Mark A. Rosen

Correction of congenital diaphragmatic hernia in utero: VI. hard-earned lessons

Extensive experimental work suggests that repair of congenital diaphragmatic hernia (CDH) in utero may salvage severely affected fetuses who otherwise have a high expected mortality despite optimal postnatal care including extracorporeal membrane oxygenation (ECMO). We have reported that repair of CDH in utero is physiologically sound and safe for the mother, but technically difficult especially when the liver is herniated into the fetal chest. In the 3 years since our last report (1989 to 1991), 61 additional patients were referred for consideration of in utero repair. Fetal repair was attempted in 14 with severe isolated left CDH diagnosed before 24 weeks gestation. Five fetuses died intraoperatively, from technical problems related to reduction of incarcerated liver and uterine contractions--problems which have subsequently been surmounted. Nine patients were successfully repaired. Four babies survived, two delivered prematurely and died, and three died in utero within 48 hours of repair. Intraoperative technical problems have been overcome; the factors limiting successful outcome are postoperative physiologic management of the maternal-fetal unit and effective tocolysis to control preterm labor.

Three-dimensional in vivo fluorescence diffuse optical tomography of breast cancer in humans.

We present three-dimensional (3D) in vivo images of human breast cancer based on fluorescence diffuse optical tomography (FDOT). To our knowledge, this work represents the first reported 3D fluorescence tomography of human breast cancer in vivo. In our protocol, the fluorophore Indocyanine Green (ICG) is injected intravenously. Fluorescence excitation and detection are accomplished in the soft-compression, parallel-plane, transmission geometry using laser sources at 786 nm and spectrally filtered CCD detection. Phantom and in vivo studies confirm the signals are due to ICG fluorescence, rather than tissue autofluorescence and excitation light leakage. Fluorescence images of breast tumors were in good agreement with those of MRI, and with DOT based on endogenous contrast. Tumorto- normal tissue contrast based on ICG fluorescence was two-to-four-fold higher than contrast based on hemoglobin and scattering parameters. In total the measurements demonstrate that FDOT of breast cancer is feasible and promising.

Phase I Trial of the Antivascular Agent Combretastatin A4 Phosphate on a 5-Day Schedule to Patients With Cancer: Magnetic Resonance Imaging Evidence for Altered Tumor Blood Flow

PURPOSE Combretastatin A4 (CA4) phosphate (CA4P) inhibits microtubule polymerization and is toxic to proliferating endothelial cells in vitro. It causes reversible vascular shutdown in established tumors in vivo, consistent with an antivascular mechanism of action. The present study investigated escalating doses of CA4P administered intravenously to patients with advanced cancer. PATIENTS AND METHODS Patients with solid malignancies and good performance status received CA4P as a 10-minute infusion daily for 5 days repeated every 3 weeks. Pharmacokinetic sampling was performed during cycle 1. Patients receiving >/= 52 mg/m2/d had serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies to measure changes in tumor perfusion with CA4P treatment. RESULTS Thirty-seven patients received 133 treatment cycles. CA4P dose levels ranged from 6 mg/m2 to 75 mg/m2 daily. Severe pain at sites of known tumor was dose limiting at 75 mg/m2. Dose-limiting cardiopulmonary toxicity (syncope and dyspnea or hypoxia) was noted as well in two patients treated at 75 mg/m2. Other toxicities included hypotension, ataxia, dyspnea, nausea or vomiting, headache, and transient sensory neuropathy. Plasma CA4P and CA4 area under the concentration-time curve and maximal concentration values increased linearly with dose. Tumor perfusion, as measured by the first-order rate constant of gadolinium plasma to tissue transfer during DCE-MRI studies, was found to decrease in eight of 10 patients. Relationships were also demonstrated between perfusion changes and pharmacokinetic indices. A partial response was observed in a patient with metastatic soft tissue sarcoma, and 14 patients exhibited disease stability for a minimum of two cycles. CONCLUSION Doses of CA4P on a daily times five schedule of 52 to 65 mg/m2 were reasonably well-tolerated. The 52 mg/m2 dose is recommended for further study based on cumulative phase I experience with CA4P. Antitumor efficacy was observed, and the use of DCE-MRI provided a valuable noninvasive measure of the vascular effects of CA4P treatment.

