ALK-positive anaplastic large cell lymphoma with a monomorphic small-cell pattern masquerading as inflammatory gastric lesions.

INTRODUCTION: Anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL) with a non-common pattern can be diagnostic challenging. Pathologists can be unavoidably and unintentionally blind to non-descript tumor cells in a lymphohistiocytic- (LH) or small-cell (SC)-pattern. We report a case of primary systemic ALK+ ALCL with a SC pattern that presented as secondary gastric lesions with a mixed LH and SC pattern that was masqueraded as inflammatory lesions. CASE REPORT: A 34-year-old woman with intractable epigastric pain was referred to have repeated endoscopy with biopsy. She was found to multiple gastric erosions and nodules that were diagnosed as inflammatory lesions both endoscopically and histologically. Meanwhile, she developed an acute onset of severe back pain associated with a pathologic compression fracture in the T3 thoracic vertebral body. Imaging studies disclosed a disseminated systemic disease involving abdominopelvic lymph nodes and cervical and thoracic vertebral bodies. The needle biopsy of the pelvic lymph node disclosed diffuse proliferation of monomorphic small round cells that were diffusely positive for CD30 and ALK. A diagnosis of ALK+ ALCL with a monomorphic SC pattern was rendered. DISCUSSION: A retrospective review of the gastric biopsies with the aid of immunohistochemistry enabled us to recognise the presence of lymphomatous infiltrates with a mixed LH and SC pattern in every piece of gastric biopsies that were repeatedly misdiagnosed as inflammatory lesions. This case illustrates a significant diagnostic pitfall of the LH- and SC-patterns in ALK+ ALCL, in which the tumour cells featuring lymphoid, plasmacytoid or histiocytoid appearance can be masqueraded as inflammatory cells.

High-quality cell block preparation from scraping of conventional cytology slide: a technical report on a modified cytoscrape cell block technique.

BACKGROUND: Immunocytochemistry (ICC) on formalin-fixed paraffin embedded cell blocks is an ancillary tool commonly recruited for differential diagnoses of fine needle aspiration cytology (FNAC) samples. However, the quality of conventional cell blocks in terms of adequate cellularity and evenness of distribution of cytologic material is not always satisfactory for ICC. We introduce a modified agarose-based cytoscrape cell block (CCB) technique that can be effectively used for the preparation of cell blocks from scrapings of conventional FNAC slides. METHODS: A decoverslipped FNAC slide was mounted with a small amount of water. The cytological material was scraped off the slide into a tissue mold by scraping with a cell scraper. The cytoscrape material was pelleted by centrifugation and pre-embedded in ultra-low gelling temperature agarose and then re-embedded in conventional agarose. The final agarose gel disk was processed and embedded in paraffin. RESULTS: The quality of the ICC on the CCB sections was identical to that of the immunohistochemical stains on histological sections. By scrapping and harvesting the entirety of the cytological material off the cytology slide into a compact agarose cell button, we could avoid the risk of losing diagnostic material during the CCB preparation. CONCLUSION: This modified CCB technique enables concentration and focusing of minute material while maintaining the entire amount of the cytoscrape material on the viewing spot of the CCB sections. We believe this technique can be effectively used to improve the level of confidence in diagnosis of FNAC especially when the FNAC slides are the only sample available.

Radiation-induced angiogenic signaling pathway in endothelial cells obtained from normal and cancer tissue of human breast.

