Monkeypox Outbreak - Nine States, May 2022.

On May 17, 2022, the Massachusetts Department of Public Health (MDPH) Laboratory Response Network (LRN) laboratory confirmed the presence of orthopoxvirus DNA via real-time polymerase chain reaction (PCR) from lesion swabs obtained from a Massachusetts resident. Orthopoxviruses include Monkeypox virus, the causative agent of monkeypox. Subsequent real-time PCR testing at CDC on May 18 confirmed that the patient was infected with the West African clade of Monkeypox virus. Since then, confirmed cases* have been reported by nine states. In addition, 28 countries and territories,† none of which has endemic monkeypox, have reported laboratory-confirmed cases. On May 17, CDC, in coordination with state and local jurisdictions, initiated an emergency response to identify, monitor, and investigate additional monkeypox cases in the United States. This response has included releasing a Health Alert Network (HAN) Health Advisory, developing interim public health and clinical recommendations, releasing guidance for LRN testing, hosting clinician and public health partner outreach calls, disseminating health communication messages to the public, developing protocols for use and release of medical countermeasures, and facilitating delivery of vaccine postexposure prophylaxis (PEP) and antivirals that have been stockpiled by the U.S. government for preparedness and response purposes. On May 19, a call center was established to provide guidance to states for the evaluation of possible cases of monkeypox, including recommendations for clinical diagnosis and orthopoxvirus testing. The call center also gathers information about possible cases to identify interjurisdictional linkages. As of May 31, this investigation has identified 17§ cases in the United States; most cases (16) were diagnosed in persons who identify as gay, bisexual, or men who have sex with men (MSM). Ongoing investigation suggests person-to-person community transmission, and CDC urges health departments, clinicians, and the public to remain vigilant, institute appropriate infection prevention and control measures, and notify public health authorities of suspected cases to reduce disease spread. Public health authorities are identifying cases and conducting investigations to determine possible sources and prevent further spread. This activity was reviewed by CDC and conducted consistent with applicable federal law and CDC policy.¶.

[Cold Plasma to Treat Therapy-Refractive Corneal Ulcers]. / Kaltplasma zur Behandlung therapierefraktärer Hornhautulzera.

BACKGROUND: The integrity of the ocular surface and the transparency of the cornea is crucial to obtain a good visual acuity - a requirement to actively participate in both social and professional environments. The homeostasis of the ocular surface is constantly endangered by microbes and by intrinsic factors with negative influence on wound healing. Furthermore, widespread use of contact lenses obtain a risk of corneal infection even resulting in corneal perforation and loss of the eye. Current therapies include topical and systemic antibiotics and antimycotics, often applied in an in-ward setting. PATIENTS/MATERIALS AND METHODS: Some microbes can be therapy-resistent or -refractory and therefore cause a deterioration of the clinical aspect. In this study, the effects of cold plasma treatment of corneal ulcers on reduction of microbial load in vitro, in tissue ex vivo and in a therapy-refractory ulcer. RESULTS: In vitro, ex vivo and in the patient microbial load could be reduced or the clinical findings improved. CONCLUSIONS: Plasma medicine and its disinfective properties could open a novel approach to treat microbial infections of the cornea. The can result in reduced treatment times, a faster demission of the patients and overall in a reduction of health care costs.

Hydrazine N-N Bond Cleavage over Silica-Supported Tantalum-Hydrides.

Hydrazine reacts with silica-supported tantalum-hydrides [(≡SiO)2TaHx] (x = 1, 3), 1, under mild conditions (100 °C). The IR in situ monitoring of the reaction with N2H4 or (15)N2H4, and the solid-state MAS NMR spectra of the fully (15)N labeled compounds (CP (15)N, (1)H-(15)N HETCOR, (1)H-(1)H double-quantum, and (1)H-(1)H triple-quantum spectra) were used to identify stable intermediates and products. DFT calculations were used for determining the reaction pathway and calculating the (15)N and (1)H NMR chemical shifts. Combining the experimental and computational studies led to the following results. At room temperature, only hydrazine adducts, 1-N2H4, are formed. Upon heating at 100 °C, the hydrazine adducts are converted to several species among which [(≡SiO)2Ta(═NH)(NH2)], 2, [(≡SiO)2TaH(NH2)2], 3, and [(≡SiO)2TaH2(NH-NH2)], 4, were identified. The final product 2 is also formed in the reaction of N2 with the same silica-supported tantalum-hydride complexes, and the species identified as 3 and 4 had been previously suggested by DFT studies as intermediates on the reaction pathway for N-N cleavage in N2. The present computational studies (cluster models with M06 functional complemented by selected calculations with periodic calculations) show that 2 is formed via 3 and 4, with either N2 or N2H4. This strengthens the previous proposal of the existence of 3 and 4 as intermediates in the reaction of N2 with the tantalum-hydrides. However, the reaction of N2 does not imply the formation of N2H4 or its hydrazido monoanionic or dianionic ligand as an intermediate. For this reason, this study informs both on the similarities and differences of the reaction pathways involving N2 and N2H4 with tantalum-hydrides.

