PRACTICAL PARALLEL IMAGING COMPRESSED SENSING MRI: SUMMARY OF TWO YEARS OF EXPERIENCE IN ACCELERATING BODY MRI OF PEDIATRIC PATIENTS.

For the last two years, we have been experimenting with applying compressed sensing parallel imaging for body imaging of pediatric patients. It is a joint-effort by teams from UC Berkeley, Stanford University and GE Healthcare. This paper aims to summarize our experience so far. We describe our acquisition approach: 3D spoiled-gradient-echo with poisson-disc random undersampling of the phase encodes. Our re-construction approach: ℓ1-SPIRiT, an iterative autocalibrating parallel imaging reconstruction that enforces both data consistency and joint-sparsity in the wavelet domain. Our implementation: an on-line parallelized implementation of ℓ1-SPIRiT on multi-core CPU and General Purpose Graphics Processors (GPGPU) that achieves sub-minute 3D reconstructions with 8-channels. Clinical results showing higher quality reconstruction and better diagnostic confidence than parallel imaging alone at accelerations on the order of number of coils.

Cortical reactivity and effective connectivity during REM sleep in humans.

We recorded the electroencephalographic (EEG) responses evoked by transcranial magnetic stimulation (TMS) during the first rapid eye movement (REM) sleep episode of the night and we compared them with the responses obtained during previous wakefulness and NREM sleep. Confirming previous findings, upon falling into NREM sleep, cortical activations became more local and stereotypical, indicating a significant impairment of the intracortical dialogue. During REM sleep, a state in which subjects regain consciousness but are almost paralyzed, TMS triggered more widespread and differentiated patterns of cortical activation, that were similar to the ones observed in wakefulness. Similarly, TMS/hd-EEG may be used to probe the internal dialogue of the thalamocortical system in brain injured patients that are unable to move and communicate.

Image-guided robotic radiosurgery

PURPOSE: To describe the design and performance of a novel frameless system for radiosurgery. This technology, called image-guided radiosurgery (IGR), eliminates the need for stereotactic frame fixation by relating the identified lesion to radiographic landmarks. CONCEPT: IGR uses a lightweight x-band linear accelerator, computer-controlled robotic arm (Fanuc manipulator [Fanuc Robotics North America, Inc., Rochester Hills, MI]), paired orthogonal x-ray imagers, and a computer workstation that performs rapid image-to-image registration. During radiosurgery, the x-ray imaging system determines the location of the lesion and communicates these coordinates to the robot, which adjusts the pointing of the linear accelerator beam to maintain alignment with the target. RATIONALE: Existing stereotactic techniques require rigid cranial fixation to establish and maintain a system of reference for targeting. Such frames cause pain for the patient, limit the use of fractionation, and necessitate a prolonged period of general anesthesia if children are to be treated. Furthermore, skeletal or any other type of rigid fixation is difficult to achieve beyond the cranium. IGR was designed to overcome these limitations, which are inherent to nearly all current radiosurgical methods. DISCUSSION: Preliminary testing and early clinical experience have demonstrated the practicality and potential of the IGR concept and have identified the most important directions for improvement. For example, an IGR prototype accurately tracked target displacements in three dimensions but showed reduced accuracy when confronted by rotational movements. This observation led to development of a new generation of tracking algorithm that promises to improve tracking in all six dimensions. Further experience indicated that improvements in the quality of the x-ray images were needed to allow the system to locate and treat target sites outside the cranium. Consequently, a new x-ray imaging technology with superior resolution and increased sensitivity has been added to the system. These improvements should make it possible to apply IGR techniques to a variety of targets located throughout the body. This article describes and critiques the components of the IGR and summarizes our preliminary clinical experience.

Molecular Action and Clinical Relevance of Aromatase Inhibitors.