Despite strong possibility that endothelial cells (ECs) of tumors and normal tissues may differ in various aspects, most previous studies on ECs have used normal cells. Here, we purified ECs from tumorous and normal human breast tissues, and studied the effect of radiation on angiogenesis and relevant molecular mechanisms in these cells. We found that in normal tissue-derived ECs (NECs), 4 Gy irradiation increased tube formation, matrix metalloproteinase 2 (MMP-2) expression and extracellular signal-regulated kinase (ERK) pathway activation. In cancer-derived ECs (CECs), however, 4 Gy irradiation significantly reduced tube formation, increased the production of angiostatin and interleukin-6 (IL-6), and upregulated AKT and c-Jun N-terminal kinase (JNK) pathway activation. Knockdown experiments showed that siMMP-2 efficiently inhibited tube formation by irradiated NECs, whereas siPlasminogen effectively attenuated the radiation-induced suppression of tube formation and the upregulation of angiostatin in CECs. Moreover, siIL-6 clearly inhibited the radiation-induced generation of angiostatin in CECs. Inhibition of ERK with a pharmacological inhibitor or small interfering RNAs (siRNAs) markedly suppressed the radiation-induced tube formation and MMP-2 upregulation in NECs, whereas the inhibition of either AKT or JNK with pharmacological inhibitor or siRNA treatment of CECs markedly attenuated the inhibition of tube formation and the upregulation of angiostatin and IL-6 caused by 4 Gy irradiation. These observations collectively demonstrate that there are distinct differences in the radiation responses of NECs and CECs, and might provide important clues for improving the efficacy of radiation therapy.

Thromboelastography-guided transfusion decreases intraoperative blood transfusion during orthotopic liver transplantation: randomized clinical trial.

OBJECTIVE: To test in a prospective randomized study the hypothesis that use of thromboelastography (TEG) decreases blood transfusion during major surgery. MATERIAL AND METHODS: Twenty-eight patients undergoing orthotopic liver transplantation were recruited over 2 years. Patients were randomized into 2 groups: those monitored during surgery using point-of-care TEG analysis, and those monitored using standard laboratory measures of blood coagulation. Specific trigger points for transfusion were established in each group. RESULTS: In patients monitored via TEG, significantly less fresh-frozen plasma was used (mean [SD], 12.8 [7.0] units vs 21.5 [12.7] units). There was a trend toward less blood loss in the TEG-monitored patients; however, the difference was not significant. There were no differences in total fluid administration and 3-year survival. CONCLUSION: Thromboelastography-guided transfusion decreases transfusion of fresh- frozen plasma in patients undergoing orthotopic liver transplantation, but does not affect 3-year survival.

An appraisal of timely magnetic resonance imaging in diagnosing spinal cord compression.

INTRODUCTION: Spinal cord compression is a very debilitating condition and could be secondary to many causes. Urgent magnetic resonance (MR) imaging of the spine is crucial in making the diagnosis and guiding further management. Our objectives were to assess the nature of MR imaging requests, the diagnostic yield, and the subsequent management according to relevant MR imaging findings. METHODS: We focused on all the urgent MR imagings of the spine conducted from July 1, 2007 to December 31, 2007. Clinical data, including the demographical information, presenting symptoms, radiological diagnosis, waiting time for MR imaging and treatment, was reviewed. RESULTS: A total of 33 cases of urgent MR imaging of the spine were performed. Patients were aged 29-85 years, with 18 males and 15 females. Most of them (84.8 percent) presented with neurological symptoms. 84 percent of the MR imaging was performed within 24 hours. 76 percent of the examinations yielded significant cord compression, of which 56 percent were due to vertebral metastasis, while others were due to epidural haematoma (12 percent), infective spondylodiscitis (8 percent), vertebral fracture (8 percent) and disc herniation (16 percent). Of the vertebral metastasis patients, 43 percent had one region imaged. 64 percent of the cord compression patients received surgical treatment or radiotherapy, with a mean waiting time of 1.7 days. CONCLUSION: The urgent MR imaging spine service was able to react promptly with a high diagnostic yield. One-third of the patients with vertebral metastasis had multiple levels involved, and imaging of the whole spine would be useful.

Is ultrasonography-guided modified coaxial core biopsy of the breast a better technique?

