Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases.

BACKGROUND: Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models. PATIENTS AND METHODS: This was a phase I study of tucatinib with trastuzumab, without chemotherapy, in patients with progressive, measurable HER2-positive brain metastases. The study tested two schedules of tucatinib: cohort A was twice daily and cohort B was once daily. The primary objective was determination of the maximum tolerated dose (MTD). Secondary end points included objective response (intracranial and extracranial) using modified RECIST and clinical benefit rate (CBR). RESULTS: Overall, 41 patients were enrolled (cohort A, n = 22; cohort B, n = 19). Patients had a median of two prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The MTD of tucatinib for cohort A was 300 mg twice daily and for cohort B was 750 mg once daily. The most common dose-limiting toxicities included thrombocytopenia and aspartate transaminase/alanine aminotransferase elevation. Grade 3/4 aspartate transaminase/alanine aminotransferase elevation occurred in nine of 41 patients (22%). Intracranial responses were observed in two of 17 (12%) patients in cohort A and one of 17 (6%) patients in cohort B treated at the MTD. In cohort A, CBR at 16 weeks was 35% (n = 6). In cohort B, CBR at 16 weeks was 53% (n = 9). Of 15 patients overall who experienced clinical benefit, 12 (80%) had received prior neratinib and/or lapatinib. Median progression-free survival for cohorts A and B was 3.4 and 4.1 months, respectively. CONCLUSION: The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases. CLINICAL TRIAL REGISTRATION: NCT01921335.

Intense star formation within resolved compact regions in a galaxy at z = 2.3.

Massive galaxies in the early Universe have been shown to be forming stars at surprisingly high rates. Prominent examples are dust-obscured galaxies which are luminous when observed at sub-millimetre wavelengths and which may be forming stars at a rate of 1,000 solar masses (M(middle dot in circle)) per year. These intense bursts of star formation are believed to be driven by mergers between gas-rich galaxies. Probing the properties of individual star-forming regions within these galaxies, however, is beyond the spatial resolution and sensitivity of even the largest telescopes at present. Here we report observations of the sub-millimetre galaxy SMMJ2135-0102 at redshift z = 2.3259, which has been gravitationally magnified by a factor of 32 by a massive foreground galaxy cluster lens. This magnification, when combined with high-resolution sub-millimetre imaging, resolves the star-forming regions at a linear scale of only 100 parsecs. We find that the luminosity densities of these star-forming regions are comparable to the dense cores of giant molecular clouds in the local Universe, but they are about a hundred times larger and 10(7) times more luminous. Although vigorously star-forming, the underlying physics of the star-formation processes at z approximately 2 appears to be similar to that seen in local galaxies, although the energetics are unlike anything found in the present-day Universe.

Embryo quality but not pronuclear score is associated with clinical pregnancy following IVF.

PURPOSE: The association between pronuclear (PN) scoring of embryos from assisted reproductive technology (ART) and clinical pregnancy remains controversial. We hypothesized that embryos with PNs scored on the day of fertilization check offer better embryo selection on day 3 and higher CPR compared to non-PN scored embryos. METHODS: Patients (19-46 years) undergoing IVF/ICSI cycles at Montefiore's Institute for Reproductive Medicine and Health between January 2006 and December 2009 were included in our study. We analyzed fresh day 3 cycles only with autologous oocytes and partner's fresh sperm (n = 344). A total of 1,899 embryos were included. We compared CPR from non-PN scored embryos (Group 1, n = 835) with PN scored embryos (Group 2, n = 1,064). Composite scores by patient were developed based on embryo disposition. We also assessed traditional embryo grading derived from cell number, fragmentation and cell symmetry. Data analysis included chi square and t test to determine if PN scoring was associated with improved CPR, and to compare the additional variables. RESULTS: CPR between Group 1 and Group 2 were not different (p = 0.91). CPR was significantly associated with female age, number of mature oocytes retrieved, number of day 3 embryos and grade of embryos transferred on day 3 (p < 0.05). CONCLUSION: PN scoring was not associated with improved CPR in day 3 embryo transfers. Mean grade of transferred embryos continues to be a well-established, independent predictor of CPR. We conclude that further refinement of embryo grading by PN scoring is not beneficial.

The Opioid Analgesic Reduction Study (OARS) Pilot: A Double-Blind Randomized Multicenter Trial.