Intravenous Remifentanil Placental Transfer, Maternal and Neonatal Effects

Background Remifentanil has not been studied in obstetric patients. This study evaluates the placental transfer of remifentanil and the neonatal effects when administered as an intravenous infusion. Methods Nineteen parturients underwent nonemergent cesarean section with epidural anesthesia and received 0.1 [micro sign]g [middle dot] kg‐1 [middle dot] min‐1 remifentanil intravenously, which was continued until skin closure. Maternal arterial (MA), umbilical arterial (UA), and umbilical venous (UV) blood samples were obtained at delivery for analysis of drug concentrations of remifentanil, its metabolite, and blood gases. Maternal vital signs were monitored continuously, and pain and sedation levels were assessed intermittently. Apgar scores were obtained at 1, 5, 10, and 20 min, and Neonatal and Adaptive Capacity Scores were noted 30 and 60 min after delivery. Parturients and newborns were observed for at least 24 h after surgery for side effects. Results The means and SDs of UV:MA and UA:UV ratios for remifentanil were 0.88 +/‐ 0.78 and 0.29 +/‐ 0.07, respectively. Mean clearance was 93 ml [middle dot] min‐1 [middle dot] kg‐1. The mean UV:MA and UA:MV ratios for remifentanil acid were 0.56 +/‐ 0.29 and 1.23 +/‐ 0.89, respectively. The mean MA (remifentanil acid):MA (remifentanil) ratio was 2.92 +/‐ 3.65. There were no adverse effects on the neonates, but there was a sedative effect and respiratory depressant effect on the mothers. Conclusions Remifentanil crosses the placenta but appears to be rapidly metabolized, redistributed, or both. Maternal sedation and respiratory changes occur, but without adverse neonatal or maternal effects.

Diffuse optical tomography of breast cancer during neoadjuvant chemotherapy: a case study with comparison to MRI.

We employ diffuse optical tomography (DOT) to track treatment progress in a female subject presenting with locally advanced invasive carcinoma of the breast during neoadjuvant chemotherapy. Three-dimensional images of total hemoglobin concentration and scattering identified the tumor. Our measurements reveal tumor shrinkage during the course of chemotherapy, in reasonable agreement with magnetic resonance images of the same subject. A decrease in total hemoglobin concentration contrast between tumor and normal tissue was also observed over time. The results demonstrate the potential of DOT for measuring physiological parameters of breast lesions during chemotherapy.

Operating on placental support: The ex utero intrapartum treatment procedure

While treating eight fetuses with predictable airway obstruction, the authors developed a systematic approach, the ex utero intrapartum treatment procedure, to secure the airway during delivery. Six patients had their trachea plugged or clipped in utero for treatment of congenital diaphragmatic hernia, and two patients had prenatally diagnosed cystic hygroma of the neck and oropharynx. The ex utero intrapartum treatment procedure was performed by using high doses of inhaled halogenated agents to facilitate uterine relaxation during cesarean section, securing the fetal airway while feto-placental circulation remained intact, and then dividing the umbilical cord. A variety of procedures were performed during the ex utero intrapartum treatment procedure including bronchoscopy, orotracheal intubation, tracheostomy, tracheostomy with retrograde orotracheal intubation, tracheoplasty, removal of internal tracheal plug, removal of external tracheal clip, central line placement, and instillation of surfactant. There were minimal maternal or fetal complications during the procedure. This approach requires the coordinated efforts of pediatric surgeons, obstetricians, anesthesiologists, sonographers, and neonatologists. The combination of intensive maternal-fetal monitoring, cesarean section with maximal uterine relaxation, and maintenance of intact feto-placental circulation provides a controlled environment for securing the airway in babies with prenatally diagnosed airway obstruction.

FETAL SURGERY FOR CONGENITAL HYDRONEPHROSIS

ALTHOUGH many fetal anatomic abnormalities can now be diagnosed by sonography, only a few will affect prenatal management.1 In the fetus with severe bilateral hydronephrosis secondary to urethral o...

Locally Advanced Breast Cancer: MR Imaging for Prediction of Response to Neoadjuvant Chemotherapy—Results from ACRIN 6657/I-SPY TRIAL