OBJECTIVE: To compare the diagnostic rate, patient comfort, and complications of ultrasonography-guided breast biopsy using a modified coaxial technique with ultrasonography-guided fine needle aspiration and traditional core biopsy. A secondary objective was to describe the use of the coaxial technique for the biopsy of breast lesions and our initial experience. DESIGN: Retrospective study. SETTING: A regional hospital in Hong Kong. PATIENTS: Patients, who were referred for ultrasonography-guided fine needle aspiration or biopsy from 23 November 2007 to 19 March 2008, were divided into three groups. For breast lesions of 8 mm or smaller, fine needle aspirations were performed. For breast lesions larger than 8 mm, the patients were randomly divided into groups receiving traditional core biopsies and coaxial biopsies. The pathological reports were reviewed. MAIN OUTCOME MEASURES: Diagnostic rate, patient comfort assessed in terms of pain, and any procedural complications. RESULTS: A total of 45 ultrasonography-guided fine needle aspirations or biopsies of breast lesions were performed. All core biopsies using the traditional core technique (n=15) and coaxial technique (n=16) were diagnostic. While for fine needle aspirations, three (21%) of 14 were not diagnostic and repeat biopsies were undertaken for the corresponding patients. Except for one breast lesion biopsied with the coaxial technique that revealed invasive ductal carcinoma, all others yielded benign lesions. The average pain score for coaxial biopsies was 2.2, while for traditional core biopsies and fine needle aspirations, average scores were 3.7 and 3.8, respectively (P=0.022). No procedure-related complication was documented with either of the three techniques. CONCLUSION: Modified coaxial core biopsy of the breast has an optimal diagnostic rate and hence avoids the need for repeat biopsies. It is associated with better patient comfort and no increase in the risk of complications.

Oesophageal gastro-intestinal stromal tumour presenting with rupture into pleural cavity.

Gastro-intestinal stromal tumours are rarely found in the oesophagus and it is uncommon for these tumours to present with rupture. In this paper, we report a case where the tumour ruptured through the distal oesophagus. As a result, the patient underwent surgical tumour dissection. A histopathological examination of the tumour mass confirmed that it was a gastro-intestinal stromal tumour. In this report, we review the diagnosis, pathology, and treatment of a patient presenting with a ruptured oesophageal gastro-intestinal stromal tumour.

Performance of AEP Monitor/2-derived composite index as an indicator for depth of sedation with midazolam and alfentanil during gastrointestinal endoscopy.

BACKGROUND AND OBJECTIVE: The A-Line auditory evoked potential index (AAI) (AEP Monitor/2, Danmeter A/S, Odense, Denmark) is a newly developed composite parameter representing the degree of hypnosis. We conducted a prospective, observational study to explore the performance and validity of the AAI during conventional sedation for gastrointestinal (GI) endoscopy. METHODS: Thirty adults of either sex, age <65, scheduled for combined oesophagogastroduodenoscopy (OGD) and colonoscopy under sedation with intravenous (i.v.) midazolam and alfentanil were enrolled. The sedative end-point was set at the Observer's Assessment of Alertness/Sedation (OAA/S) score less than 4. An AEP Monitor/2 was used in all patients. AAI, sedation scores, heart rate (HR), blood pressure (BP) and SPO2 were recorded every 2 min up to the end of the procedure. Receiver operator characteristic analysis was used to test validity and to select optimal sedation. RESULTS: There was a significantly positive correlation between AAI and OAA/S scores (rho = 0.886; P < 0.001). The AAI also showed significant differences between subsequent levels of sedation scores (P < 0.001). AAI greater than 54 indicated fully awake or minimal sedation and values between 54 and 42 were suggestive of moderate sedation. Values between 42 and 34 were associated with moderate to deep sedation and readings below 34 were associated with deep sedation. The relative risk of SPO2 < 95% for OAA/S = 2 compared with 3 was 15.98 (95% confidence interval (CI): 3.94-64.81). CONCLUSIONS: AAI is an effective tool for monitoring sedation during GI endoscopy induced by i.v. midazolam and alfentanil.

Idiopathic myelofibrosis with extramedullary haemopoiesis involving the urinary bladder in a Chinese lady.