BACKGROUND: With addiction rates and opioid deaths increasing, health care providers are obligated to help stem the opioid crisis. As limited studies examine the comparative effectiveness of fixed-dose combination nonopioid analgesia to opioid-containing analgesia, a comparative effectiveness study was planned and refined by conducting a pilot study. METHODS: The Opioid Analgesic Reduction Study (OARS) pilot, a stratified, randomized, multisite, double-blind clinical trial, was designed to test technology and procedures to be used in the full OARS trial. Participants engaged in the full protocol, enabling the collection of OARS outcome data. Eligible participants reporting to 1 of 5 sites for partial or full bony impacted mandibular third molar extraction were stratified by biologic sex and randomized to 1 of 2 treatment groups, OPIOID or NONOPIOID. OPIOID participants were provided 20 doses of hydrocodone 5 mg/acetaminophen 300 mg. NONOPIOID participants were provided 20 doses of ibuprofen 400 mg/acetaminophen 500 mg. OARS outcomes data, including pain experience, adverse effects, sleep quality, pain interference, overall satisfaction, and remaining opioid tablets available for diversion, were collected via surveys, electronic medication bottles, eDiary, and activity/sleep monitor. RESULTS: Fifty-three participants were randomized with 50 completing the OARS pilot protocol. Across all outcome pain domains, in all but 1 time period, NONOPIOID was better in managing pain than OPIOID (P < 0.05 level). Other outcomes suggest less pain interference, less adverse events, better sleep quality, better overall satisfaction, and fewer opioid-containing tablets available for diversion. DISCUSSION: Results suggest patients requiring impacted mandibular third molar extraction would benefit from fixed-dose combination nonopioid analgesia. KNOWLEDGE TRANSFER STATEMENT: Study results suggest fixed-dose nonopioid combination ibuprofen 400 mg/acetaminophen 500 mg is superior to opioid-containing analgesic (hydrocodone 5 mg/acetaminophen 500 mg). This knowledge should inform surgeons and patients in the selection of postsurgical analgesia.

An inactivating caspase 11 passenger mutation originating from the 129 murine strain in mice targeted for c-IAP1.

A recent study revealed that ES (embryonic stem) cell lines derived from the 129 murine strain carry an inactivating mutation within the caspase 11 gene (Casp4) locus [Kayagaki, Warming, Lamkanfi, Vande Walle, Louie, Dong, Newton, Qu, Liu, Heldens, Zhang, Lee, Roose-Girma and Dixit (2011) Nature 479, 117-121]. Thus, if 129 ES cells are used to target genes closely linked to caspase 11, the resulting mice might also carry the caspase 11 deficiency as a passenger mutation. In the present study, we examined the genetic loci of mice targeted for the closely linked c-IAP (cellular inhibitor of apoptosis) genes, which were generated in 129 ES cells, and found that, despite extensive backcrossing into a C57BL/6 background, c-IAP1(-/-) animals are also deficient in caspase 11. Consequently, data obtained from these mice should be re-evaluated in this new context.

Impact of DHCWs' Safety Perception on Vaccine Acceptance and Adoption of Risk Mitigation Strategies.

OBJECTIVES: To estimate the association between safety perception on vaccine acceptance and adoptions of risk mitigation strategies among dental health care workers (DHCWs). METHODS: A survey was emailed to DHCWs in the New Jersey area from December 2020 to January 2021. Perceived safety from regular SARS-CoV-2 testing of self, coworkers, and patients and its association with vaccine hesitancy and risk mitigation were ascertained. Risk Mitigation Strategy (RiMS) scores were computed from groupings of office measures: 1) physical distancing (reduced occupancy, traffic flow, donning of masks, minimal room crowding), 2) personal protective equipment (fitted for N95; donning N95 masks; use of face shields; coverings for head, body, and feet), and 3) environmental disinfection (suction, air filtration, ultraviolet, surface wiping). RESULTS: SARS-CoV-2 testing of dental professionals, coworkers, and patients were perceived to provide safety at 49%, 55%, and 68%, respectively. While dentists were least likely to feel safe with regular self-testing for SARS-CoV-2 (P < 0.001) as compared with hygienists and assistants, they were more willing than hygienists (P = 0.004; odds ratio, 1.79 [95% CI, 1.21 to 2.66]) and assistants (P < 0.001; odds ratio, 3.32 [95% CI, 1.93 to 5.71]) to receive the vaccine. RiMS scores ranged from 0 to 19 for 467 participants (mean [SD], 10.9 [2.9]). RiMS scores did not significantly differ among groups of DHCWs; however, mean RiMS scores were higher among those who received or planned to receive the COVID-19 vaccine than those with who did not (P = 0.004). DHCWs who felt safer with regular testing had greater RiMS scores than those who did not (11.0 vs. 10.3, P = 0.01). CONCLUSIONS: Understanding DHCWs' perception of risk and safety is crucial, as it likely influences attitudes toward testing and implementation of office risk mitigation policies. Clinical studies that correlate risk perception and RiMS with SARS-CoV-2 testing are needed to demonstrate the effectiveness of RiMS in dental care settings. KNOWLEDGE TRANSFER STATEMENT: Educators, clinicians, and policy makers can use the results of this study when improving attitudes toward testing and implementation of risk mitigation policies within dental offices, for current and future pandemics.