Relationships between computer-extracted mammographic texture pattern features and BRCA1/2 mutation status: a cross-sectional study.

INTRODUCTION: Mammographic density is similar among women at risk of either sporadic or BRCA1/2-related breast cancer. It has been suggested that digitized mammographic images contain computer-extractable information within the parenchymal pattern, which may contribute to distinguishing between BRCA1/2 mutation carriers and non-carriers. METHODS: We compared mammographic texture pattern features in digitized mammograms from women with deleterious BRCA1/2 mutations (n = 137) versus non-carriers (n = 100). Subjects were stratified into training (107 carriers, 70 non-carriers) and testing (30 carriers, 30 non-carriers) datasets. Masked to mutation status, texture features were extracted from a retro-areolar region-of-interest in each subject's digitized mammogram. Stepwise linear regression analysis of the training dataset identified variables to be included in a radiographic texture analysis (RTA) classifier model aimed at distinguishing BRCA1/2 carriers from non-carriers. The selected features were combined using a Bayesian Artificial Neural Network (BANN) algorithm, which produced a probability score rating the likelihood of each subject's belonging to the mutation-positive group. These probability scores were evaluated in the independent testing dataset to determine whether their distribution differed between BRCA1/2 mutation carriers and non-carriers. A receiver operating characteristic analysis was performed to estimate the model's discriminatory capacity. RESULTS: In the testing dataset, a one standard deviation (SD) increase in the probability score from the BANN-trained classifier was associated with a two-fold increase in the odds of predicting BRCA1/2 mutation status: unadjusted odds ratio (OR) = 2.00, 95% confidence interval (CI): 1.59, 2.51, P = 0.02; age-adjusted OR = 1.93, 95% CI: 1.53, 2.42, P = 0.03. Additional adjustment for percent mammographic density did little to change the OR. The area under the curve for the BANN-trained classifier to distinguish between BRCA1/2 mutation carriers and non-carriers was 0.68 for features alone and 0.72 for the features plus percent mammographic density. CONCLUSIONS: Our findings suggest that, unlike percent mammographic density, computer-extracted mammographic texture pattern features are associated with carrying BRCA1/2 mutations. Although still at an early stage, our novel RTA classifier has potential for improving mammographic image interpretation by permitting real-time risk stratification among women undergoing screening mammography.

Successive heterolytic cleavages of H2 achieve N2 splitting on silica-supported tantalum hydrides: a DFT proposed mechanism.

DFT(B3PW91) calculations have been carried out to propose a pathway for the N(2) cleavage by H(2) in the presence of silica-supported tantalum hydride complexes [(≡SiO)(2)TaH(x)] that forms [(≡SiO)(2)Ta(NH)(NH(2))] (Science 2007, 317, 1056). The calculations, performed on the cluster models {µ-O[(HO)(2)SiO](2)}TaH(1) and {µ-O[(HO)(2)SiO](2)}TaH(3), labelled as (≡SiO)(2)TaH(x) (x = 1, 3), show that the direct hydride transfers to coordinated N-based ligands in (≡SiO)(2)TaH(η(2)-N(2)) and (≡SiO)(2)TaH(η(2)-HNNH) have high energy barrier barriers. These high energy barriers are due in part to a lack of energetically accessible empty orbitals in the negatively charged N-based ligands. It is shown that a succession of proton transfers and reduction steps (hydride transfer or 2 electron reduction by way of dihydride reductive coupling) to the nitrogen-based ligands leads to more energetically accessible pathways. These proton transfers, which occur by way of heterolytic activation of H(2), increase the electrophilicity of the resulting ligand (diazenido, N(2)H(-), and hydrazido, NHNH(2)(-), respectively) that can thus accept a hydride with a moderate energy barrier. In the case of (≡SiO)(2)TaH(η(2)-HNNH), the H(2) molecule that is adding across the Ta-N bond is released after the hydride transfer step by heterolytic elimination from (≡SiO)(2)TaH(NH(2))(2), suggesting that dihydrogen has a key role in assisting the final steps of the reaction without itself being consumed in the process. This partly accounts for the experimental observation that the addition of H(2) is needed to convert an intermediate, identified as a diazenido complex [(≡SiO)(2)TaH(η(2)-HNNH)] from its ν(N-H) stretching frequency of 3400 cm(-1), to the final product. Throughout the proposed mechanism, the tantalum remains in its preferred high oxidation state and avoids redox-type reactions, which are more energetically demanding.

