Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts at diagnosis of childhood acute lymphoblastic leukemia: a pilot prognostic factor analysis

Lymphoblasts in bone marrow samples, obtained from 43 children with acute lymphoblastic leukemia at diagnosis, were incubated with 1.0 mumols/L [3H] methotrexate for 24 hours in vitro. Nonexchangeable methotrexate and methotrexate polyglutamates were separated and quantitated. Event-free survival at 5 years was 38% +/- 9% for all 43 patients (27 failures), and 44% +/- 10% for the 35 with non-T, non-B- cell acute lymphoblastic leukemia (20 failures). Of these 35 children, those whose lymphoblasts accumulated more than 100 pmol methotrexate and 500 pmol methotrexate polyglutamates per billion cells experienced better 5-year event-free survival than those whose lymphoblasts did not (65% +/- 12% v 22% +/- 9%, P = .010). This difference characterized "good-risk" patients who were female (P = .014), less than age 7 at diagnosis (P = .005), or had low initial white blood cell counts (less than 20 X 10(9)/L, P = .018). Findings were similar for the 43 children with acute lymphoblastic leukemia and for the "good-risk" children in this total group. Thus, the ability of lymphoblasts to accumulate methotrexate and form methotrexate polyglutamates may be important to the curative properties of current therapy of acute lymphoblastic leukemia in children, particularly for "good-risk" patients. In such patients, inherent rather than acquired drug resistance may be the initial event leading to treatment failure.     

Time-dependent loss of surface complement regulatory activity during storage of donor blood

The survival of transfused red cells (RBCs) diminishes with time of in vitro storage in blood banks, but the molecular mechanisms underlying the slow but incessant deterioration are incompletely understood. To investigate the possibility that impaired resistance to autologous complement attack could play a role in this phenomenon, packed RBCs stored for variable periods were assayed for decay-accelerating factor (DAF) and CD59, two glycoinositol-phospholipid (GPI)-anchored, membrane- associated complement regulatory proteins that function physiologically to protect blood cells from autologous complement activation on their surfaces. Immunoradiometric and flow cytometric assays employing DAF and CD59 monoclonal antibodies showed that levels of both surface proteins gradually declined over 6 weeks. Digestion analyses with phosphatidylinositol-specific phospholipase C, an enzyme that releases GPI-anchored proteins from cell surfaces, showed that DAF and CD59 molecules with GPI anchors containing unacylated inositol were preferentially lost. These findings suggest: 1) that DAF and CD59 molecules with acylated GPI anchors are more stable in RBC membranes than are molecules with unacylated GPI anchors, and 2) that DAF and CD59 loss may participate with other membrane alterations that occur during in vitro storage in compromising the survival of transfused cells.     

Adenylate cyclase and guanylate cyclase activity in normal and leukemic human lymphocytes

Adenylate cyclase (AC) and guanylate cyclase (GC) activities were studied in normal B-enriched and T-enriched lymphocytes, in lymphocytes of children with acute lymphocytic leukemia (ALL), and in lymphocytes of adults with chronic lymphocytic leukemia (CLL). AC activity was greater in normal B than T lymphocytes (215 pmole/min/mg protein versus 80 pmole in the membrane-enriched fraction) and i both increased greatly after stimulation with isoproterenol and more so with prostaglandins E and F2 alpha. In leukemic lymphocytes, AC showed depressed activity (20 pmole in ALL cells and 55 pmole in CLL cells) and was less sensitive to hormonal stimulation: this loss of sensitivity occurred to a greater extent in ALL than in CLL lymphocytes. GC activity was greater in normal T than B cells (in membrane-enriched fraction: 10.2 pmole versus 5.3 pmole). It increased little with isoproterenol and prostaglandins stimulation, and much more with sodium azide and dehydroascorbic acid stimulation. GC activity was increased in both types of leukemic lymphocytes (23 pmole for ALL cells and 18 pmole for CLL cells) and was insensitive to stimulation. Possible derangement of cyclase and cyclic nucleotide regulation in leukemic cells is suggested.     

Brighton合作组关于Guillain-Barré综合征的诊断定义和资料收集规范

Guillain-Barr啨综合征(GBS)和Miller Fisher综合征(MFS)的诊断标准随着临床研究的深入在不断演变。2011年1月,《疫苗》杂志发表了国际疫苗安全性监测Brighton合作组关于GBS/MFS的诊断定义和研究资料收集规范。此文献中未采用"诊断标准"而采用"诊断定义"是因为其主要目的为评价疫苗安全性而制定,而非用于神经科的GBS/     

A pilot methodology study for the photographic assessment of post‐inflammatory hyperpigmentation in patients treated with tretinoin

Background Post‐inflammatory hyperpigmentation (PIH) is a common occurrence in patients with acne vulgaris, particularly in those with skin of colour. Aims A previous study has demonstrated the benefit of tretinoin (retinoic acid) in the treatment of PIH; however, there is currently no standard protocol to evaluate change in PIH following treatment. Based on these findings, we performed a pilot, exploratory, blinded, intraindividual‐controlled methodology study that consisted of a photographic assessment protocol with facial mapping. Materials and methods The study was based on a secondary analysis of a phase 4, community‐based trial of 544 acne patients who were treated with tretinoin gel microsphere 0.04% or 0.1%. Only patients with Fitzpatrick types III–V (skin of colour) were included in the study; subjects with Fitzpatrick skin type VI were excluded because the photographic assessment did not allow for proper evaluation. Results Despite the small number of subjects evaluated (n = 25), the results revealed consistent assessment of improvement in PIH between two independent graders (weighted κ = 0.84). Conclusion Further study with a larger population is recommended to validate the accuracy of this method.     