BREAST CANCER: HIGH PREVALENCE AND RISING INCIDENCE: Breast cancer is the most common form of cancer among women in Europe, North and South America and Australasia; approximately 1 in 10 women in Western countries will develop breast cancer during their lifetime. It is estimated that the disease will affect five million women worldwide over the next decade, and the incidence of breast cancer is increasing on average by about 1% per year in industrialized countries and at a greater rate in developing countries. COMPLEX ETIOLOGY: Although the specific etiology of breast cancer remains unknown, a number of factors are recognized which increase a woman's risk of developing the disease. Genetic predisposition, or family history of breast cancer, is known to be responsible for 5% of all cases. However, the variation in incidence throughout populations, and changes relating to population migration and adoption of altered lifestyles, all point to the critical importance of nongenetic determinants. Such factors include early menarche, late menopause, late age at birth of first child or nulliparity, a history of benign breast disease, and diet. There is also evidence that hormones play a major role in the etiology of breast cancer, with the risk of developing malignancies related to the cumulative exposure of the breast to estrogen and progesterone, which stimulate the growth of tumor cells. TREATMENT FOR EARLY BREAST CANCER: SURGERY -/+ ADJUVANT THERAPY: At the time of diagnosis, approximately 50% of patients will be diagnosed with early breast cancer. This proportion is increasing as a consequence of the introduction of early detection programs. Surgery remains the primary treatment for early breast cancer, and the frequency of radical mastectomy has been replaced by breast conserving surgery. After surgery, other therapeutic modalities such as radiation, chemotherapy or endocrine therapy may be given in the adjuvant setting. Surgical cure rates vary for patients with early breast cancer; the US figure is approximately 40%, and there are no definitive means to predict those who will be cured and those who will have recurrent disease. As a result, following primary surgical treatment, adjuvant therapy is usually recommended to destroy any remaining cancer cells at the primary site, to control micrometastases and to prolong disease-free survival, with the ultimate aim of providing an overall survival benefit. Upon disease recurrence in the remaining 60% of patients, endocrine therapy and chemotherapy represent the two general classes of treatment. One of the principle decisions to be taken in advanced breast cancer is which therapy to select in order to maximize patient benefit. The choice is largely dependent upon prognostic factors and whether the patient is pre- or postmenopausal. ENDOCRINE THERAPY OR CHEMOTHERAPY IN ADVANCED BREAST CANCER: Unlike chemotherapy, endocrine therapy is not cytotoxic and is therefore better tolerated by the patient. A recent study comparing therapy for prognostically different groups showed that patients benefiting most from the use of sequential endocrine agents are those regarded as low risk. The preferred sequence of treatment has been suggested to be tamoxifen followed by selective aromatase inhibitor and then a progestin. ENDOCRINES AND ENZYMES OFFER NEW TREATMENTS FOR ADVANCED BREAST CANCER: ESTROGEN-DRIVEN BREAST CANCER: Since 1896, when Sir George Beatson demonstrated that ovariectomy induced regression of mammary tumors in women, the aim of endocrine breast cancer therapy has been to selectively deprive the body of estrogen. Ovariectomy accomplished this by removing the gland that is the predominant source of estrogens in premenopausal women. Since the avoidance of such surgery is preferable, emphasis is devoted to the pharmacological inhibitors of estrogen production. ENDOCRINE PATHWAY REVEALS "ACHILLES' HEEL": Like other steroid hormones, the two circulating estrogens-estrone and estradiol-are produced from cholesterol. Inhibiting the enzymes that are involved at earlier steps in the branching pathway of steroidogenesis could have an undesirable impact on the production of other physiologically important hormones such as aldosterone and cortisol. Since aromatase catalyzes the last step in estrogen production, it makes an ideal target for the development of selective and potent inhibitors (Fig. 1). STRUCTURE OF AROMATASE REVEALS SECRETS OF SELECTIVE INHIBITION: Aromatase is a cytochrome P450 enzyme, with both an iron-containing and a steroid-binding site. The substrate, androstenedione, sits in the enzyme's steroid-binding site, that site which otherwise catalyzes the formation of estrogen. From this structural relationship, there are, therefore, two reasonable ways to inhibit aromatase: * by occupying the steroid-binding site of the enzyme with a compound such as formestane (Lentaron®), or * by binding the iron with nitrogen-containing compounds such as aminoglutethimide (Orimeten®), the oldest aromatase inhibitor. AROMATASE INHIBITORS: STEROIDAL AND NON-STEROIDAL: Formestane (Lentaron®) is the only commercially available steroidal compound which inhibits aromatase and must be administered parenterally. Other new aromatase inhibitors such as fadrozole (Afema®) and letrozole (Femara®) are orally active nitrogen-containing compounds that bind the heme iron of aromatase. AMINOGLUTETHIMIDE VERSUS LETROZOLE: OLD VERSUS NEW: Although aminoglutethimide has long been used to treat advanced breast cancer, its aromatase inhibition is not selective. Consequently, aminoglutethimide also binds to and thereby inhibits several other cytochrome P450 enzymes in the steroidogenesis pathway. An ideal aromatase inhibitor would fit the catalytic site of aromatase optimally and would thus interact only with aromatase. The affinity of letrozole (Femara®) for the heme group of aromatase makes it a selective and potent inhibitor (Fig. 2). In fact, studies show that Femara® has little effect on the other adrenal steroids, and is the most selective aromatase inhibitor available today.