How we didn't clean up until we washed our hands: shigellosis in an elementary and middle school in North Texas.

BACKGROUND: Shigella outbreaks often continue for months and are linked frequently to poor hygiene and hand washing. Such outbreaks are found often in day care facilities, but rarely are reported in schools. We present the investigation of an outbreak in autumn 2007 at a building that housed an elementary school and a middle school in separate wings in a small Texas city north of Dallas-Fort Worth. METHODS: We canvassed local hospitals, school attendance records, and physician offices for cases. Ill individuals were interviewed using a standard questionnaire for symptoms, disease onset, and the presence of the illness in an ill person's household. RESULTS: A music teacher was the index case for this outbreak of gastrointestinal illness caused by S. sonnei. Ten percent of the students in the school building were ill, and 15 households had secondary cases. Installing liquid soap in dispensers in student restrooms was the initial control measure, followed by sustained instruction in hand washing, scheduled hand washing times, and monitored cleaning and disinfection procedures for surfaces and inanimate objects. Enhanced surveillance detected no new cases in the school district. CONCLUSIONS: Appropriate soap supplies and repeated instruction in hand washing and its monitoring were needed to control the outbreak.

Mammographic density does not differ between unaffected BRCA1/2 mutation carriers and women at low-to-average risk of breast cancer.

Elevated mammographic density (MD) is one of the strongest risk factors for sporadic breast cancer. Epidemiologic evidence suggests that MD is, in part, genetically determined; however, the relationship between MD and BRCA1/2 mutation status is equivocal. We compared MD in unaffected BRCA1/2 mutation carriers enrolled in the U.S. National Cancer Institute's Clinical Genetics Branch's Breast Imaging Study (n = 143) with women at low-to-average breast cancer risk enrolled in the same study (n = 29) or the NCI/National Naval Medical Center's Susceptibility to Breast Cancer Study (n = 90). The latter were BRCA mutation-negative members of mutation-positive families or women with no prior breast cancer, a Pedigree Assessment Tool score <8 (i.e., low risk of a hereditary breast cancer syndrome) and a Gail score <1.67. A single experienced mammographer measured MD using a computer-assisted thresholding method. We collected standard breast cancer risk factor information in both studies. Unadjusted mean percent MD was higher in women with BRCA1/2 mutations compared with women at low-to-average breast cancer risk (37.3% vs. 33.4%; P = 0.04), but these differences disappeared after adjusting for age and body mass index (34.9% vs. 36.3%; P = 0.43). We explored age at menarche, nulliparity, age at first birth, menopausal status, number of breast biopsies, and exposure to exogenous hormonal agents as potential confounders of the MD and BRCA1/2 association. Taking these factors into account did not significantly alter the results of the age/body mass index-adjusted analysis. Our results do not provide support for an independent effect of BRCA1/2 mutation status on mammographic density.

Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with [corrected] human epidermal growth factor receptor 2-positive metastatic breast cancer.

