Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab.

BACKGROUND: Central nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab. METHODS: Eligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models. RESULTS: A total of 9020 patients were included. The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02-1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statistically significant differences were found based on trastuzumab schedule or median follow-up time. No evidence of publication bias was observed. CONCLUSIONS: Adjuvant trastuzumab is associated with a significant increased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients.

Pertuzumab for the treatment of patients with previously untreated HER2-positive metastatic breast cancer.

Pertuzumab is a humanized monoclonal antibody directed at the dimerization domain of the receptor tyrosine-protein kinase erbB-2 (HER2) receptor. It possesses a unique and complimentary mechanism of action compared to trastuzumab, which has historically been the cornerstone of therapy for HER2-amplified breast cancer. Clinical trials demonstrate improved outcomes, with minimal increases in toxicity with the addition of pertuzumab to trastuzumab in patients with HER2-positive metastatic breast cancer, indicating the advantage of dual HER2 receptor blockade. Pertuzumab is approved as first-line therapy in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer, with future opportunities to investigate its efficacy in other stages of breast cancer, as well as in the treatment of other malignancies.

Responses to subsequent anti-HER2 therapy after treatment with trastuzumab-DM1 in women with HER2-positive metastatic breast cancer.

BACKGROUND: Women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) can respond to multiple lines of anti-HER2 therapy. It is unknown whether these patients will derive further clinical benefit following treatment with trastuzumab-MCC-DM1 (T-DM1). PATIENTS AND METHODS: We retrospectively identified HER2-positive MBC patients treated with T-DM1 and characterized outcomes during subsequent lines of anti-HER2 therapy. Response was determined by a blinded radiology review. Time-dependent analyses were carried out using Kaplan-Meier estimates. RESULTS: We identified 23 patients treated with single-agent T-DM1 and report on the 20 patients who discontinued protocol therapy. All patients received trastuzumab-based metastatic therapy before initiation of T-DM1 [median 7 regimens (range 3-14)]. Of these 20 patients, 75% (15 of 20) received further therapy with or without anti-HER2 agents after discontinuing T-DM1. Partial response to either first- or second-subsequent line(s) of therapy was seen in 5 of 15 (33%) treated patients, including 33% (4 of 12) who received a regimen containing trastuzumab and/or lapatinib. Median durations of therapy to first- and second-subsequent regimens after T-DM1 were 5.5 and 6.4 months, respectively. CONCLUSIONS: In heavily pretreated HER2-positive MBC patients, prior exposure to T-DM1 does not exhaust the potential benefit of ongoing anti-HER2 therapy with trastuzumab- and/or lapatinib-based regimens.

Treatment of canine leukocyte adhesion deficiency by foamy virus vectors expressing CD18 from a PGK promoter.

Proto-oncogene activation caused by retroviral vector integration can cause malignancies in gene therapy trials. This has led investigators to search for less genotoxic vectors with minimal enhancer activity and a decreased risk of influencing neighboring chromosomal gene expression after integration. We previously showed that foamy virus (FV) vectors expressing the canine CD18 gene from an internal murine stem cell virus (MSCV) promoter could cure canine leukocyte adhesion deficiency (LAD). Here, we have repeated these studies using a FV vector expressing canine CD18 from a phosphoglycerate kinase (PGK) gene promoter. In vitro analysis showed that this vector did not contain an enhancer that activated neighboring genes, and it expressed CD18 efficiently in canine neutrophils and CD34+ cells. However, dogs that received hematopoietic stem cells transduced with the PGK-CD18 vector continued to suffer from LAD, and sometimes died prematurely of the disease. These studies show that the PGK promoter cannot effectively replace the MSCV promoter in CD18-expressing FV vectors, and they suggest that vectors containing a strong promoter-enhancer may be necessary for the treatment of human LAD.

Coccidioidal spondylitis: MR findings in 15 patients.

OBJECTIVE: MR imaging studies of 15 patients with documented vertebral column coccidioidomycosis infection were retrospectively reviewed to determine the MR imaging features of coccidioidal spondylitis. CONCLUSION: On MR imaging, coccidioidal spondylitis may be unifocal or multifocal. Involvement of an intervertebral disk, vertebral body marrow, and adjacent epidural and soft tissue is generally seen.

Cervical and lumbar MRI in asymptomatic older male lifelong athletes: frequency of degenerative findings.

OBJECTIVE: The athletic activity of the adult U.S. population has increased markedly in the last 20 years. To evaluate the possible long-term effects of such activity on the cervical and lumbar spine, we studied a group of asymptomatic currently very active lifelong male athletes over age 40 (41-69 years old, av. age 53). MATERIALS AND METHODS: Nineteen active, lifelong male athletes were studied with MRI and the results compared with previous imaging studies of other populations. An athletic history and a spine history were also taken. RESULTS: Evidence of asymptomatic degenerative spine disease was similar to that seen in published series of other populations. Degenerative changes including disk protrusion and herniation, spondylosis, and spinal stenosis were present and increased in incidence with increasing patient age. In this group, all MRI findings proved to be asymptomatic and did not limit athletic activity. CONCLUSION: The incidence of lumbar degenerative changes in our study population of older male athletes was similar to those seen in other populations.

