Published histologic studies of the hilar plate or entire biliary remnant at the time of Kasai portoenterostomy (KHPE) have not provided deep insight into the pathogenesis of biliary atresia, ...relation to age at surgery, prognosis or the basis for successful drainage. We report detailed histologic findings in 172 centrally reviewed biliary remnants with an average of 6 sections per subject. Active lesions were classified as either necroinflammatory (rare/clustered in a few subjects) or active concentric fibroplasia with or without inflammation (common). Inactive lesions showed bland replacement by collagen and fibrous cords with little or no inflammation. Heterogeneity was common within a given remnant; however, relatively homogenous histologic patterns, defined as 3 or more inactive or active levels in the hepatic ducts levels, characterized most remnants. Homogeneity did not correlate with age at KHPE, presence/absence of congenital anomalies at laparotomy indicative of heterotaxy and outcome. Remnants from youngest subjects were more likely than older subjects to be homogenously inactive suggesting significantly earlier onset in the youngest subset. Conversely remnants from the oldest subjects were often homogenously active suggesting later onset or slower progression. More data are needed in remnants from subjects <30 days old at KHPE and in those with visceral anomalies. Prevalence of partially preserved epithelium in active fibroplastic biliary atresia lesions at all ages suggests that epithelial regression or injury may not be a primary event or that reepithelialization is already underway at the time of KHPE. We hypothesize that outcome after KHPE results from competition between active fibroplasia and reepithelialization of retained, collapsed but not obliterated lumens. The driver of active fibroplasia is unknown.
Learning Objectives
After completing this course, the reader will be able to:
Describe the natural history of untreated breast cancer.
Identify the characteristics of women with metastatic breast ...cancer who may have especially favorable prognoses.
Balance physician and patient perspectives in the selection of treatments for metastatic breast cancer.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
Patients with metastatic breast cancer consist of a heterogeneous group of patients whose prognoses and clinical courses can vary depending on host factors, such as comorbidity and age, and on tumor factors, such as hormone‐receptor status, grade, and anatomical site of disease. Although the median survival time for patients with metastatic breast cancer is 2–4 years, subsets of patients with either indolent or limited metastatic disease may have prolonged survival times. Further, expectations of treatment, both in terms of efficacy and of toxicity, vary greatly based upon the specific treatment, patient characteristics, and tumor characteristics. Thus, the goals of treatment for patients with metastatic breast cancer are influenced by estimates of prognoses as well as a balance between physician and patient preferences regarding efficacy and toxicity considerations. Traditionally, objective measures of response and survival have been the targeted end points in clinical trial design and in physician selection of therapy for metastatic breast cancer. More recently, issues of quality of life have surfaced as important end points, especially from the perspective of the patient. The decision‐making process in selecting the optimal treatment for patients with metastatic breast cancer is, therefore, a multidimensional process involving subjective as well as objective goals of treatment. Ultimately, the benefits of treatment must justify the risks and toxicities of the treatment, and the impact of treatment should be measured in relation to specified goals. Both physician and patient perspectives are important in establishing the objectives of treatment, and this process is optimally an interactive and ongoing process throughout the course of disease.
We hypothesized that if infection is the proximate cause of congenital biliary atresia, an appropriate response to antigen would occur in lymph nodes contiguous with the biliary remnant. We compared ...the number of follicular germinal centers (GC) in 79 surgically excised hilar lymph nodes (LN) and 27 incidentally discovered cystic duct LNs in 84 subjects at the time of hepatic portoenterostomy (HPE) for biliary atresia (BA) to autopsy controls from the pancreaticobiliary region of non-septic infants >3 months old at death. All 27 control LN lacked GC, a sign in infants of a primary response to antigenic stimulation. GC were found in 53% of 106 LN in 56 of 84 subjects. Visible surgically excised LN contiguous with the most proximal biliary remnants had 1 or more well-formed reactive GC in only 26/51 subjects. Presence of GC and number of GC/LN was unrelated to age at onset of jaundice or to active fibroplasia in the biliary remnant but was related to older age at HPE. Absent GC in visible and incidentally removed cystic duct LNs predicted survival with the native liver at 2 and 3 years after HPE, P = .03, but significance was lost at longer intervals. The uncommon inflammatory lesions occasionally found in remnants could be secondary either to bile-induced injury or secondary infection established as obstruction evolves. The absence of consistent evidence of antigenic stimulation in LN contiguous with the biliary remnant supports existence of at least 1 major alternative to infection in the etiology of biliary atresia.