PURPOSE: To evaluate safety and efficacy of trastuzumab with pertuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who had progressive disease on trastuzumab-based therapy. EXPERIMENTAL DESIGN: Patients with measurable HER2(+) metastatic breast cancer, < or = 3 trastuzumab-based regimens, and left ventricular ejection fraction (LVEF) > or = 55% received 8 or 6 mg/kg trastuzumab and 840 mg pertuzumab i.v. followed by 6 mg/kg trastuzumab and 420 mg pertuzumab every 3 weeks. Cardiac evaluation and tumor response were assessed every 3 and 6 weeks, respectively. RESULTS: Eleven patients received 64 cycles of trastuzumab plus pertuzumab. A total of 92 echocardiograms and 8 cardiac magnetic resonance imaging studies were done. With the lower limit of normal LVEF 55%, left ventricular systolic dysfunction was observed in six patients, three grade 1, two grade 2, and one grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The objective response rate was 18%. Two patients had partial responses, three had stable disease, and six had progressive disease. The median time to progression was 6 weeks. In baseline tumors from formalin-fixed paraffin-embedded primary and/or metastatic tumor biopsies, pHER2-Y1248 trended toward an increase in patients with partial response compared with those with stable disease/progressive disease (P = 0.095). CONCLUSION: Trastuzumab plus pertuzumab may have clinical benefit in selected patients who have previously been treated with trastuzumab. Cardiac toxicity, although asymptomatic in most cases, was associated with this treatment. Further evaluation of efficacy of this combination is required to define the overall risks and benefits.

Progressive preclinical interstitial lung disease in rheumatoid arthritis.

BACKGROUND: Early detection and treatment for interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) may ameliorate disease progression. The objective of this study was to identify asymptomatic lung disease and potential therapeutic targets in patients having RA and preclinical ILD (RA-ILD). METHODS: Sixty-four adults with RA and 10 adults with RA and pulmonary fibrosis (RAPF) were referred to the National Institutes of Health, Bethesda, Maryland, and underwent high-resolution computed tomography (HRCT) and pulmonary physiology testing. Proteins capable of modulating fibrosis were quantified in alveolar fluid. RESULTS: Twenty-one of 64 patients (33%) having RA without dyspnea or cough had preclinical ILD identified by HRCT. Compared with patients without lung disease, patients with RA-ILD had statistically significantly longer histories of cigarette smoking (P< .001), increased frequencies of crackles (P= .02), higher alveolar-arterial oxygen gradients (P= .004), and higher HRCT scores (P< .001). The HRCT abnormalities progressed in 12 of 21 patients (57%) with RA-ILD. The alveolar concentrations of platelet-derived growth factor-AB and platelet-derived growth factor-BB were statistically significantly higher in patients having RA-ILD (mean [SE], 497.3 [78.6] and 1473 [264] pg/mL, respectively) than in patients having RA without ILD (mean [SE], 24.9 [42.4] and 792.7 [195.0] pg/mL, respectively) (P< .001 and P=.047, respectively). The concentrations of interferon gamma and transforming growth factor beta(2) were statistically significantly lower in patients having RAPF (mean [SE], 5.59 [1.11] pg/mL and 0.94 [0.46] ng/mL, respectively) than in patients having RA without ILD (mean [SE], 14.1 [1.9] pg/mL and 2.30 [0.39] ng/mL, respectively) (P=.001 and P=.006, respectively) or with preclinical ILD (mean [SD], 11.4 [2.6] pg/mL and 3.63 [0.66] ng/mL, respectively) (P=.04 and P=.007, respectively). Compared with patients having stable RA-ILD, patients having progressive RA-ILD had statistically significantly higher frequencies of treatment using methotrexate and higher alveolar concentrations of interferon gamma and transforming growth factor beta(1) (P=.046, P=.04, and P=.04, respectively). CONCLUSIONS: Asymptomatic preclinical ILD, which is detectable by HRCT, may be prevalent and progressive among patients having RA. Cigarette smoking seems to be associated with preclinical ILD in patients having RA, and treatment using methotrexate may be a risk factor for progression of preclinical ILD. Quantification of alveolar proteins indicates that potential pathogenic mechanisms seem to differ in patients having RA-ILD and symptomatic RAPF.

Age-dependent incidence, time course, and consequences of thymic renewal in adults.