Tempus Fugit.

In northern hemispheres, October heralds the onset of autumn and we are reminded that its cool breezes will soon blow wintry as 1996 draws to a close. Tempus fugit! The swift passage of time also reminds us that the first volume of The Oncologist will soon conclude with its sixth issue in December. However, before 1996 becomes history, let's pause and reflect on the pledges we made to our readership at the beginning of the year. The Founding Editors conceived the Journal to provide authoritative, topical, innovative articles in an attractive format for a very special reader: the busy, practicing physician who cares for cancer patients. Our commitment is to critically review and publish papers designed to interpret the vast amounts of data available to physicians. As the famed radiotherapist and Founding Editor, Eli Glatstein, summarized, "The Oncologist emphasizes the interpretation rather than the data." The Oncologist to date has published more than forty manuscripts from international authorities. The inaugural issue featured, among other highly acclaimed papers, "Locally Advanced Breast Cancer," by Valero, Buzdar and Hortobagyi, and David Kuter's "Thrombopoietin: Biology and Clinical Applications." Fidias, Chabner and Grossbard contributed "Purine Analogs for the Treatment of Low-Grade Lymphoproliferative Disorders" in the next issue, and Pavletic and Armitage proffered an update on "Bone Marrow Transplantation for Cancer." Issue 4 highlighted Jemi Olak and Arthur Ng's "Diagnosis and Management of Early-Stage Non-Small Cell Lung Cancer," as well as "Multimodality Therapy for Esophageal Cancer" by Siewert, Stein and Fink. In this current issue, "Dose Intensity of Chemotherapy for Childhood Cancers," by Smith, Abrams, Trimble and Ungerleider, and "Surgical Sphincter Preservation in Rectal Cancer" by Peter M. Schlag present contemporary and authoritative views of two important clinical topics which also document the Journal's intent to discuss both adult and pediatric cancer care. Our Meet The Professor section is fast becoming a popular feature which attracts comments from readers and responses from the author professor. We call your attention to Professor Barrie R. Cassileth's fascinating article, "Alternative and Complementary Cancer Treatments," and her commentary in this issue. The Physician Education section has presented hematopoiesis through informative and beautifully illustrated papers with texts by distinguished hematologists and molecular biologists. In this issue, we feature the first Patient Care section, From The Bethesda Post, wherein clinical trials and experimental treatments are announced. In cooperation with The Cancer Letter, The Oncologist News Bulletin presents late-breaking news pertinent to the world's cancer care community. With this issue, we have instituted an addition to this section, featuring information from Memorial Sloan-Kettering Cancer Center on a study involving Ashkenazi Jewish women. We urge cancer centers, pharmaceutical and biotechnology companies to avail themselves of this section by sending our editorial office your newsworthy reports. We hope that our readers are benefiting from the Journal and enjoying the art which has graced it. In order to assess how well we are fulfilling our pledges to our readership, we need to hear from you. Tell us how we can make The Oncologist more relevant to your medical practice. We promise to share your comments with our Editorial Board to further enhance the Journal. In so doing, we will draw closer to fulfilling our pledge to you, our readers.