The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation.

The folding of both wild-type and mutant forms of the cystic-fibrosis transmembrane-conductance regulator (CFTR), a plasma-membrane chloride-ion channel, is inefficient. Most nascent CFTR is retained in the endoplasmic reticulum and degraded by the ubiquitin proteasome pathway. Aberrant folding and defective trafficking of CFTRDeltaF508 is the principal cause of cystic fibrosis, but how the endoplasmic-reticulum quality-control system targets CFTR for degradation remains unknown. CHIP is a cytosolic U-box protein that interacts with Hsc70 through a set of tetratricorepeat motifs. The U-box represents a modified form of the ring-finger motif that is found in ubiquitin ligases and that defines the E4 family of polyubiquitination factors. Here we show that CHIP functions with Hsc70 to sense the folded state of CFTR and targets aberrant forms for proteasomal degradation by promoting their ubiquitination. The U-box appeared essential for this process because overexpresion of CHIPDeltaU-box inhibited the action of endogenous CHIP and blocked CFTR ubiquitination and degradation. CHIP is a co-chaperone that converts Hsc70 from a protein-folding machine into a degradation factor that functions in endoplasmic-reticulum quality control.

Boston biorepository, recruitment and integrative network (BBRAIN): A resource for the Gulf War Illness scientific community.

AIMS: Gulf War Illness (GWI), a chronic debilitating disorder characterized by fatigue, joint pain, cognitive, gastrointestinal, respiratory, and skin problems, is currently diagnosed by self-reported symptoms. The Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) is the collaborative effort of expert Gulf War Illness (GWI) researchers who are creating objective diagnostic and pathobiological markers and recommend common data elements for GWI research. MAIN METHODS: BBRAIN is recruiting 300 GWI cases and 200 GW veteran controls for the prospective study. Key data and biological samples from prior GWI studies are being merged and combined into retrospective datasets. They will be made available for data mining by the BBRAIN network and the GWI research community. Prospective questionnaire data include general health and chronic symptoms, demographics, measures of pain, fatigue, medical conditions, deployment and exposure histories. Available repository biospecimens include blood, plasma, serum, saliva, stool, urine, human induced pluripotent stem cells and cerebrospinal fluid. KEY FINDINGS: To date, multiple datasets have been merged and combined from 15 participating study sites. These data and samples have been collated and an online request form for repository requests as well as recommended common data elements have been created. Data and biospecimen sample requests are reviewed by the BBRAIN steering committee members for approval as they are received. SIGNIFICANCE: The BBRAIN repository network serves as a much needed resource for GWI researchers to utilize for identification and validation of objective diagnostic and pathobiological markers of the illness.

A foldable CFTR{Delta}F508 biogenic intermediate accumulates upon inhibition of the Hsc70-CHIP E3 ubiquitin ligase.

CFTRDeltaF508 exhibits a correctable protein-folding defect that leads to its misfolding and premature degradation, which is the cause of cystic fibrosis (CF). Herein we report on the characterization of the CFTRDeltaF508 biogenic intermediate that is selected for proteasomal degradation and identification of cellular components that polyubiquitinate CFTRDeltaF508. Nonubiquitinated CFTRDeltaF508 accumulates in a kinetically trapped, but folding competent conformation, that is maintained in a soluble state by cytosolic Hsc70. Ubiquitination of Hsc70-bound CFTRDeltaF508 requires CHIP, a U box containing cytosolic cochaperone. CHIP is demonstrated to function as a scaffold that nucleates the formation of a multisubunit E3 ubiquitin ligase whose reconstituted activity toward CFTR is dependent upon Hdj2, Hsc70, and the E2 UbcH5a. Inactivation of the Hsc70-CHIP E3 leads CFTRDeltaF508 to accumulate in a nonaggregated state, which upon lowering of cell growth temperatures, can fold and reach the cell surface. Inhibition of CFTRDeltaF508 ubiquitination can increase its cell surface expression and may provide an approach to treat CF.