Extramedullary haemopoiesis (EMH) associated with idiopathic myelofibrosis most commonly involves the reticuloendothelial organs, such as the spleen and liver, although ectopic haemopoietic tissue has also been described rarely in the lymph nodes, skin, gastrointestinal tract, pleura, peritoneum, central nervous system, and genital and urinary tracts. We report on a 54-year-old Chinese lady with a long history of idiopathic myelofibrosis who presented with gross haematuria and left hydronephrosis due to EMH in the bladder trigone. Cystoscopic examination revealed a sessile necrotic papillary growth at the trigone, obstructing the left ureteric orifice. Transurethral resection of the bladder tumour was performed, and microscopic examination of the tumour chips demonstrated atypical megakaryocytes, immature granulocytes and normoblasts, confirming the presence of EMH. The residual bladder tumour responded well to low dose radiotherapy, with subsequent disappearance of haematuria and normalization of ultrasonogram findings.

Hierarchical protein folding: asymmetric unfolding of an insulin analogue lacking the A7-B7 interchain disulfide bridge.

The landscape paradigm of protein folding can enable preferred pathways on a funnel-like energy surface. Hierarchical preferences may be manifest as a nonrandom pathway of disulfide pairing. Stepwise stabilization of structural subdomains among on-pathway intermediates is proposed to underlie the disulfide pathway of proinsulin and related molecules. Here, effects of pairwise serine substitution of insulin's exposed interchain disulfide bridge (Cys(A7)-Cys(B7)) are characterized as a model of a late intermediate. Untethering cystine A7-B7 in an engineered monomer causes significantly more marked decreases in the thermodynamic stability and extent of folding than occur on pairwise substitution of internal cystine A6-A11 [Weiss, M. A., Hua, Q. X., Jia, W., Chu, Y. C., Wang, R. Y., and Katsoyannis, P. G. (2000) Biochemistry 39, 15429-15440]. Although substantially disordered and without significant biological activity, the untethered analogue contains a molten subdomain comprising cystine A20-B19 and a native-like cluster of hydrophobic side chains. Remarkably, A and B chains make unequal contributions to this folded moiety; the B chain retains native-like supersecondary structure, whereas the A chain is largely disordered. These observations suggest that the B subdomain provides a template to guide folding of the A chain. Stepwise organization of insulin-like molecules supports a hierarchic view of protein folding.

Prostaglandins may participate in opioidergic and cholinergic control of the diurnal changes of tuberoinfundibular dopaminergic neuronal activity and serum prolactin level in ovariectomized, estrogen-treated rats.

The roles of prostaglandins (PGs) involved in opioidergic, cholinergic, and serotonergic regulation of the diurnal changes of tuberoinfundibular dopaminergic (TIDA) neuronal activities were investigated in ovariectomized, estrogen-treated rats. Treatment with naloxone [10 mg/kg, intraperitoneal (i.p.)], atropine (5 mg/kg, i.p.), or ketanserin (10 mg/kg, i.p.) at either 1200 or 1400 h prevented the afternoon decrease of TIDA neuronal activity and the prolactin (PRL) surge. Intracerebroventricular (i.c.v.) injection of PGE(1) (5 microg/3 microl/rat) at 1500 h significantly reversed the effects of naloxone and atropine, but not that of ketanserin. In ovariectomized, estrogen-primed rats pretreated with indomethacin, i.c.v. injection of either nicotine (10 ng/rat) or fentanyl (10 ng/rat) failed to suppress the TIDA neuronal activity and to stimulate the PRL secretion. These data suggest that PG may be involved in opioidergic and cholinergic control of the diurnal changes of TIDA neuronal activity and the PRL secretion in ovariectomized (OVX) + E(2) rats.

Prostaglandins play an important role in diurnal changes of tuberoinfundibular dopaminergic neuronal activity and prolactin secretion in ovariectomized, estrogen-treated rats.

