Phase II study of neoadjuvant therapy with docetaxel, cisplatin, panitumumab, and radiation therapy followed by surgery in patients with locally advanced adenocarcinoma of the distal esophagus (ACOSOG Z4051).

BACKGROUND: Preoperative chemoradiotherapy (CRT) improves outcomes in patients with locally advanced but resectable adenocarcinoma of the esophagus. ACOSOG Z4051 evaluated CRT with docetaxel, cisplatin, and panitumumab (DCP) in this patient group with a primary end point of a pathologic complete response (pCR) ≥35%. PATIENTS AND METHODS: From 15 January 2009 to 22 July 2011, 70 patients with locally advanced but resectable distal esophageal adenocarcinoma were enrolled. Patients received docetaxel (40 mg/m(2)), cisplatin (40 mg/m(2)), and panitumumab (6 mg/kg) on weeks 1, 3, 5, 7, and 9 with RT (5040 cGy, 180 cGy/day × 28 days) beginning week 5. Resection was planned after completing CRT. PCR was defined as no viable residual tumor cells. Secondary objectives included near-pCR (≤10% viable cancer cells), toxicity, and overall and disease-free survival. Adverse events were graded using the CTCAE Version 3.0. RESULTS: Five of 70 patients were ineligible. Of 65 eligible patients (59 M; median age 61), 11 did not undergo surgery, leaving 54 assessable. PCR rate was 33.3% and near-pCR was 20.4%. Secenty-three percent of patients completed DCP (n = 70) and 92% completed RT. 48.5% had toxicity ≥grade 4. Lymphopenia (43%) was most common. Operative mortality was 3.7%. Adult respiratory distress syndrome was encountered in two patients (3.7%). At median follow-up of 26.3 months, median overall survival was 19.4 months and 3-year overall survival was 38.6% (95% confidence interval 24.5% to 60.8%). CONCLUSIONS: Neoadjuvant CRT with DCP is active (pCR + near-pCR = 53.7%) but toxicity is significant. Further evaluation of this regimen in an unselected population is not recommended. CLINICALTRIALSGOV IDENTIFIER: NCT00757172.

1 -Antitrypsin deficiency: a variant with no detectable 1 -antitrypsin.

No alpha(1)-antitrypsin could be detected in the serum of a 24-year-old man with advanced pulmonary emphysema by agarose electrophoresis, immnuno-electrophoresis, double diffusion in agarose gel, or alpha(1)-antitrypsin genetic typing by a combination of starch-gel electrophoresis and crossed antigen-antibody electrophoresis. A circulating alpha(1)-antitrypsin inactivator could not be demonstrated. Evidence was obtained in family members of genetic transmission of this new alpha(1)-antitrypsin variant.

Worldwide esophageal cancer collaboration.

The aim of this study is to report assemblage of a large multi-institutional international database of esophageal cancer patients, patient and tumor characteristics, and survival of patients undergoing esophagectomy alone and its correlates. Forty-eight institutions were approached and agreed to participate in a worldwide esophageal cancer collaboration (WECC), and 13 (Asia, 2; Europe, 2; North America, 9) submitted data as of July 1, 2007. These were used to construct a de-identified database of 7884 esophageal cancer patients who underwent esophagectomy. Four thousand six hundred and twenty-seven esophagectomy patients had no induction or adjuvant therapy. Mean age was 62 +/- 11 years, 77% were men, and 33% were Asian. Mean tumor length was 3.3 +/- 2.5 cm, and esophageal location was upper in 4.1%, middle in 27%, and lower in 69%. Histopathologic cell type was adenocarcinoma in 60% and squamous cell in 40%. Histologic grade was G1 in 32%, G2 in 33%, G3 in 35%, and G4 in 0.18%. pT classification was pTis in 7.3%, pT1 in 23%, pT2 in 16%, pT3 in 51%, and pT4 in 3.3%. pN classification was pN0 in 56% and pN1 in 44%. The number of lymph nodes positive for cancer was 1 in 12%, 2 in 8%, 3 in 5%, and >3 in 18%. Resection was R0 in 87%, R1 in 11%, and R2 in 3%. Overall survival was 78, 42, and 31% at 1, 5, and 10 years, respectively. Unlike single-institution studies, in this worldwide collaboration, survival progressively decreases and is distinctively stratified by all variables except region of the world. A worldwide esophageal cancer database has been assembled that overcomes problems of rarity of this cancer. It reveals that survival progressively (monotonically) decreased and was distinctively stratified by all variables except region of the world. Thus, it forms the basis for data-driven esophageal cancer staging. More centers are needed and encouraged to join WECC.