Intracerebral hemorrhage in complement C3-deficient mice.

The complement cascade is activated and contributes to brain damage after intracerebral hemorrhage (ICH). The present study investigated ICH-induced brain damage in complement C3-deficient mice. This study was divided into 2 parts. Male C3-deficient and C3-sufficient mice received an infusion of 30-microl autologous whole blood into the right basal ganglia. In the first part of our study, mice were killed 3 days later for brain water content measurement. Behavioral assessments including forelimb use asymmetry and corner turn tests were also preformed before and after ICH. In the second part of the study, brain heme oxygenase-1 (HO-1) was measured by Western blot analysis and immunohistochemistry 3 days after the infusion. We found that brain water content in the ipsilateral basal ganglia 3 days after ICH was less in C3-deficient mice compared to C3-sufficient mice (p < 0.05). The C3-deficient mice had reduced ICH-induced forelimb use asymmetry deficits compared with C3-sufficient mice (p < 0.05), although there was no significant difference in the corner turn test score. Western blot analysis showed that HO-1 contents were significantly lower in C3-deficient mice (day 3: 2024 +/- 560 vs. 5140 +/- 1151 pixels in the C3-sufficient mice, p < 0.05). We conclude that ICH causes less brain edema and behavioral deficits in complement C3-deficient mice. These results suggest that complement C3 is a key factor contributing to brain injury following ICH.

Risk of pneumonitis in breast cancer patients treated with radiation therapy and combination chemotherapy with paclitaxel.

BACKGROUND: Some chemotherapy (CT) drugs, including taxanes, may enhance the effectiveness of radiation therapy (RT). However, combining these therapies may increase the incidence of radiation pneumonitis, a lung inflammation. In a retrospective cohort study, we evaluated the incidence of radiation pneumonitis in breast cancer patients treated with RT and standard adjuvant CT by use of doxorubicin (Adriamycin) and cyclophosphamide, with and without paclitaxel. METHODS: Forty-one patients with breast cancer were treated with RT and adjuvant CT, including paclitaxel. Paclitaxel and RT (to breast-chest wall in all and lymph nodes in some) were delivered sequentially in 20 patients and concurrently in 21 patients. Paclitaxel was given weekly in some patients and every 3 weeks in other patients. The incidence of radiation pneumonitis was compared with that among patients in our database whose treatments did not include paclitaxel (n = 1286). The percentage of the lung volume irradiated was estimated. The Cox proportional hazards model was used to find covariates that may be associated with the observed outcomes. All P values were two-sided. RESULTS: Radiation pneumonitis developed in six of the 41 patients. Three patients received paclitaxel concurrently with RT, and three received it sequentially (P =.95). The mean percentage of lung volume irradiated was 20% in patients who developed radiation pneumonitis and 22% in those who did not (P =.6). For patients treated with CT including paclitaxel, the crude rate of developing radiation pneumonitis was 14.6% (95% confidence interval [CI] = 5.6% to 29.2%). For patients treated with CT without paclitaxel, the crude rate of pneumonitis was 1.1% (95% CI = 0.2% to 2.3%). The difference between the crude rates with or without paclitaxel is highly statistically significant (P<.0001). The mean time to develop radiation pneumonitis in patients treated concurrently with RT and paclitaxel was statistically significantly shorter in patients receiving paclitaxel weekly than in those receiving it every 3 weeks (P =.002). CONCLUSIONS: The use of paclitaxel and RT in the primary treatment of breast cancer should be undertaken with caution. Clinical trials with the use of combination CT, including paclitaxel plus RT, whether concurrent or sequential, must evaluate carefully the incidence of radiation pneumonitis.

Docetaxel administered on a weekly basis for metastatic breast cancer.