Intracerebroventricular injection of prostaglandins (PGs) has long been shown to stimulate the secretion of prolactin (PRL). The action of specific PG and the underlying mechanism, however, remain inconclusive. In this study, we evaluated the involvement of PGs in the diurnal changes of the tuberoinfundibular dopaminergic (TIDA) neurons and PRL secretion in ovariectomized (OVX) rats treated with estrogen (E2). Prior treatment of indomethacin (50 mg/kg, subcutaneous) for 24 h significantly prevented the afternoon decrease of TIDA neuronal activity and blocked the PRL surge. Intracerebroventricular injection of PGE(1) (5 microg/3 microl/rat) at 1000 h significantly lowered the activity of TIDA neurons, while similar treatment of PGE2 was without effect. In OVX + E(2) rats pretreated with indomethacin, PGE(1) given at 15, but not 30 or 180 min before decapitation at 1500 h significantly reversed the effects of indomethacin on TIDA neuronal activity, while the blocked PRL surge was not reversed. The PGs also exhibited a stimulatory effect on nigrostriatal dopamine (DA) neurons with PGE2 being the most effective agent. These results indicate that endogenous PGs play a significant role in the control of central DA neurons, especially the diurnal changes of TIDA neuronal activity and PRL secretion in OVX + E2 rats.

Reversal of mivacurium chloride: edrophonium of spontaneous recovery in microscopic laryngeal surgery.

BACKGROUND: A double-blind, randomized study was designed to compare the recovery manner of mivacurium infusion with or without edrophonium reversal in microscopic laryngeal surgery. Neuromuscular blockade was quantified using the train-of-four stimuli to the ulnar nerve and quantification of the ratio of the fourth twitch to the first twitch. METHODS: With the approval of the Human Studies Committee of the Taipei Veterans General Hospital and patient informed consent, 40 healthy (ASA I or II) patients with age from 24 to 54 years, undergoing microscopic laryngeal surgery were randomly selected for study. Mivacurium chloride 0.2 mg/kg was given intravenously, and then it was given in continuous infusion to maintain muscle relaxation at 90% twitch block during the procedure. At the end of operation, mivacurium infusion was terminated. In a double-blind manner, group I patients (n = 20) received intravenous edrophonium 1 mg/kg and atropine 0.01 mg/kg for reversal when T1 was at 10% recovery whereas patients in Group II (n = 20) received placebo in the same manner. Mean infusion rate, recovery index (RI50, time from T1 25% to T1 50%; RI75, time from T1 25% to T1 75%), extubation time, and discharge time between groups were compared. Nausea, vomiting, and dysrhythmias were also documented until the patient was discharged from hospital. RESULTS: The demographic data between two groups were similar. The recovery index (RI75) for group I was shorter than that of placebo group (5.3 +/- 2.19 min vs. 7.3 +/- 0.9 min) and the difference was statistically significant (P = 0.017). There were no statistically significant differences in mean infusion rate, incidence of nausea and vomiting, and discharge time from the POR. The incidence of tachycardia or arrhythmia in group I was significantly greater than that in group placebo. CONCLUSIONS: Mivacurium, a short-acting nondepolarizing agent, is a suitable muscle relaxant for patients receiving microscopic laryngeal surgery. Recovery time with the use of edrophonium as reversal agent was shorter than with placebo, but extubation and discharge time did not differ in two groups. The time which could be saved by the use of edrophonium for reversal of mivacurium to hasten the maximal recovery appears to be less than a few minutes. Therefore, clinically, the value of routine use of edrophonium to obtain a faster recovery does not outweigh its demerits of cost and risk and is not worthy of recommendation.

Hierarchical protein "un-design": insulin's intrachain disulfide bridge tethers a recognition alpha-helix.