Adrenergic mechanisms and the adenyl cyclase system in atopic dermatitis.

Patients with atopic dermatitis have abnormal autonomic responses of the arterioles, pilomotor smooth muscle, and sweat glands. Their lesions have been reported to contain increased amounts of the neurohumors, acetylcholine and norepinephrine, as well as increased activity of acetylcholinesterase and catechol-O-methyltransferase. In vitro studies of epidermis show that beta adrenergic agonists fail to evoke the normal inhibition of mitosis of basal cells of patients with atopic dermatitis. Epidermis removed not only from the lesions, but also from normal-appearing skin, responded abnormally. The increase in intracellular levels of cAMP after exposure to catecholamines was similar in normal and atopic epidermis. Lymphocytes and PMN leukocytes isolated from patients with atopic dermatitis show both a decreased physiologic response (glycogenolysis and inhibition of lysosome enzyme release) and a decreased rise in intracellular levels of cAMP upon incubation with beta agonists, but a normal response to PGE1. Cortisol increases the response of lymphocyte adenyl cyclase to both agonists and, in the case of the patients with atopic disease, more than overcomes the depressed response to beta agonists. Because the leukocytes respond normally to PGE1 and because others have reported normal activities of skin and adenyl cyclase, phosphodiesterase, and protein kinases, we conclude that the step responsible for the diminished beta adrenergic response lies antecedent to the catalytic site of adenyl cyclase.

Nocturnal asthma: approach to the patient.

Nocturnal asthma can be diagnosed by asking patients whether they awaken at night with asthmatic symptoms and feel the need to use an aerosol bronchodilator. The primary objective in treating nocturnal asthma is to help patients sleep through the night. The bronchoconstriction that underlies nocturnal asthmatic symptoms is a reflection of bronchial hyperresponsiveness, and this hyperresponsiveness is greatly increased by airway inflammation. In patients with allergic asthma, airway inflammation can be reduced by reducing exposure to allergens and, in some cases, by immunotherapy. Nocturnal bronchoconstriction is best controlled by scheduling sustained-release bronchodilators, particularly theophylline, to provide the maximal theophylline blood concentration at the time of maximal obstruction, usually between 4:00 and 6:00 A.M.

Nocturnal asthma and timing of treatment.

Nocturnal deterioration of pulmonary function in asthmatic patients is a well-recognized and well-documented phenomenon. The mechanism of this "morning dip," however, remains uncertain. Although the circadian rhythms of body temperature, corticosteroid, catecholamine, histamine, and opiate peptide levels, and even sleep itself have been shown to be in phase with the diurnal variation in asthma, a causal relationship has yet to be established. Increased nighttime bronchial reactivity to histamine, acetylcholine, and house dust allergen have been demonstrated. In general, continuous treatment with theophylline, beta-adrenergic agonists, or corticosteroids attenuates the degree of morning dip but does not completely eliminate the circadian rhythm of asthma. The significance of nocturnal asthma is emphasized by the observation that asthma deaths occur more frequently during nighttime hours and are often preceded by large daily swings in peak expiratory flow. Further studies examining the etiology and treatment of nocturnal asthma are needed.

Timing of once-a-day theophylline dose to match peak blood level with diurnal variation in severity of asthma.

To test the hypothesis that nighttime and early morning signs and symptoms of air flow obstruction in patients with moderately severe asthma would be better controlled by theophylline given on a once-a-day evening dosing schedule chosen to provide a peak blood level in the early morning than by the traditional twice-a-day dosing schedule designed to maintain levels more constant throughout the 24-hour period, the effects on nocturnal asthma of Uniphyl once a day and Theo-Dur twice a day were studied in 14 patients with moderately severe asthma. Although both regimens were effective, more patients preferred the Uniphyl dosing schedule. Nighttime symptoms were better controlled, without an increase in daytime symptoms or significant side effects. Optimal timing of theophylline dosing is an important consideration in the management of asthma.

Surgical cure of hypoglycemia associated with cystosarcoma phyllodes and elevated nonsuppressible insulin-like protein.

A woman with a large, benign cystosarcoma phyllodes of the breast was found to have recurrent, profound hypoglycemia. Plasma levels of nonsuppressible insulin-like protein were increased (15.18 micrograms/ml; normal = 1 to 4 micrograms/ml), whereas levels of insulin and nonsuppressible insulin activity soluble in acid ethanol were normal. Surgical excision of the tumor resulted in immediate and lasting correction of the metabolic abnormalities, although nonsuppressible insulin-like protein levels did not completely return to normal. Surprisingly, preoperative nonsuppressible insulin-like protein levels were highest in blood distant from the tumor site.