Fast SE MRI of the chest: parameter optimization and comparison with conventional SE imaging.

OBJECTIVE: This study was performed to optimize scanning parameters for fast spin echo (FSE) T2-weighted scans of the chest and to compare FSE T2-weighted images with conventional spin echo (CSE) T2-weighted scans. MATERIALS AND METHODS: Thirty-nine FSE T2-weighted scans of the chest were obtained in 12 subjects to determine the effect of cardiac gating (with gating n = 20; without gating n = 19) and combinations of number of excitations (NEX) (2,4,8,16) and echo train length (ETL) (2,4,8,16) on scan quality and visibility of thoracic structures. An additional 15 chest MR examinations consisting of FSE T2- and CSE T1-, proton-density- (PD), and T2-weighted scans were obtained in 15 patients with a variety of thoracic abnormalities. The FSE T2-weighted scans were compared with CSE T2-weighted scans, and the combination of CSE T1- and FSE T2-weighted scans was compared with the combination of CSE PD- and T2-weighted scans. RESULTS: Little difference in image quality was found between cardiac-gated and nongated FSE scans. Increasing the ETL resulted in increased motion artifact. Forty lesions were detected with FSE and 42 lesions with CSE T2-weighted scans. Fifty-three lesions were detected with the combination of CSE T1- and FSE T2-weighted sequences, whereas 44 lesions were detected with the combination of CSE PD- and T2-weighted scans. CONCLUSIONS: The combination of cardiac-gated CSE T1- and non-cardiac-gated FSE T2-weighted scans was 20% more sensitive and twice as fast as the combination of cardiac-gated CSE PD- and T2-weighted scans.

Mental status guide: FROMAJE for use with frail elders.

1. There is no single pathognomonic sign, symptom, or clinical or laboratory test for making the diagnosis of dementia. A key element of the examination must be the inclusion of a mental status evaluation. 2. The FROMAJE--an acronym for Function, Reasoning, Orientation, Memory, Arithmetic, Judgment, and Emotion--Mental Status Guide (FMSG) has the advantage of a clear relationship between the acronym and the characteristics being measured. 3. The FMSG is meant to serve as a guide for the primary care clinician, who may have little experience in formal mental status testing. It is a convenient cognitive screening instrument to detect dementia in the elderly.

MR detection of white matter disease of the brain in patients with HIV infection: fast spin-echo vs conventional spin-echo pulse sequences.

OBJECTIVE: Although fast spin-echo images and slower spin-echo images have similar contrast characteristics, the two techniques have not yet been shown to be equivalent in all aspects of brain imaging. To determine if the two sequences are equivalent, we compared detection of white matter lesions, image quality, and artifact degradation on fast spin-echo and spin-echo proton density-weighted and T2-weighted MR images of the brain in prospectively selected patients who were seropositive for HIV. SUBJECTS AND METHODS: Fast spin-echo and spin-echo MR images of the brain were obtained in 153 consecutive subjects. The images were reviewed independently by three experienced neuroradiologists. The size, number, and location of white matter lesions were compared for the two techniques. Image quality, motion artifact, CSF flow artifact, and gray-white matter differentiation were graded on a five-point scale. RESULTS: No statistical difference was found in gray-white matter differentiation. Overall image quality, CSF flow artifacts, and motion artifacts were slightly worse on the fast spin-echo images (p < .05). Although some variability existed in the detection of lesions less than 5 mm in diameter, the differences was small, and all larger lesions were detected by both techniques. Agreement between fast spin-echo and conventional spin-echo techniques was nearly exact with respect to characterizing findings in brain as either normal or abnormal. CONCLUSIONS: Fast spin-echo and spin-echo MR of the brain produce images of similar quality and show white matter lesions equally well. These results support the replacement of slower, conventional spin-echo pulse sequences with faster fast spin-echo sequences.

Extraspinal abnormalities detected on MR images of the spine.

Surface-coil MR imaging of the spine is one of the most commonly performed MR imaging procedures. As the spine is the region of interest in these studies, extraspinal abnormalities may be overlooked. Such lesions can be difficult to perceive because they are out of the area of interest or distant from the surface coil. MR studies may be interpreted without other radiographic studies for comparison, as the other studies often have been performed elsewhere. Consequently, it is important for radiologists to be aware of the extraspinal anatomy and the appearances of extraspinal abnormalities. We describe the appearances of some common extraspinal diseases and normal variants detected with surface-coil MR imaging of the spine.

Cystosarcoma phyllodes of the prostate: MRI findings.

Cystosarcoma phyllodes of the prostate is a rare, relatively benign sarcoma of the prostate. We describe the magnetic resonance imaging findings in an unusual case of cystosarcoma phyllodes which resulted in extensive local recurrence and sarcomatous degeneration. Although uncommon, radiologists should be aware of the existence of cystosarcoma phyllodes of the prostate.