PURPOSE: To evaluate the safety and efficacy of weekly docetaxel in women with metastatic breast cancer. PATIENTS AND METHODS: Twenty-nine women were enrolled onto a study of weekly docetaxel given at 40 mg/m(2)/wk. Each cycle consisted of 6 weeks of therapy followed by a 2-week treatment break, repeated until disease progression or removal from study for toxicity or patient preference. Fifty-two percent of patients had been previously treated with adjuvant chemotherapy; 21% had received prior chemotherapy for metastatic breast cancer, and 31% had previously received anthracyclines. All patients were assessable for toxicity; two patients were not assessable for response but are included in an intent-to-treat analysis. RESULTS: Patients received a median of 18 infusions, with a median cumulative docetaxel dose of 720 mg/m(2). There were no complete responses. Twelve patients had partial responses (overall response rate, 41%; 95% confidence interval, 24% to 61%), all occurring within the first two cycles. Similar response rates were observed among subgroups of patients previously treated either with any prior chemotherapy or with anthracyclines. An additional 17% of patients had stable disease for at least 6 months. The regimen was generally well tolerated. There was no grade 4 toxicity. Only 28% of patients had any grade 3 toxicity, most commonly neutropenia and fatigue. Acute toxicity, including myelosuppression, was mild. Fatigue, fluid retention, and eye tearing/conjunctivitis became more common with repetitive dosing, although these side effects rarely exceeded grade 2. Dose reductions were made for eight of 29 patients, most often because of fatigue (n = 5). CONCLUSION: Weekly docetaxel is active in treating patients with metastatic breast cancer, with a side effect profile that differs from every-3-weeks therapy.

Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer.

PURPOSE: To determine the response rate and toxicity profile of trastuzumab administered concurrently with weekly vinorelbine in women with HER2-overexpressing advanced breast cancer. PATIENTS AND METHODS: Forty women with HER2-positive (+3 by immunohistochemistry, n = 30; +2 or positive, n = 10) breast cancer were enrolled onto a study of trastuzumab (4 mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose adjusted each week for neutrophil count). Eighty-two percent of women had received prior chemotherapy as part of adjuvant (30%), metastatic (25%), or both (28%) treatment, including substantial portions of patients who had previously received either anthracyclines (20%), taxanes (15%), or both types (38%) of chemotherapy. RESULTS: Responses were observed in 30 of 40 patients (overall response rate, 75%, conditional corrected 95% confidence interval, 57% to 89%). The response rate was 84% in patients treated with trastuzumab and vinorelbine as first-line therapy for metastatic disease, and 80% among HER2 +3 positive patients. High response rates were also seen in women treated with second- or third-line therapy, and among patients previously treated with anthracyclines and/or taxanes. Combination therapy was feasible; patients received concurrent trastuzumab and vinorelbine in 93% of treatment weeks. Neutropenia was the only grade 4 toxicity. No patients had symptomatic heart failure. Grade 2 cardiac toxicity was observed in three patients. Prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-existing cardiac function were associated with grade 2 cardiac toxicity. CONCLUSION: Trastuzumab in combination with vinorelbine is highly active in women with HER2-overexpressing advanced breast cancer and is well tolerated.

Cystic fibrosis transmembrane conductance regulator as a model substrate to study endoplasmic reticulum protein quality control in mammalian cells.

Components of the ubiquitin-proteasome system function on the surface of the endoplasmic reticulum (ER) to select misfolded proteins for degradation. Herein we describe methods that allow for the study of the pathway for proteasomal degradation of the cystic fibrosis transmembrane conductance regulator (CFTR). The experimental system described employs transiently transfected HEK-293 cells and is utilized to monitor the biogenesis of CFTR by Western blot and pulse-chase analysis.

Circulating HER-2/erbB-2/c-neu (HER-2) extracellular domain as a prognostic factor in patients with metastatic breast cancer: Cancer and Leukemia Group B Study 8662.