A hierarchical pathway of protein folding can enable segmental unfolding by design. A monomeric insulin analogue containing pairwise substitution of internal A6-A11 cystine with serine [[Ser(A6),Ser(A11),Asp(B10),Lys(B28),Pro(B29)]insulin (DKP[A6-A11](Ser))] was previously investigated as a model of an oxidative protein-folding intermediate [Hua, Q. X., et al. (1996) J. Mol. Biol. 264, 390-403]. Its structure exhibits local unfolding of an adjoining amphipathic alpha-helix (residues A1-A8), leading to a 2000-fold reduction in activity. Such severe loss of function, unusual among mutant insulins, is proposed to reflect the cost of induced fit: receptor-directed restoration of the alpha-helix and its engagement in the hormone's hydrophobic core. To test this hypothesis, we have synthesized and characterized the corresponding alanine analogue [[Ala(A6),Ala(A11),Asp(B10),Lys(B28), Pro(B29)]insulin (DKP[A6-A11](Ala))]. Untethering the A6-A11 disulfide bridge by either amino acid causes similar perturbations in structure and dynamics as probed by circular dichroism and (1)H NMR spectroscopy. The analogues also exhibit similar decrements in thermodynamic stability relative to that of the parent monomer as probed by equilibrium denaturation studies (Delta Delta G(u) = 3.0 +/- 0.5 kcal/mol). Despite such similarities, the alanine analogue is 50 times more active than the serine analogue. Enhanced receptor binding (Delta Delta G = 2.2 kcal/mol) is in accord with alanine's greater helical propensity and more favorable hydrophobic-transfer free energy. The success of an induced-fit model highlights the applicability of general folding principles to a complex binding process. Comparison of DKP[A6-A11](Ser) and DKP[A6-A11](Ala) supports the hypothesis that the native A1-A8 alpha-helix functions as a preformed recognition element tethered by insulin's intrachain disulfide bridge. Segmental unfolding by design provides a novel approach to dissecting structure-activity relationships.

Myositis ossificans of the chest wall simulating malignant neoplasm.

Myositis ossificans originating from the chest wall is extremely rare. We report a case of myositis ossificans occurring in a young woman with progressive painful swelling in the chest wall. Preoperative examination suggested a malignant neoplasm originating from soft tissue. Although rare, myositis ossificans is one of the potential causes of painful swelling in the chest wall, and can be mistaken for a malignant neoplasm.

Churg-Strauss syndrome with perforating ulcers of the colon.

We report a case of a 72-year-old woman with Churg-Strauss syndrome, who presented with intestinal perforation. She has had bronchial asthma with peripheral blood eosinophilia for 30 years. Gross findings of a resected colon showed multiple ulcers with perforation. Histologic findings demonstrated transmural inflammation infiltrated with large numbers of eosionophils, neutrophils and lymphoplasma cells, and characteristic extravascular granuloma in the subserosa. There were multifocally-distributed transmural vasculitis showing all stages of activity in medium and small-sized arteries and veins located in the submucosa, and proper muscle and subserosal layers of the colon, some of which revealed granulomatous inflammation. Histologic finding of liver showed chronic viral hepatitis B with mild inflammatory activity and macronodular cirrhosis. Immunohistochemical findings, acid fuschin orange G staining and electromicroscope found no evidence of hepatitis B virus infection contributing to the pathogenesis of this lesion.

Metastatic renal cell carcinoma in a meningioma: a case report.

Tumor-to-tumor metastasis is rare. We report a case of metastatic renal cell carcinoma in meningioma. A 67-year-old woman presented a two-week history of motor dysphagia and decreased short-term memory. She had undergone a left radical nephrectomy for a renal cell carcinoma 7 years ago, and had not received any adjuvant therapy. MRI disclosed a 3.0 x 3.0 x 3.0-cm sized round tentorial-based extraaxial mass with peritumoral edema in the left posterior temporal lobe. During operation, the tumor was found to be an encapsulated mass firmly attached to the tentorium. Histologically, the tumor was a meningotheliomatous meningioma extensively infiltrated by metastatic renal cell carcinoma, accompanying widespread coagulative necrosis. Immunohistochemical staining for cytokeratin revealed strong positivity only in the renal cell carcinoma component. The patient's postoperative course was uneventful. Post-operative radiation therapy was applied to the whole brain. Three months after operation, the patient developed right hemiparesis and dysphagia. Brain MRI at that time did not reveal recurrence or any other causative lesions, although the whole body scan disclosed uptake at the second lumbar vertebra and rib. The patient refused further treatment.