Abnormal Doppler ultrasound signals were detected in 44 of 47 patients with primary malignant tumors of the liver, kidney, adrenal gland, or pancreas (94%). Two different signal types were noted: a high-velocity signal (n = 38) with Doppler shifts exceeding 3 kHz (at an insonating frequency of 3 MHz) and a very low-impedance signal (n = 9) demonstrating little systolic-diastolic variation. In three patients, both types were present. In 19 patients, histologic (n = 12) and/or angiographic (n = 16) correlation was available. Among 13 patients with angiographic studies and signals over 3 kHz, arteriovenous shunting was demonstrated in six. The ratio of the systolic to diastolic Doppler shift is a function of vascular impedance. This systolic/diastolic index was less than 3 in eight patients with histologic correlation. All eight had prominent vascular spaces, and the flow in such thin-walled, endothelium-lined spaces would account for the low-impedance signals. Of nine patients with systolic/diastolic indexes of 3 or less and angiographic correlation, three had marked and four had moderate tumor staining.

Immune reactivity to self-antigens in both cancer and autoimmune diseases can be enhanced by systemic immune modulation, posing a challenge in cancer immunotherapy. To distinguish the genetic and immune regulation of tumor immunity versus autoimmunity, immune responses to human ErbB-2 (Her-2) and mouse thyroglobulin (mTg) were tested in transgenic mice expressing Her-2 that is overexpressed in several cancers, and HLA-DRB1*0301 (DR3) that is associated with susceptibility to several human autoimmune diseases, as well as experimental autoimmune thyroiditis (EAT). To induce Her-2 response, mice were electrovaccinated with pE2TM and pGM-CSF encoding the extracellular and transmembrane domains of Her-2 and the murine granulocyte macrophage colony-stimulating factor, respectively. To induce EAT, mice received mTg i.v. with or without lipopolysaccharide. Depletion of regulatory T cells (Treg) with anti-CD25 monoclonal antibody enhanced immune reactivity to Her-2 as well as mTg, showing control of both Her-2 and mTg responses by Treg. When immunized with mTg, Her-2xDR3 and B6xDR3 mice expressing H2 b xDR3 haplotype developed more profound mTg response and thyroid pathology than Her-2 or B6 mice that expressed the EAT-resistant H2 b haplotype. In Her-2xDR3 mice, the response to mTg was further amplified when mice were also immunized with pE2TM and pGM-CSF. On the contrary, Her-2 reactivity was comparable whether mice expressed DR3 or not. Therefore, induction of Her-2 immunity was independent of DR3 but development of EAT was dictated by this allele, whereas Tregs control the responses to both self-antigens. These results warrant close monitoring of autoimmunity during cancer immunotherapy, particularly in patients with susceptible MHC class II alleles. [Cancer Res 2007;67(14):7020-7]

Modulation of the immune system to amplify anti-tumor immunity carries the risk of developing autoimmune diseases, including hypothyroidism, as seen with cancer patients undergoing clinical trials for immunotherapeutic regimens. Although there is a tendency to view autoimmunity as a positive indicator for cancer immunotherapy, some autoimmune manifestations can be life-threatening and necessitate prolonged medical intervention or removal from trial. We have established murine test models to assess such risks by monitoring, simultaneously, the immune reactivity to tumor-associated rat erbB-2 (neu) and another self Ag, mouse thyroglobulin (mTg). We previously reported that in wild-type, thyroiditis-resistant BALB/c mice that underwent regression of neu+ TUBO tumors following regulatory T cell (Treg) depletion, immune responses to rat neu and mTg with resultant autoimmune thyroiditis (EAT) were both enhanced. In this study, we tested the balance between tumor immunity and autoimmunity in neu-transgenic BALB NeuT female mice. First, growth and progression of neu+ tumor were compared in neu tolerant mice treated with either CD25 mAb to deplete Tregs and/or DNA vaccination. Only Treg depletion followed by neu DNA vaccination abrogated tolerance to neu, resulting in complete regression of neu+ tumors, as well as long-term protection from spontaneous tumorigenesis in 58% of mice. The risk of developing EAT was then assessed by incorporated mTg immunization with or without LPS as adjuvant. In mice with induced tumor regression, mTg response was enhanced with modest increases in EAT development. Therefore, tumor regression induced by Treg depletion and DNA vaccination can exacerbate autoimmunity, which warrants close monitoring during immunotherapy.

Of 398 patients in whom there was a clinical suspicion of ectopic pregnancy, 96 (24%) were found to have the condition. Of the 96, 70 underwent duplex Doppler imaging. A viable ectopic fetus was seen in 10 of 70 (14%), and an extrauterine sac without an identifiable fetus was seen in an additional 27, giving a sensitivity for imaging alone of 53%. Fetal heart activity was detected with Doppler in 13 (19%). High-velocity flow, which suggested the presence of an ectopic pregnancy, was detected in 38 of 70 (54%) patients (total preoperative sensitivity, 73%). In the 91 patients who did not have an ectopic pregnancy, duplex Doppler imaging of the intrauterine contents alone allowed an ectopic pregnancy to be excluded in 29 (32%) on the first examination and in a further 21 on the second scan (specificity, 55%). Nine vascular adnexal masses were falsely considered to be ectopic pregnancies (specificity, 90%). The positive predictive values were 47% for imaging alone and 85% for Doppler. The negative predictive values were 60% for imaging alone and 81% for Doppler.

The vascularity of 49 renal masses (26 malignant and 23 benign lesions) was investigated with duplex Doppler ultrasound. Doppler signals obtained at the margins of renal masses were defined as "tumor signals" when the Doppler-shifted frequency of the lesion exceeded the frequency shift in the ipsilateral main renal artery. These exceeded 2.5 kHz with a 3-MHz insonating frequency. Among the 26 renal masses that subsequently proved to be malignant, tumor signals were obtained in 15 of 18 (83%) untreated renal cell carcinomas, in three of four Wilms tumors, and in two patients with metastases to the kidney, but not in the one patient with lymphoma. None of the 23 benign renal masses demonstrated tumor signals. Tumor vascularity in malignant lesions gives rise to abnormal, high-velocity, Doppler-shifted signals that can help in the differential diagnosis of renal masses.