An improvement in radiation dose schedule is necessary to increase local tumor control and survival in limited-stage small-cell lung cancer. The goal of this study was to determine the ...maximum-tolerated dose (MTD) of radiation (RT) in both standard daily and hyperfractionated-accelerated (HA) twice-daily RT schedules in concurrent chemoradiation.
The study design consisted of a sequential dose escalation in both daily and HA twice-daily RT regimens. RT dose to the initial volume was kept at 40 to 40.5 Gy, while it was gradually increased to the boost volume by adding a 7% to 11 % increment of total dose to subsequent cohorts. The MTD was defined as the radiation dose level at one cohort below that which resulted in more than 33% of patients experiencing grade > or = 4 acute esophagitis and/or grade > or = 3 pulmonary toxicity. The study plan included nine cohorts, five on HA twice-daily and four on daily regimens for the dose escalation. Chemotherapy consisted of three cycles of cisplatin 33 mg/m2/d on days 1 to 3 over 30 minutes, cyclophosphamide 500 mg/m2 on day 1 intravenously (IV) over 1 hour, and etoposide 80 mg/m2/d on days 1 to 3 over 1 hour every 3 weeks (PCE) and two cycles of PE. RT was started at the initiation of the fourth cycle of chemotherapy.
Fifty patients were enrolled onto the study. The median age was 60 years (range, 38-79), sex ratio 2.3:1 for male to female, weight loss less than 5% in 73%, and performance score 0 to 1 in 94% and 2 in 6% of patients. In HA twice-daily RT, grade > or = 4 acute esophagitis was noted in two of five (40%), two of seven (29%), four of six (67%), and five of six patients (86%) at 50 (1.25 Gy twice daily), 45, 50, and 55.5 Gy in 1.5 Gy twice daily, 5 d/wk, respectively. Grade > or = 3 pulmonary toxicity was not seen in any of these 24 patients. Therefore, the MTD for HA twice-daily RT was judged to be 45 Gy in 30 fractions over 3 weeks. In daily RT, grade > or = 4 acute esophagitis was noted in zero of four, zero of four, one of five (20%), and two of six patients (33%) at 56, 60, 66, and 70 Gy on a schedule of 2 Gy per fraction per day, five fractions per week. Grade > or = 3 pneumonitis was not observed in any of the 19 patients. Thus, the MTD for daily RT was judged to be at least 70 Gy in 35 fractions over 7 weeks. Grade 4 granulocytopenia and thrombocytopenia were observed in 53% and 6% of patients, respectively, during the first three cycles of PCE. During chemotherapy cycles 4 to 5, grade 4 granulocytopenia and thrombocytopenia were noted in 43% and 29% of patients at 45 Gy in 30 fractions over 3 weeks (MTD) by HA twice-daily RT and 50% and 17% at 70 Gy in 35 fractions over 7 weeks (MTD) by daily RT, respectively. The overall tumor response consisted of complete remission (CR) in 51% (24 of 47), partial remission (PR) in 38% (1 8 of 47), and stable disease in 2% (one of 47). The median survival time of all patients was 24.4 months and 2- and 3-year survival rates were 53% and 28%, respectively. With regard to the different radiation schedules, 2- and 3-year survival rates were 52% and 25% for the HA twice-daily and 54% and 35% for the daily RT cohorts.
The MTD of HA twice-daily RT was determined to be 45 Gy in 30 fractions over 3 weeks, while it was judged to be at least 70 Gy in 35 fractions over 7 weeks for daily RT. A phase III randomized trial to compare standard daily RT with HA twice-daily RT at their MTD for local tumor control and survival would be a sensible research in searching for a more effective RT dose-schedule than those that are being used currently.