Homeostatic regulation of T cells involves an ongoing balance of new T cell generation, peripheral expansion, and turnover. The recovery of T cells when this balance is disrupted provides insight into the mechanisms that govern homeostasis. In a long-term, single cohort study, we assessed the role of thymic function after autologous transplant in adults, correlating serial computed tomography imaging of thymic size with concurrent measurements of peripheral CD4(+) T cell populations. We established the age-dependent incidence, time course, and duration of thymic enlargement in adults and demonstrated that these changes were correlated with peripheral recovery of naive CD45RA(+)CD62L(+) and signal-joint TCR rearrangement excision circle-bearing CD4(+) populations with broad TCR diversity. Furthermore, we demonstrated that renewed thymopoiesis was critical for the restoration of peripheral CD4(+) T cell populations. This recovery encompassed the recovery of normal CD4(+) T cell numbers, a low ratio of effector to central memory cells, and a broad repertoire of TCR Vbeta diversity among these memory cells. These data define the timeline and consequences of renewal of adult thymopoietic activity at levels able to quantitatively restore peripheral T cell populations. They further suggest that structural thymic regrowth serves as a basis for the regeneration of peripheral T cell populations.

Effect of raloxifene on mammographic density and breast magnetic resonance imaging in premenopausal women at increased risk for breast cancer.

BACKGROUND: Mammographic density is a risk factor for breast cancer. Mammographic density and breast magnetic resonance imaging (MRI) volume (MRIV) assess the amount of fibroglandular tissue in the breast. Mammographic density and MRIV can be modulated with hormonal interventions, suggesting that these imaging modalities may be useful as surrogate endpoint biomarkers for breast cancer chemoprevention trials. We evaluated the effect of raloxifene on mammographic density and MRIV in premenopausal women at increased risk for breast cancer. METHODS: Mammograms and MRI were obtained at baseline and after 1 and 2 years of 60 mg raloxifene by mouth daily for 27 premenopausal women. Mammographic percent dense area was calculated using a semiquantitative thresholding technique. T(1)-weighted spoiled gradient-echo MRI with fat suppression was used to determine breast MRIV using a semiautomatic method. Mean change in mammographic density and median change in MRIV were assessed by the Wilcoxon signed-rank test. RESULTS: No significant change in mammographic density was seen after treatment with raloxifene. Mean change after 1 year was 1% [95% confidence interval (95% CI), -3 to +5] and after 2 years was 1% (95% CI, -2 to +5). MRIV decreased on raloxifene. Median relative change in MRIV after 1 year was -17% (95% CI, -28 to -9; P = 0.0017) and after 2 years was -16% (95% CI, -31 to -4; P = 0.0004). CONCLUSIONS: In high-risk premenopausal women, mammographic density did not change on raloxifene, whereas MRIV significantly declined. Our findings suggest that MRIV is a promising surrogate biomarker in premenopausal women at increased risk for breast cancer and should be investigated further in breast cancer prevention trials.

Glutamate-induced retinal lipid and protein damage: the protective effects of catechin.

Glutamate toxicity has been implicated in various retinal diseases. Green tea leaf extract catechin has protective effects against cellular toxicity. This study investigated the effects of catechin on the glutamate-treated retina. Porcine retinal homogenates were incubated with glutamate (20 nmol) at 37 degrees C for 60 min. Catechin was co-incubated with the glutamate-treated retina in the same condition. The malondialdehyde (MDA) levels were determined as an index of lipid peroxidation (LPO). Differential protein expressions were derived from two-dimensional gel electrophoresis. Mass spectrometry was conducted to identify the proteins. Glutamate increased the retinal MDA (p<0.0001) and catechin reversed the effect (p<0.0001). There were significant changes in seven proteins after the glutamate treatment (p<0.05), namely, heterogeneous ribonucleoprotein, thioredoxin peroxidase, 5-hydroxytryptamine receptor, pyruvate dehydrogenase, ARHA protein, peroxiredoxin 6 and proteasome. Catechin significantly reversed the changes in thioredoxin peroxidase, 5-hydroxytryptamine receptor, peroxiredoxin 6 and pyruvate dehydrogenase (p<0.05). Our study shows that (a) retinal glutamate toxicity is mediated by LPO and protein modification, and (b) catechin ameliorates the toxicity.

Argon Cold Plasma-A Novel Tool to Treat Therapy-resistant Corneal Infections.