PURPOSE To compare magnetic resonance (MR) imaging findings and clinical assessment for prediction of pathologic response to neoadjuvant chemotherapy (NACT) in patients with stage II or III breast cancer. MATERIALS AND METHODS The HIPAA-compliant protocol and the informed consent process were approved by the American College of Radiology Institutional Review Board and local-site institutional review boards. Women with invasive breast cancer of 3 cm or greater undergoing NACT with an anthracycline-based regimen, with or without a taxane, were enrolled between May 2002 and March 2006. MR imaging was performed before NACT (first examination), after one cycle of anthracyline-based treatment (second examination), between the anthracycline-based regimen and taxane (third examination), and after all chemotherapy and prior to surgery (fourth examination). MR imaging assessment included measurements of tumor longest diameter and volume and peak signal enhancement ratio. Clinical size was also recorded at each time point. Change in clinical and MR imaging predictor variables were compared for the ability to predict pathologic complete response (pCR) and residual cancer burden (RCB). Univariate and multivariate random-effects logistic regression models were used to characterize the ability of tumor response measurements to predict pathologic outcome, with area under the receiver operating characteristic curve (AUC) used as a summary statistic. RESULTS Data in 216 women (age range, 26-68 years) with two or more imaging time points were analyzed. For prediction of both pCR and RCB, MR imaging size measurements were superior to clinical examination at all time points, with tumor volume change showing the greatest relative benefit at the second MR imaging examination. AUC differences between MR imaging volume and clinical size predictors at the early, mid-, and posttreatment time points, respectively, were 0.14, 0.09, and 0.02 for prediction of pCR and 0.09, 0.07, and 0.05 for prediction of RCB. In multivariate analysis, the AUC for predicting pCR at the second imaging examination increased from 0.70 for volume alone to 0.73 when all four predictor variables were used. Additional predictive value was gained with adjustments for age and race. CONCLUSION MR imaging findings are a stronger predictor of pathologic response to NACT than clinical assessment, with the greatest advantage observed with the use of volumetric measurement of tumor response early in treatment.

Correction of congenital diaphragmatic hernia in utero, V. Initial clinical experience

Review of our experience with 45 cases of prenatally diagnosed congenital diaphragmatic hernia (CDH) confirms that most fetuses (77%) will not survive despite optimal pre- and postnatal care. Polyhydramnios, associated anomalies, early diagnosis, and a large volume of herniated viscera (including liver) are associated with a particularly dismal prognosis. After extensive experimental work demonstrated the efficacy, feasibility, and safety of repair in utero, we attempted to salvage six highly selected fetuses with severe CDH by open fetal surgery. Five had liver incarcerated in the chest: three died at operation because attempts to reduce the liver compromised umbilical venous return. In one, a Goretex diaphragm was constructed around the liver, but the baby died after birth. The last two fetuses, one with incarcerated liver, were successfully repaired. Both demonstrated rapid growth of the lung in utero, had surprisingly good lung function after birth despite prematurity, had the abdominal patch removed at 2 weeks, and subsequently died of nonpulmonary problems (an unrelated nursery accident in one and intestinal complications in the other). The only maternal complication was amniotic fluid leak and preterm labor. All six women are well and four have had subsequent normal children. From this phase I experience, we conclude that fetal surgery appears safe for the mother and her reproductive potential, that fetal CDH repair is feasible in selected cases, and that the fetal lung responds quickly after decompression. However, fetal repair remains a formidable technical challenge.

Prostate cancer: sextant localization at MR imaging and MR spectroscopic imaging before prostatectomy--results of ACRIN prospective multi-institutional clinicopathologic study.

PURPOSE To determine the incremental benefit of combined endorectal magnetic resonance (MR) imaging and MR spectroscopic imaging, as compared with endorectal MR imaging alone, for sextant localization of peripheral zone (PZ) prostate cancer. MATERIALS AND METHODS This prospective multicenter study, conducted by the American College of Radiology Imaging Network (ACRIN) from February 2004 to June 2005, was institutional review board approved and HIPAA compliant. Research associates were required to follow consent guidelines approved by the Office for Human Research Protection and established by the institutional review boards. One hundred thirty-four patients with biopsy-proved prostate adenocarcinoma and scheduled to undergo radical prostatectomy were recruited at seven institutions. T1-weighted, T2-weighted, and spectroscopic MR sequences were performed at 1.5 T by using a pelvic phased-array coil in combination with an endorectal coil. Eight readers independently rated the likelihood of the presence of PZ cancer in each sextant by using a five-point scale-first on MR images alone and later on combined MR-MR spectroscopic images. Areas under the receiver operating characteristic curve (AUCs) were calculated with sextant as the unit of analysis. The presence or absence of cancer at centralized histopathologic evaluation of prostate specimens was the reference standard. Reader-specific receiver operating characteristic curves for values obtained with MR imaging alone and with combined MR imaging-MR spectroscopic imaging were developed. The AUCs were estimated by using Mann-Whitney statistics and appropriate 95% confidence intervals. RESULTS Complete data were available for 110 patients (mean age, 58 years; range, 45-72 years). MR imaging alone and combined MR imaging-MR spectroscopic imaging had similar accuracy in PZ cancer localization (AUC, 0.60 vs 0.58, respectively; P > .05). AUCs for individual readers were 0.57-0.63 for MR imaging alone and 0.54-0.61 for combined MR imaging-MR spectroscopic imaging. CONCLUSION In patients who undergo radical prostatectomy, the accuracy of combined 1.5-T endorectal MR imaging-MR spectroscopic imaging for sextant localization of PZ prostate cancer is equal to that of MR imaging alone.