Athlete shoulder injuries: CT arthrographic findings

Forty-three professional and amateur athletes with persistent shoulder pain that interfered with their sports activities were evaluated by computed tomographic (CT) arthrography. In 19 patients, glenohumeral instability (14 anterior, two posterior, three multidirectional) was diagnosed with CT arthrography based on the simultaneous presence of labral and capsular lesions. The findings were crucial in establishing the diagnosis of instability in six patients in whom the condition was not suggested or could not be confirmed clinically. Another significant injury consisted of labral lesions not associated with glenohumeral instability. These tears often involved the anterior and parasuperior segments of this structure. Other, less frequently detected lesions included segmental labral enlargement and several labra with abnormal orientation (everted labrum). Early onset of degenerative disease was present in many athletes, especially those with a long history of sports activity. CT arthrographic findings were correlated with arthroscopic or surgical results in 19 patients.     

Use of Compressive Osseointegration Endoprostheses for Massive Bone Loss From Tumor and Failed Arthroplasty: A Viable Option in the Upper Extremity

Background

Endoprostheses using principles of compressive osseointegration have shown good survivorship in several studies involving the lower extremity; however, no series to our knowledge have documented the use of this technology in the management of massive bone loss in the upper limb.

Questions/purposes

(1) What proportion of upper extremity implants using compressive osseointegration fixation principles achieved durable short-term fixation, and what were the modes of failure? (2) What surgical complications resulted from reconstruction using this technique?

Methods

A multiinstitutional retrospective review identified nine patients (five women; four men) who underwent 13 endoprosthetic replacements between 2003 and 2014 using compressive osseointegration (Compliant^® Pre-stress Device [CPS]; Biomet Inc, Warsaw, IN, USA) in the upper extremity, including two proximal humeri, two humeral diaphyses, seven distal humeri, and two proximal ulna. During the early part of that period, the indication for use of a compressive prosthesis in our centers was revision of a previous tumor reconstruction (allograft-prosthetic composite or stemmed endoprosthetic reconstruction) (three patients; five implants), or revision arthroplasty with massive bone loss (three patients, four implants); more recently, indications became somewhat more permissive and included posttraumatic bone loss (one patient, one implant), primary bone sarcoma, and resections with very short remaining end segments after diaphyseal resections (two patients, three implants). Minimum followup was 24 months; one patient (one implant) was lost to followup before that time with the implant intact at 14 months and no patients have died. The mean age of the patients was 45 years (range, 21–62 years). Mean followup was 68 months (range, 24–141 months). Implant revision for any cause and for failure of the CPS mechanism was recorded. Modes of failure were categorized as soft tissue, aseptic loosening, structural, infection, and tumor progression; CPS modes of failure were defined as lack of fixation, with or without bone or implant fracture.

Results

Of the 12 implants accounted for beyond 2 years, six had undergone revision of any kind. Only two revisions in two patients were attributable to lack of CPS fixation at the bone-implant interface; one of the patients also had periprosthetic and implant fracture develop through the traction bar. Other modes of failure were aseptic loosening of the standard ulnar component (two patients, two implants), bushing wear (one patient; one implant) and infection resulting in two-stage exchange and free soft tissue transfer with retention of the CPS spindle (one patient, one implant). Complications for all nine patients included one transient radial nerve palsy, one ulnar nerve sensory neurapraxia, one superficial infection, and two glenohumeral subluxations, one underwent revision surgery with implantation of a constrained liner.

Conclusions

A compressive osseointegration endoprosthesis is an option for very difficult revisions or sarcoma resection in the upper extremity in which the remaining segment of host bone is too short for a conventional prosthesis. However, surgeons must inform patients that these are salvage operations, and revision surgery is common. Long-term followup of more patients is necessary to further document the survivorship of these implants in the upper extremity.

Level of Evidence

Level IV, therapeutic study.

     

Myocardial infarct size quantification by MR imaging early after coronary artery occlusion in dogs

The feasibility of using magnetic resonance (MR) imaging to estimate myocardial infarct size was explored in an in vitro model using only the inherent differences in contrast between infarcted and noninfarcted myocardium. Eight dogs underwent coronary occlusion; their hearts were removed 6 hours later. Estimates of T2 for normal and infarcted myocardium were derived from MR images. Infarct size was quantified anatomically using triphenyltetrazolium-chloride (TTC) staining and compared with MR estimates. The T2 values derived from the images clearly discriminated between infarcted (126 +/- 22 msec) and normal myocardium (88 +/- 10 msec, P less than .05), providing images with good contrast between normal and infarcted myocardium. Comparable differences in T2 values were also noted from spectrometric determinations. Estimates of infarct size by MR imaging compared well with TTC estimates (r = 0.98) over a wide range of infarct sizes from 3% to 29% of the left ventricular mass. These results suggest the potential for in vivo quantification of infarct size based on the inherent contrast difference between infarcted and normal myocardium.     

Visual contrast enhancement with a patterned overlay

A dot-screen pattern was devised and superimposed on computed tomography images to improve contrast at a viewbox. The phenomenon is believed to be probably related to lateral inhibition. To evaluate its usefulness, the device was used on 12 images (eight showed metastatic liver lesions, and four were normal); each image was viewed without the device by ten observers. Three control images were viewed a second time without the device. The remaining nine images were viewed a second time with the device. The overlay improved diagnostic performance in nine observers. Sensitivity improved by 12%, and confidence in true-positive findings increased by 41.6%. Forty-five percent of false-negative findings were converted to true positive with the use of the overlay.