PURPOSE: To test whether therapy-resistant corneal infections can be successfully treated with argon cold plasma to reduce or eliminate pathogen microorganisms without affecting corneal cell viability. DESIGN: First-in-human case series and experimental study. METHODS: Cold plasma effects on viability of primary human corneal limbal epithelial cells were studied using exposure times from 0.5 to 10 minutes (metabolic activity, oxidative stress, apoptosis). Disinfective potential of cold plasma was tested against common pathogens (Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans) on culture medium and evaluated by counting colony-forming units and optical density measurements, as well as against S aureus in a human cornea infection model. Additionally, in a first-in-human trial 4 patients with therapy-resistant corneal ulcers were treated to evaluate the clinical potential of cold plasma. RESULTS: Cells treated for 0.5-5 minutes completely recovered within 24 hours without changes in morphology; only 10-minute treatment impaired the cells permanently. No evident oxidative stress, apoptosis, or damage to the corneal structure could be found. All pathogens were susceptible to cold plasma treatments, with different levels of sensitivity. The condition of all 4 patients significantly improved after cold plasma treatment combined with antibiotic therapy. CONCLUSIONS: Our results indicate that argon cold plasma treatment reduces or eliminates common pathogens without impairing corneal epithelial cells in vitro, ex vivo, and in direct application on patients' eyes. We conclude that argon cold plasma therapy offers a potential supplement or alternative therapy for therapy-resistant corneal infections. A larger, comparative study is necessary to further confirm these findings.

A phase I trial and pharmacokinetic study of tipifarnib, a farnesyltransferase inhibitor, and tamoxifen in metastatic breast cancer.

PURPOSE: Farnesyltransferase (FTase) inhibitors, which were designed to inhibit oncogenic Ras, act synergistically with tamoxifen in preclinical breast cancer models. We studied the safety and toxicity of tipifarnib in combination with tamoxifen in metastatic breast cancer. The pharmacokinetics and pharmacodynamics of tipifarnib were also assessed. PATIENTS AND METHODS: Patients with metastatic, hormone receptor-positive breast cancer were enrolled. Two cohorts of patients were treated with tipifarnib at either 200 or 300 mg p.o. twice daily for 21 of 28 days. Tamoxifen (20 mg once daily) was started after 1 week of tipifarnib monotherapy to perform pharmacokinetics and FTase inhibition levels in peripheral blood mononuclear cells with tipifarnib alone and with tipifarnib and tamoxifen. RESULTS: A total of 12 heavily pretreated patients with prior progression on hormonal therapy were enrolled. Minimal toxicity was observed at the 200-mg dose level of tipifarnib. At the 300-mg dose, all six patients required dose reduction of tipifarnib due to toxicities that included grade 2 nausea, rash, and fatigue and grade 3 diarrhea and neutropenia. Tipifarnib pharmacokinetic and pharmacodynamic variables were similar in the presence and absence of tamoxifen. Average FTase inhibition was 42% at 200 mg and 54% at 300 mg in peripheral blood mononuclear cells. Of the 12 patients treated, there were two partial responses and one stable disease for >6 months. CONCLUSIONS: Tipifarnib (200 mg twice daily for 21 of 28 days) and tamoxifen (20 mg once daily) can be given safely with minimal toxicity. Tamoxifen does not have a significant effect on tipifarnib pharmacokinetics.

Allogeneic lymphocytes induce tumor regression of advanced metastatic breast cancer.

PURPOSE: Allogeneic T lymphocytes can induce regression of metastatic breast cancer through an immune-mediated graft-versus-tumor (GVT) effect in murine models. To determine if a clinical GVT effect exists against metastatic breast cancer, allogeneic lymphocytes were used as adoptive cellular therapy after a reduced-intensity chemotherapy conditioning regimen and allogeneic hematopoietic stem-cell transplantation (HSCT) from human leukocyte antigen-matched siblings. PATIENTS AND METHODS: Sixteen patients with metastatic breast cancer that had progressed after treatment with anthracyclines, taxanes, hormonal agents, and trastuzumab, received allogeneic HSCT. The reduced-intensity transplant conditioning regimen consisted of cyclophosphamide and fludarabine. To distinguish an immunological GVT effect from any antitumor effect of cytotoxic chemotherapy in the transplant-conditioning regimen, allogeneic T lymphocytes were removed from the stem-cell graft and were subsequently administered late postallogeneic HSCT. Allogeneic lymphocytes containing 1 x 10(6), 5 x 10(6), and 10 x 10(6) CD3(+) cells/kg were infused on days +42, +70, and +98 post-allogeneic HSCT, respectively. RESULTS: Objective tumor regressions occurred after day +28 post-allogeneic HSCT in six patients and were attributed to allogeneic lymphocyte infusions. Two of these responding patients had disease progression post-allogeneic HSCT before subsequent tumor regression. Tumor regressions occurred concomitantly with the establishment of complete donor T-lymphoid engraftment, were associated with the development of graft-versus-host disease (GVHD), and were abrogated by subsequent systemic immunosuppression for GVHD. CONCLUSION: Allogeneic lymphocytes can induce regression of advanced metastatic breast cancer. These results indicate that an immunological GVT effect from allogeneic lymphocytes exists against metastatic breast cancer and provide rationale for further development of allogeneic cellular therapy for this largely incurable disease.