N-acetyl-beta-glucosaminidase activity in normal and malignant leukocytes.

An improved cytochemical method demonstrating N-acetyl-beta-glucosaminidase in peripheral blood and bone marrow leukocytes is described. A significant elevation in enzyme activity in circulating monocytes from patients with solid tumor malignancies was observed. In a large series of cases of acute nonlymphocytic leukemia, elevated levels were found in the vast majority of those leukemias that had a predominant monocytic component identified either morphologically or by standard cytochemical methods. This reaction would appear to be useful as a monocyte marker.

Aerosol beclomethasone dipropionate compared with theophylline as primary treatment of chronic, mild to moderately severe asthma in children.

OBJECTIVE: To compare the benefits and adverse reactions of theophylline and beclomethasone (BDP) in the long-term control of mild to moderate chronic asthma in children. DESIGN: Multicentered, double-blind, double-placebo, randomized, controlled trial. PATIENTS: One hundred ninety-five children between the ages of 6 and 16 years with mild to moderate asthma. INTERVENTION: Treatment with either BDP, 84 micrograms four times a day, or sustained-release theophylline administered twice daily in doses adjusted for optimum control of symptoms. MAIN OUTCOME MEASURES: Daily diary record of symptoms, peak flow rates, supplemental bronchodilator and glucocorticoid treatment, doctor and hospital visits, absence from work and school, and side effects. RESULTS: Aerosol BDP and sustained-release theophylline were effective primary treatments for mild to moderate chronic asthma. Beclomethasone resulted in comparable symptom control with less bronchodilator use and fewer courses of systemic steroids than did theophylline. Side effects were observed significantly more frequently with theophylline than with BDP. Growth velocity suppression was noted with BDP and was more pronounced in boys. Suppression was not associated with alterations in cortisol measurements either at baseline or following stimulation. CONCLUSION: Both theophylline and BDP are effective therapy for mild to moderate asthma. Caution must be used with the administration of BDP in children because of possible growth velocity suppression.

Proper use of aerosol corticosteroids to control asthma.

Aerosol glucocorticoids are highly effective in the treatment of bronchial asthma. Clinically apparent systemic hypercortisolism is virtually nonexistent in patients who receive such therapy, although local effects of candidiasis or dysphonia may occur. Treatment failures can often be attributed to poor patient compliance or incorrect use of the pressurized aerosol inhaler. The addition of a spacer device to the inhaler improves the technique and the results in many patients. Furthermore, many patients with asthma require 2 or 3 times the conventional dose of aerosol corticosteroids for optimal control of pulmonary function. Careful coaching is essential for the successful use of aerosol corticosteroids.

Bronchial challenge with formaldehyde gas: lack of bronchoconstriction in 13 patients suspected of having formaldehyde-induced asthma.

We studied 13 selected patients with symptoms suggestive of asthma who suspected exposure to formaldehyde as a cause. These patients had a history of exposure to formaldehyde gas which either coincided with the onset of or aggravated their symptoms of asthma. The levels of exposure at their homes or at work ranged from 0.1 to 1.2 parts per million (ppm) of formaldehyde gas. The patients were tested with bronchial challenges of 0.1-, 1-, and 3-ppm concentrations of formaldehyde gas and randomly interspersed room-air placebos. The formaldehyde gas or placebo was delivered via a Dynacalibrator . The period of exposure to formaldehyde gas or placebo with each challenge was 20 minutes. Pulmonary function was measured before and for 24 hours after each bronchial challenge. No patient had a significantly greater decrease in the forced expiratory volume in 1 second after exposure to formaldehyde than after exposure to air. In no case were we able to substantiate that exposure to formaldehyde gas (3 ppm or less) was indeed causing or aggravating the asthmatic symptoms.

Airway responses to inhaled ouabain in subjects with and without asthma.

Challenges with ouabain and histamine were performed a week apart in 10 patients with asthma and 5 normal subjects. Concentrations were increased cumulatively until specific airway conductance decreased by 30% or the maximal concentration of 1.0% was reached. At low concentrations, ouabain induced bronchodilatation in six patients who had asthma. Bronchodilatation gradually decreased with increasing concentrations and was followed by bronchoconstriction in two patients with asthma who had high airway sensitivity to histamine. Ouabain caused only bronchoconstriction in three patients with severe asthma. The normal subjects showed mild bronchodilatation or no response to ouabain. Several possible biochemical mechanisms may be responsible for the bronchodilatory response to low doses of ouabain, such as stimulation of adenylate cyclase or (Na+,K+)-adenosine triphosphatase. The absence of a bronchodilatory response to ouabain in patients with severe asthma suggests an impairment in the activity of these enzymes.