Cluster headache has not been fully investigated in Asians. One hundred and four patients (90M/14F; mean age 39.2 ± 12.2 years) with cluster headache were recruited from two major headache clinics in ...Taiwan. They filled out a structured cluster headache questionnaire. All participants were diagnosed to have episodic cluster headache. Mean age of onset was 26.9 years; mean latency of diagnosis was 8.1 years. A trend of decrease in male/female ratio with time was noted. Seventy-three percent were ex- or current smokers (M: 79%, F: 36%). Restlessness was reported by 51% patients. Only 1 patient (1%) reported visual aura. Patients responded well to standard acute and prophylactic treatment. The monthly incidence of cluster period was inversely related to sunshine duration. Compared to Western series, our patients were different in several aspects including the absence of chronic cluster headaches and a low prevalence of restlessness and aura. Racial and geographical factors might contribute to these discrepancies.
The diseases of cystic fibrosis, chronic obstructive pulmonary disease (COPD), and chronic bronchitis are characterized by mucus-congested and inflamed airways. Anti-inflammatory agents that can ...simultaneously restore or enhance mucociliary clearance through cystic fibrosis transmembrane conductance regulator (CFTR) activation may represent new therapeutics in their treatment. Herein, we report the activation of CFTR-mediated chloride secretion by phosphodiesterase (PDE) 4 inhibitors in T84 monolayer using (125)I anion as tracer. In the absence of forskolin, the iodide secretion was insensitive to PDE4 inhibitor L-826,141 4-2-(3,4-bis-difluoromethoxyphenyl)-2-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl-ethyl-3-methylpyridine-1-oxide, roflumilast, or to PDE3 inhibitor trequinsin. However, these inhibitors potently augmented iodide secretion after forskolin stimulation, with efficacy coupled to the activation states of adenylyl cyclase. The iodide secretion from PDE3 or PDE4 inhibition was characterized at first by a prolonged efflux duration, followed by progressively elevated peak efflux rates at higher inhibitor concentrations. Paralleled with an increased phosphor-cAMP response element-binding protein formation, the CFTR activation dissociated from a global cAMP elevation and was blocked by H89 N-2-((p-bromocinnamyl)amino)ethyl-5-isoquinolinesulfonamide. 2-(4-Fluorophenoxy)-N-(1S)-1-(4-methoxyphenyl)ethylnicotinamide, a stereoselective PDE4D inhibitor, augmented iodide efflux more efficiently than its less potent (R)-isomer. The peak efflux from maximal PDE4 and PDE3 inhibition matched that from full adenylyl cyclase activation. These data suggest that PDE3 and PDE4 (mainly PDE4D) form the major cAMP diffusion barrier in T84 cells to ensure a compartmentalized CFTR signaling. Together with their potent anti-inflammatory properties, the potentially enhanced airway mucociliary clearance from CFTR activation may have contributed to the efficacy of PDE4 inhibitors in COPD and asthmatic patients. PDE4 inhibitors may represent new opportunities to combat cystic fibrosis and other respiratory diseases in future.
To determine the dose per fraction that could be used when gamma knife or linear accelerator–based stereotactic treatments are delivered in 2 or more fractions.
The linear-quadratic (LQ) model was ...used to calculate the dose per fraction for a multiple-fraction regimen which is biologically equivalent to a given single-fraction treatment. The results are summarized in lookup tables.
The tables can be used by practicing clinicians as a guide in planning fractionated treatment. For the large doses used in typical stereotactic treatments and for small fraction numbers, the model is not very sensitive to the value of the α/β ratio in the LQ model. A simple rule of thumb is found that for two-fraction and three-fraction treatments the dose per fraction is roughly two-thirds and one-half of the single-fraction treatment dose, respectively.
The authors sought to evaluate the initial response of trigeminal neuralgia (TN) to gamma knife surgery (GKS) based on the number of shots delivered and radiation dose.