Evaluation of biologic end points and pharmacokinetics in patients with metastatic breast cancer after treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor.

PURPOSE: To evaluate changes in epidermal growth factor receptor (EGFR) phosphorylation and its downstream signaling in tumor and surrogate tissue biopsies in patients with metastatic breast cancer treated with erlotinib, an EGFR tyrosine kinase inhibitor, and to assess relationships between biomarkers in tumor and normal tissues and between biomarkers and pharmacokinetics. PATIENTS AND METHODS: Eighteen patients were treated orally with 150 mg/d of erlotinib. Ki67, EGFR, phosphorylated EGFR (pEGFR), phosphorylated mitogen-activated protein kinase (pMAPK), and phosphorylated AKT (pAKT) in 15 paired tumor, skin, and buccal mucosa biopsies (at baseline and after 1 month of therapy) were examined by immunohistochemistry and analyzed quantitatively. Pharmacokinetic sampling was also obtained. RESULTS: The stratum corneum layer and Ki67 in keratinocytes of the epidermis in 15 paired skin biopsies significantly decreased after treatment (P = .0005 and P = .0003, respectively). No significant change in Ki67 was detected in 15 tumors, and no responses were observed. One was EGFR-positive and displayed heterogeneous expression of the receptor, and 14 were EGFR-negative. In the EGFR-positive tumor, pEGFR, pMAPK, and pAKT were reduced after treatment. Paradoxically, pEGFR was increased in EGFR-negative tumors post-treatment (P = .001). Although markers were reduced in surrogate and tumor tissues in the patient with EGFR-positive tumor, no apparent associations were observed in patients with EGFR-negative tumor. CONCLUSION: Erlotinib has inhibitory biologic effects on normal surrogate tissues and on an EGFR-positive tumor. The lack of reduced tumor proliferation may be attributed to the heterogeneous expression of receptor in the EGFR-positive patient and absence of target in this cohort of heavily pretreated patients.

Rhabdomyolysis in patients with west nile encephalitis and meningitis.

Since 1999, more than 6,500 cases of West Nile virus neuroinvasive disease (WNND) have been reported in the United States. Patients with WNND can present with muscle weakness that is often assumed to be of neurological origin. During 2002, nearly 3,000 persons with WNV meningitis or encephalitis (or both) were reported in the United States; in suburban Cook County, Illinois, with 244 persons were hospitalized for WNV illnesses. The objective of this investigation was to describe the clinical and epidemiological features of identified cases of WNV neuroinvasive disease and rhabdomyolysis. Public health officials investigated patients hospitalized in Cook County, and identified a subset of WNV neuroinvasive disease patients with elevated creatine kinase levels. Cases were defined as hospitalized persons with a WNV infection, encephalitis or meningitis, and rhabdomyolysis. Retrospective medical record reviews were conducted and data was abstracted with a standardized data collection instrument. Eight patients with West Nile encephalitis and one with West Nile meningitis were identified with rhabdomyolysis. Median age of the nine patients was 70 years (range, 45-85 years), and eight were men. For all nine patients, the peak CK level was documented a median of 2 days after hospitalization (range, 1-24 days). Median CK level during hospitalization for all case-patients was 3,037 IU (range, 1,153-42,113 IU). Six patients had history of recent falls prior to admission. Although the temporal relationship of rhabdomyolysis and neurological WNV illness suggested a common etiology, these patients presented with complex clinical conditions which may have led to development of rhabdomyolysis from other causes. The spectrum of WNV disease requires further investigation to describe this and other clinical conditions associated with WNV infection.

A phase II trial of neoadjuvant docetaxel and capecitabine for locally advanced breast cancer.