Diseases of the lumbar spine: findings on fat-suppression MR imaging.

Fat-suppression MR techniques have been useful in imaging both the head and neck and the orbit. The lumbar spine is not as complex as the head and neck and does not contain as much fat as the orbit. Nevertheless, high signal from epidural and marrow fat in the lumbar spine can make it difficult to detect and define pathologic processes. In addition, the administration of gadopentetate dimeglumine can cause some infectious and neoplastic lesions of the spine to become isointense with fat on T1-weighted images. Compared with conventional MR imaging without fat suppression, contrast-enhanced fat-suppression MR imaging can better differentiate these enhancing lesions from surrounding fat. In this essay, we illustrate the findings of fat-suppression MR imaging in a variety of diseases of the lumbar spine.

Frontal sinus fractures: evaluation of CT scans in 132 patients.

PURPOSE: To determine the frequency of detection of frontal sinus fractures on initial CT scans of patients with intracranial injuries, and to characterize associated injuries. METHODS: The initial head CT scans in 132 patients with clinical or radiographic evidence of a frontal sinus fracture were retrospectively reviewed to further characterize the fracture. Additional radiographic studies and medical records were reviewed to determine associated injuries, therapy, clinical outcome, and complications. RESULTS: In 90% (124) of the patients, the frontal sinus fractures were visualized on initial head CT scans that were obtained to evaluate suspected intracranial injury. Complex fractures involving both the anterior and posterior wall of the sinus accounted for 65% of cases (86 patients), whereas fractures of the anterior wall only or posterior wall only occurred in 24% (32) and 11% (14) of patients, respectively. Significant intracranial hemorrhage occurred in over 90% of patients with fractures involving the posterior wall. CONCLUSIONS: In general, fractures that involved the posterior wall had more complications and a worse clinical outcome than fractures that only involved the anterior wall; nearly all frontal sinus fractures can be detected on head CT studies in patients with intracranial injuries.

Osseous metastasis in medulloblastoma: MRI findings in an unusual case.

An 11-year-old boy with a history of medulloblastoma developed blastic osseous metastases. The metastases were detected by noting diffuse areas of low signal intensity within the calvarium on T1-weighted and T2-weighted magnetic resonance (MR) scans of the brain. The MR appearance of osseous metastases in medulloblastoma has not been reported previously. Extraneural metastases in medulloblastoma are relatively rare. The literature is briefly reviewed.

Mechanism of the positive inotropic effect of milrinone in cultured embryonic chick ventricular cells.

Milrinone, a potent positive inotropic and vasodilating agent, has shown promise in the clinical treatment of congestive heart failure, but significant controversy about its mechanism of action exists. To approach these mechanistic problems in a non-innervated, non-diffusion-limited system, the effects of milrinone on cultured embryonic chick ventricular cells were examined. At 37 degrees C in physiologic buffer, milrinone produced a rapid, concentration-dependent increase in amplitude of contraction that was 45% of the maximum increment in contraction produced by elevated extracellular calcium; the EC50 was 8 microM. This peak response was quantitatively similar to the contractile response produced by isobutyl methylxanthine, a potent phosphodiesterase inhibitor. Milrinone inhibited 70% of total phosphodiesterase activity of cultured ventricular cells with an EC50 of 11 microM. Exposure to 1 X 10(-4) M milrinone resulted in rapid increase in cyclic AMP content to levels greater than 100% above control within 4 min. The same concentration also produced a 43% increase in the rate of transsarcolemmal 45Ca uptake. The stimulation of 45Ca uptake rate was similar to the response produced by 1 microM isoproterenol and could be completely abolished by 10 microM verapamil. Thus, in cultured embryonic chick myocardial cells, the positive inotropic effect of milrinone is largely, if not entirely, attributable to phosphodiesterase inhibition, leading to intracellular cyclic AMP accumulation and stimulation of transsarcolemmal calcium influx via the slow calcium channel.

Immunological assay of pancreatic ribonuclease in serum as an indicator of pancreatic cancer.

Serum levels of RNase activity, presumed to originate in the pancreas, have been suggested to be of use in the diagnosis of pancreatic cancer. We have used a radioimmunological assay of human pancreatic-like RNase to quantitate this protein in serum from normal blood donors and patients with a variety of diseases. Serum pancreatic-like RNase rises gradually with age, and its level is usually higher in males than females. Although many patients with pancreatic cancer show elevated serum levels of immunologically cross-reactive enzyme, others are apparently normal. In several other types of cancer, a similar pattern of elevated RNase is apparent. However, in kidney or bladder carcinoma and in patients with severe kidney disease, RNase levels are almost always greater than normal. Regardless of the nature of the disease, an elevated level of pancreatic-like enzyme is usually accompanied by above-normal levels of serum urea nitrogen. Hence, elevated circulating levels of pancreatic-like RNase are best related to kidney function and do not serve as a specific marker for cancers of the pancreas or other organs.