Between September 1998 and ...September 2003, some 63 patients with TN refractory to medical or surgical management underwent GKS at Upstate Medical University. Ten patients had multiple sclerosis and 25 patients had undergone prior invasive treatment. Gamma knife surgery was delivered to the trigeminal nerve root entry zone in one shot in 27 patients or two shots in 36 patients. The radiation dose was escalated to less than or equal to 80 Gy in 20 patients, 85 Gy in 21 patients, and greater than or equal to 90 Gy in 22 patients. Pain before and after GKS was assessed using the Barrow Neurological Institute Pain Scale and the improvement score was analyzed as a function of dose grouping and number of shots. Sixty patients were available for evaluation, with an initial overall and complete response rate of 90% and 27%, respectively. There was a greater improvement score for patients who were treated with two shots compared with one shot, mean 2.83 compared with 1.72 (p < 0.001). There was an increased improvement in score at each dose escalation level: less than or equal to 80 Gy (p = 0.017), 85 Gy (p < 0.001), and greater than or equal to 90 Gy (p < 0.001). Linear regression analysis also indicated that there was a greater response with an increased dose (p = 0.021). Patients treated with two shots were more likely to receive a higher dose (p < 0.001). There were no severe complications. Five patients developed mild facial numbness.
Gamma knife surgery is an effective therapy for TN. Initial response rates appear to correlate with the number of shots and dose.
We have developed a simple, one-step procedure for the preparation of competent Escherichia coli that uses a transformation and storage solution TSS; 1 × TSS is LB broth containing 10% (wt/vol) ...polyethylene glycol, 5% (vol/vol) dimethyl sulfoxide, and 50 mM Mg2+ at pH 6.5. Cells are mixed with an equal volume of ice-cold 2 × TSS and are immediately ready for use. Genetic transformation is equally simple: plasmid DNA is added and the cells are incubated for 5-60 min at 4 degrees C. A heat pulse is not necessary and the incubation time at 4 degrees C is not crucial, so there are no critical timing steps in the transformation procedure. Transformed bacteria are grown and selected by standard methods. Thus, this procedure eliminates the centrifugation, washing, and long-term incubation steps of current methods. Although cells taken early in the growth cycle (OD600 0.3-0.4) yield the highest transformation efficiencies (107-108 transformats per μ g of plasmid DNA), cells harvested at other stages in the growth cycle (including stationary phase) are capable of undergoing transformation (105-107 transformats per μ g of DNA). For long-term storage of competent cells, bacteria can be frozen in TSS without addition of other components. Our procedure represents a simple and convenient method for the preparation, transformation, and storage of competent bacterial cells.
The problem of a cylindrically anisotropic tube or bar was seemed to be first examined by Lekhnitskii (1981) Lekhnitskii, S.G., 1981. Theory of Elasticity of an Anisotropic Body. (Trans. from the ...revised 1977 Russian edition.) Mir, Moscow. Recently, a thorough investigation of the subject was performed by Ting (1996) Ting, T.C.T., 1996. Pressuring, shearing, torsion and extension of a circular tube or bar of cylindrically anisotropic material. Proc. Roy. Soc. Lond. A452, 2397–2421 in which a formulation akin to that of Stroh’s formalism is employed to resolve the boundary value problem subjected to a uniform pressure, shearing, torsion and uniform extension. In a continuing paper, Ting (1999) Ting, T.C.T., 1999. New solutions to pressuring, shearing, torsion and extension of a cylindrically anisotropic elastic circular tube or bar. Proc. Roy. Soc. Lond, to appear. rederived the solutions based on a modified formalism of Lekhnitskii, in which the solutions are in terms of elastic compliances, reduced elastic compliances as well as doubly reduced compliance. The results are much more compact and simpler than those of the earlier one. Independently, in this work, we construct the governing system also under the Lekhnitskii’s framework. Nevertheless, the present work and Ting’s formulation (1999) are not alike. Besides the loads considered in Ting (1996, 1999), we add the effect of a uniform temperature change in the formulation. The assumption that
the stresses depend only on r makes it possible to incorporate the various loading cases considered. In addition to the explicit forms of admissible stresses, we derive the admissible displacements which are ensured to be single-valued for a multiply-connected domain. In contrast to the Ting’s works (1996, 1999), which often require superpositions of two or more basic solutions, the present solutions offer complete forms of solutions ready for direct calculations. We also report that, as in rectilinearly anisotropic solids, an entire analogy is observed between the fields of a uniform axial extension and a uniform temperature change in cylindrically anisotropic solids.
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