PURPOSE: This study evaluated the toxicity and efficacy of docetaxel/capecitabine as neoadjuvant treatment for stage 2/3 breast cancer. EXPERIMENTAL DESIGN: Subjects with newly diagnosed invasive stage 2 and 3 breast cancer were eligible. The first cohort of patients was treated at dose A with neoadjuvant docetaxel (75 mg/m(2) i.v. day 1) and capecitabine (1000 mg/m(2) orally twice daily days 2-15) for four cycles. A second cohort of subjects was treated with a reduced dose, dose B, of docetaxel (60 mg/m(2) i.v. day 1) and capecitabine (937.5 mg/m(2) orally twice daily days 2-15). RESULTS: Thirty patients were enrolled. Eight of 10 patients treated at dose A required dose reductions of either docetaxel or capecitabine secondary to grade 3 or 4 toxicities: mucositis (1), hand-foot syndrome (3), diarrhea (2), perirectal abscess (1), and neutropenia (2). Because of a high rate of dose reductions, the next 20 patients were treated at dose B. The mean cumulative administered dose of docetaxel was 285 and 231 mg/m(2) at dose A and dose B, respectively. For capecitabine, the mean cumulative dose at dose A and B were similar at 1585 and 1627 mg/m(2)/day, respectively. The overall clinical response rate was 90% with 31% of patients having a complete response and 59% having a partial response. A pathological complete response in the breast was achieved in 10% of patients after four cycles of docetaxel/capecitabine. CONCLUSIONS: Docetaxel/capecitabine is a highly active regimen in the neoadjuvant setting. Neoadjuvant therapy with 75 mg/m(2) docetaxel and 1600 mg/m(2)/day days 2-15 is recommended.

Phase I trial of the cyclin-dependent kinase inhibitor flavopiridol in combination with docetaxel in patients with metastatic breast cancer.

PURPOSE: The purpose of this study was to determine the toxicities and characterize the pharmacokinetics of docetaxel and flavopiridol in patients with metastatic breast cancer. EXPERIMENTAL DESIGN: Docetaxel was administered at an initial dose of 60 mg/m(2) followed in 24 hours by a 72-hour infusion of flavopiridol at 50 mg/m(2)/d every 3 weeks. Because dose-limiting myelosuppression occurred, the schedule was amended to docetaxel, 50 mg/m(2), followed by escalating doses of flavopiridol (starting dose, 26 mg/m(2)/d) as a 1-hour infusion daily for 3 days. Pharmacokinetic studies were performed. Ki67, p53, and phosphorylated retinoblastoma protein (phospho-Rb) in paired tumor and buccal mucosa biopsies (obtained pre- and posttreatment) were examined by immunohistochemistry. RESULTS: Eleven patients were enrolled. Five patients received docetaxel and 72-hour flavopiridol. Dose-limiting toxicity was grade 4 neutropenia. Six patients received docetaxel and 1-hour flavopiridol, and the dose-limiting toxicity was grade 3 hypotension. Pharmacokinetics of flavopiridol and docetaxel were consistent with historical data. Nuclear staining with p53 increased and phospho-Rb decreased in 10 pairs of buccal mucosa biopsies posttreatment (P = 0.002 and P = 0.04, respectively). No significant changes in Ki67, p53, or phospho-Rb were detected in six paired tumors. Two patients sustained stable disease for >3 months (72-hour flavopiridol), and one partial response was observed (1-hour flavopiridol). CONCLUSIONS: Docetaxel combined with 72-hour flavopiridol was not feasible because of dose-limiting neutropenia. Dose escalation of a 1-hour infusion of flavopiridol with docetaxel was also not possible. The changes in p53 and phospho-Rb in buccal mucosa suggest that a biological effect with flavopiridol was achieved.

Imaging in inflammatory breast carcinoma.

In this section, imaging findings of inflammatory breast carcinoma using the following modalities - mammography, ultrasonography, computerized tomography, and positron emission tomography - are described. Differential diagnoses are presented. The key finding in IBC is its inflammatory component, which can be well demonstrated on all of the modalities. Because no pathognomonic feature exists for IBC, biopsy is always needed for diagnosis. Nevertheless, there is a substantial and expanding role for imaging in the characterization and definition of the extent of disease, and in the monitoring its therapy.