PURPOSE: The HER-2/erbB-2/c-neu (HER-2) proto-oncogene is a M(r) 185,000 transmembrane tyrosine kinase that is amplified and/or overexpressed by 20-40% of breast cancers. HER-2 has been associated with worse prognosis and resistance or sensitivity to specific treatment. We evaluated circulating levels of extracellular domain of HER-2 (ECD/HER-2) in metastatic breast cancer patients and investigated the prognostic and predictive significance of circulating HER-2 levels regarding endocrine therapy or chemotherapy. EXPERIMENTAL DESIGN: Plasma samples from 242 patients were assayed for circulating ECD/HER-2 levels, using a sandwich enzyme immunoassay. ECD/HER-2 was correlated with clinical data gathered from these patients while they were participating in prospective Cancer and Leukemia Group B (CALGB) therapeutic protocols for metastatic breast cancer. RESULTS: Eighty-nine (37%) of 242 patients had elevated ECD/HER-2 levels (> or =10.5 ng/ml). ECD/HER-2 was significantly associated with tumor burden, progesterone receptor levels, and presence of visceral metastases. Patients with elevated pretreatment levels had a significantly shorter OS but not time-to-progression than did those with ECD/HER-2 levels <10.5 ng/ml in univariate analysis. In univariate but not multivariate subset analyses, among patients treated with endocrine therapy (megestrol acetate), elevated initial ECD/HER-2 was associated with worse OS compared with nonelevated patients. However, among patients treated with chemotherapy (mainly anthracycline-containing regimens), OS did not differ significantly. Rates of response to either endocrine therapy or chemotherapy were similar for patients with elevated and nonelevated ECD/HER-2 levels. CONCLUSIONS: ECD/HER-2 levels are elevated in 35-40% of patients with metastatic breast cancer. Elevated ECD/HER-2 levels are associated with a poorer prognosis in these patients. However, no predictive role for ECD/HER-2 was identified, either for endocrine therapy or for anthracycline-based chemotherapy in the metastatic setting.

Relationship of pain and ancestry in African American women.

BACKGROUND: African Americans are reported to be more sensitive to pain than European Americans. Pain sensitivity has been shown to be genetically linked in animal models and is likely to be in humans. METHODS: Exactly, 11,239 self-identified African American post-menopausal women enrolled in the Women's Health Initiative had percentage African ancestry determined by ancestry informative markers, "Pain Construct" measurements and covariate information. They answered five questions about specific types and location of pain, such as joint, neck, low back, headache and urinary. They also answered two questions which were used to derive a "Pain Construct", a measure of general pain scored on a scale of 1-100. Associations were tested in linear regression models adjusting for age, self-reported medical conditions, neighbourhood socio-economic status, education and depression. RESULTS: In the unadjusted model of the five specific types of pain measures, greater pain perception was associated with a higher proportion of African ancestry. However, some of the specific types of pain measures were no longer associated with African ancestry after adjustment for other study covariates. The Pain Construct was statistically significantly associated with African ancestry in both the unadjusted [ß = -0.132, 95% confidence interval (CI) = -099 to -0.164; r = -0.075, 95% CI -0.056 to -0.093] and the adjusted models (ß = -0.069 95% CI = -0.04 to -0.10). CONCLUSIONS: Greater African ancestry was associated with higher levels of self-reported pain, although this accounted for only a minor fraction of the overall variation in the Pain Construct.

Systemic complement depletion diminishes perihematomal brain edema in rats.

BACKGROUND AND PURPOSE: The complement cascade is activated after experimental intracerebral hemorrhage (ICH). It remains unclear, however, whether depleting the complement system will improve injury resulting from ICH. This study investigated the effects of systemic complement depletion on brain edema formation after ICH. METHODS: Fifty-six pentobarbital-anesthetized Sprague-Dawley rats were used. Treatment animals were complement-depleted with cobra venom factor (CVF) (intraperitoneally). Control rats received an equal volume of saline injection (intraperitoneally). In both treatment and control rats, autologous blood (100 microL) was infused stereotaxically into the right basal ganglia. Rats were killed 2, 24, or 72 hours later for brain water, ion, and tumor necrosis factor-alpha (TNF-alpha) measurements, for Western blot analysis, and for immunohistochemical studies. Brain edema was quantitated by wet/dry weight. TNF-alpha levels were measured by enzyme-linked immunosorbent assay. Western blot analysis was applied for C9 semiquantification. Immunohistochemistry was used to detect complement C3d, C5a, C9, and myeloperoxidase. RESULTS: Perihematomal brain edema was reduced by systemic complement depletion at 24 hours (78.8+/-0.6% versus 81.5+/-0.8% in control, P:<0.01) and 72 hours (81.5+/-1.5% versus 83.6+/-0.9% in control, P:<0.05), while cerebellar water content was unaffected (78.2+/-0.3% versus 78.0+/-0. 1%). Complement depletion reduced TNF-alpha production 2 hours after ICH. Immunocytochemistry showed that complement depletion significantly reduced perihematomal C9 deposition, C3d production, and the number of C5a- and myeloperoxidase-positive cells. CONCLUSIONS: Complement depletion by CVF attenuates brain edema in ICH, indicating that complement activation plays an important role in ICH-induced brain edema. Preventing complement activation may be effective in the treatment of ICH.