Allergic reactions to latex among health-care workers.

With the emergence of the acquired immunodeficiency syndrome (AIDS) epidemic and the practice of protecting health-care workers from all body fluids, the use of rubber gloves has increased, as has occupational allergy to latex among health-care workers. During 1991, 49 Mayo Medical Center employees sought assessment and treatment of rhinitis, conjunctivitis, contact urticaria, contact dermatitis, asthma, or eczema thought to be related to exposure to latex. Most of these persons had a history of atopy and worked in areas where rubber gloves were used and changed frequently. Of the 49 subjects, 34 had positive results of skin tests to latex products, and the sera from 19 of 35 persons tested contained increased latex-specific IgE antibodies. Employees with sensitivity to latex (and co-workers in the immediate areas) should use vinyl gloves and should notify their own health-care providers of their sensitization. Changes in job assignment may be necessary for some persons.

Efficacy of beclomethasone nasal solution, flunisolide, and cromolyn in relieving symptoms of ragweed allergy.

Although three effective topical treatments for allergic rhinitis are available, little information to assist the clinician in choosing among them has been reported. Therefore, we conducted a randomized clinical trial to compare beclomethasone nasal solution, flunisolide, and cromolyn with placebo in 120 patients with hay fever during the ragweed season of 1984. We found that all three agents were superior to placebo (P less than 0.001) and that the glucocorticoids were more effective than cromolyn (P less than 0.001). Surprisingly, we also found that these intranasal treatments considerably reduced the symptoms of seasonal asthma. Further study of this therapeutic advantage is needed.

Interobserver variability in medical record review: an epidemiological study of asthma.

Interobserver variability during the data collection for a large retrospective study of asthma was assessed. After extensive training by three physician investigators, two nurses collected study data from existing medical records using an explicit protocol. At four time intervals, samples of records already abstracted by one nurse were reviewed and re-abstracted by another nurse assigned to the project. The unweighted kappa coefficient was used to evaluate observer reliability. Most of the kappa coefficients were > or = 0.6, suggesting good to excellent agreement. Agreement was highest for demographic, clinical and medication variables, while judgement variables had the lowest kappa coefficients. The well known dependence of kappa on the prevalence of the variable studied was evident in these data. We strongly recommend periodic monitoring of observer reliability in any study using more than one individual to collect data to ensure reliable data collection.

Basic mechanisms of asthma. Role of inflammation.

It is now recognized that the basic reason for airway obstruction in asthma is chronic airway inflammation. The hyperresponsiveness and "bronchospasm" are, in part at least, a consequence of the inflammation. Optimum patient care needs to focus on preventing inflammation when possible and using anti-inflammatory drugs when prevention is not possible. When chronic asthma is mild, aerosol glucocorticoids or cromolyn suffice. Acute exacerbations that do not respond fully to bronchodilator drugs usually should be treated by a course of oral glucocorticoids. A few patients with severe disease require oral glucocorticoid therapy indefinitely.

Antigens and allergic asthma.

There are few reliable epidemiologic data on the overall frequency and importance of allergy. We describe a practical method for quantifying the concentration of both amorphous and morphologically defined antigens in the air. A high volume air sampler is used to collect airborne particles and has a facility to separate samples into different particle sizes. Samples are tested for allergenic activity by radioallergosorbent test inhibition assay. Preliminary findings from studies of community wide, amorphous and common household allergens are reported.

Thoracic endometriosis. Recurrence following hysterectomy with bilateral salpingo-oophorectomy and successful treatment with talc pleurodesis.

This is a report of an unusual patient who had four of the five manifestations of thoracic endometriosis, including right pneumothorax, left hemothorax, chest pain, and hemoptysis. This patient shows that recurrence of symptoms can occur while a patient is receiving hormonal replacement therapy even after hysterectomy and bilateral salpingo-oophorectomy; estrogen replacement should probably be delayed for several months to allow complete regression of the ectopic endometrial tissue. Alternatively, chemical pleurodesis can be effective in treating recurrent pneumothorax or hemothorax while the patient is receiving hormonal replacement. Bilateral pleural involvement and hemoptysis suggest microembolization of endometrial tissue as the pathogenic mechanism for thoracic endometriosis.