function, and propylthiouracil treatment was initiated until thyroid ablation could be performed. CONCLUSION: Gastrointestinal potassium loss during prostaglandin-induced abortion may unmask previously undiagnosed periodic paralysis.

Bedside polysomnography as an adjunct in the management of infants with Robin sequence.

Objective indications for tongue-lip adhesion in infants with Robin sequence have been lacking because of the difficulty in assessing the clinical significance of airway obstruction. In 1988, we began to use 20-hour, four-channel polysomnography to assist us in the management of infants with Robin sequence. The four channels included electrocardiogram, respiratory motion, airflow, and oxygen saturation. Infants demonstrating significant episodes of airway obstruction during sleep were recommended for tongue-lip adhesion. Fifteen infants with Robin sequence were evaluated during a 3-year period. Two babies were having severe, clinically obvious events on admission and underwent tongue-lip adhesion without polysomnography. Polysomnography was done on the other 13 infants. No significant events were seen in 7 infants, and they were discharged after a mean hospitalization of 8 days. Six studies documented significant airway obstruction, and tongue-lip adhesion was recommended. Follow-up polysomnography performed after successful tongue-lip adhesion failed to show any significant events, and the infants only required hospitalization for a mean of 12 days. We conclude that polysomnography is a useful adjunct in the management of infants with Robin sequence, providing objective indications for surgical intervention and shortening hospitalization.