Rapid reduction of platelet count in essential hemorrhagic thrombocythemia by discontinuous flow plateletpheresis.

Dramatic reduction of the platelet count by discontinuous flow plateletpheresis was achieved safely and swiftly in a patient with essential hemorrhagic thrombocythemia. The patient had a history of thrombo-occlusive arterial disease and on admission had gastrointestinal bleeding. This technic is recommended as an effective means of rapidly controlling marked increase in the platelet count and its consequences in the interval before chemotherapy becomes effective.

Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages.

PURPOSE: To determine the efficacy, dose-response relationship, and safety of 30, 60, and 90 mg of a single intravenous dose of an aminobisphosphonate, pamidronate (APD), for the treatment of moderate to severe hypercalcemia of malignancy. PATIENTS AND METHODS: Patients with histologically proven cancer and a corrected serum calcium level of at least 12.0 mg/dL after 48 hours of normal saline hydration were enrolled in a double-blind, multicenter, randomized clinical trial. Pamidronate in 30-, 60-, or 90-mg doses was administered as a single 24-hour infusion. Serum calcium corrected for albumin, urine hydroxyproline, and calcium excretion, and serum parathyroid hormone (PTH) (1-84) were determined before and after pamidronate therapy. RESULTS: Thirty-two men and 18 women entered the study. A dose-response relationship for normalization of corrected serum calcium was seen after pamidronate administration. Corrected serum calcium normalized in 40% of patients who received 30 mg, in 61% of patients who received 60 mg, and in 100% of patients who received 90 mg of pamidronate. The decline in the serum calcium level was associated with decreased osteoclastic skeletal resorption evidenced by a decrease in urine calcium and hydroxyproline excretion. Among those with a normalized corrected serum calcium level, the mean (median) duration of normalization of the corrected serum calcium value was 9.2 (4), 13.3 (5), and 10.8 (6) days in the 30-, 60-, and 90-mg treatment groups, respectively. The response of hypercalcemia to pamidronate was not significantly influenced by the presence of skeletal metastases. PTH 1-84, suppressed in patients on entry into this study, increased to a greater extent in those patients with osteolytic skeletal metastases compared with those with humoral hypercalcemia of malignancy. Clinical improvement, including improved mental status and decreased anorexia, accompanied the decline in the corrected serum calcium level in all three treatment groups. Side effects included low-grade fever, asymptomatic hypocalcemia, hypomagnesemia, and hypophosphatemia. CONCLUSIONS: A single-dose infusion of 60 to 90 mg of pamidronate was highly effective and well tolerated and normalized corrected serum calcium in nearly all patients (61% to 100%) with hypercalcemia of malignancy.

Usefulness of hypotension during dobutamine echocardiography in predicting perioperative cardiac events.

This study was undertaken to determine the prognostic significance of hypotension induced during preoperative dobutamine stress echocardiography (DSE) before vascular and noncardiac thoracic surgery. Wall motion abnormality during DSE predicts perioperative risk. Although hypotension during DSE has not been shown to correlate with the presence or severity of coronary artery disease, its significance in perioperative risk assessment is unknown. We retrospectively studied 300 patients who had DSE within 6 months of noncardiac surgery. Perioperative events including death, myocardial infarction, ischemia, and arrhythmias were recorded. Odds ratios with 95% confidence intervals were used to examine the association between clinical and echocardiographic variables and perioperative events. A hypotensive response during DSE was seen in 85 patients (28%). Forty-eight patients (16%) had 54 perioperative complications including 4 cardiac-related deaths, 10 myocardial infarctions, 12 myocardial ischemic events, and 28 arrhythmias. Hypotension during DSE was predictive of the combined end point of perioperative cardiac mortality, myocardial infarction, and ischemia (odds ratio 4.04, 95% confidence interval 1.72 to 9.51). In a multivariate logistic regression model, hypotension during DSE remained a significant predictor (odds ratio 4.10, p<0.01). DSE-related hypotension was predictive of perioperative cardiac events and therefore may have a role in risk stratification before vascular or noncardiac thoracic surgery.