CXCL12-induced VLA-4 activation is impaired in trisomy 12 chronic lymphocytic leukemia cells: a role for CCL21

Homing to distinct lymphoid organs enables chronic lymphocytic leukemia (CLL) cells to receive pro-survival and proliferative signals. Cytogenetic aberrations can significantly affect CLL cell compartmentalization. Trisomy 12 (tri12) defines a CLL subgroup with specific clinical features and increased levels of the negative prognostic marker CD49d, the α4-subunit of the integrin VLA-4, which is a key regulator of CLL cell homing to bone marrow (BM). Chemokine-induced inside-out VLA-4 activation, particularly via the CXCL12-CXCR4 axis, increases the arrest of various cell types on VCAM-1 presenting endothelium. Here, we demonstrate that high CD49d expression in tri12 CLL is accompanied by decreased CXCR4 expression. Dissecting functional consequences of these alterations, we observed that tri12 CLL cell homing to murine BM is not affected by CXCR4-CXCL12 blockage using AMD3100 or olaptesed pegol/NOX-A12. In line, CCL21-CCR7 rather than CXCL12-CXCR4 interactions triggered VLA-4-mediated arrests of tri12 CLL cells to VCAM-1 under blood flow conditions. Concordantly, in real-time kinetic analyses we found CCL21 but not CXCL12 being capable to induce inside-out VLA-4 conformational changes in this CLL subgroup. Our results provide novel insights into the peculiar clinico-biological behaviour of tri12 CLL and emphasize its specific chemokine and integrin utilization during pathophysiologically and therapeutically relevant interactions with the microenvironment.     

Postgraduate training in Oral- and Maxillofacial Surgery: Results of a survey among 74 German interns

The aim of this study was to asses a survey of residents to obtain relevant information about their current situation in training in Oral and Maxillofacial Surgery in Germany. Special focus was given to the personal and clinical preferences of the residents, their main subjects of interest and plans after residency. Furthermore, the different principles of education at German teaching hospitals were evaluated.Overall, 74 questionnaires were completed on a voluntary and anonymous basis by German residents for Oral and Maxillofacial Surgery. Participants’ mean age was 32.74 years (68% male, 27% female). Most participants were in the fifth year of training (32%) and members of the German Association of Oral and Maxillofacial Surgery (70%). This rate increased with progress in residency (p = 0.006). Most residents (70%) were employed at university hospitals, followed by non-university hospitals (26%) and private practices (4%). Residents from university hospitals (3.06 ± 0.39 years) were less advanced in training compared to residents from non-university hospitals and private practices (4.10 ± 0.54 years; p = 0.005). Part-time employed residents were significantly younger (30.64 ± 2.37 years) than full-time employed residents (33.25 ± 0.64 years, p = 0.002).Structured concepts of training existed in 64% of the hospitals, while training depending on the current year of residency (42%) was most common. Most of the residents would prefer a systematic rotation system (59%). Main subjects of clinical interest were aesthetic (50%) and orthognathic surgery (46%). The interest in dento-alveolar surgery (34%) significantly increased with participants’ age (p = 0.008). Clefts and malformations were favoured by few residents (16%). Most participants planned to specialize in facial plastic surgery after residency (76%).The data collected might give evidence for an increasing importance of structured training concepts in Oral and Maxillofacial Surgery. It might be relevant to enhance the interest and the excitement of residents for oncology, traumatology, cleft and malformation surgery.     

Postoperative complications after bimaxillary orthognathic surgery: A retrospective study with focus on postoperative ventilation strategies and posterior airway space (PAS)

PurposeThe aim of this study was to evaluate the impact of extubation time on postoperative complications in patients undergoing bimaxillary orthognathic surgery. We therefore retrospectively compared the effect of early extubating (EE) in the operating room versus delayed extubating (LE) on the intensive care unit (ICU) regarding postoperative complications and length of ICU/hospital stay (LOICUS/LOHS). Furthermore, we analyzed the influence of the PAS change on postoperative complications.MethodsThe clinical data of 117 patients were retrospective analyzed regarding postoperative complications using Clavian-Dindo Classification. Volumetric calculations of the pre- and postoperative PAS were conducted using ITK-SNAP software. The Fisher's exact test was performed to evaluate the significance of differences between categorical variables. Continuous variables were analyzed using the Mann–Whitney U-Test or the Kruskal–Wallis one-way analysis of variance. Regression analysis was used estimating predictors for postoperative complications.ResultsEE led to significant shortening of LOICUS (p < 0.001) and LOHS (p = 0.023). In total, we recorded 38 complications (minor n = 30; major n = 8) within the hospital stay. Complication rates were without significant differences with respect to the postoperative ventilation strategy. Large changes in PAS volume led to an increase in the major complication rates (p = 0.031). Increase or decrease of PAS was independent from postoperative complication rates (p = 1.000). Higher body mass index (p = 0.04) and a higher ASA PS score (p = 0.016) were associated with increased major complication rates.ConclusionEarly extubation after surgery is a safe procedure and is associated with a reduced LOICUS and LOHS. Complications seem to occur more frequently in marked changes of the PAS and should be considered in perioperative risk stratification.     

Is panendoscopy a necessary staging procedure in patients with lacking risk factors and oral squamous cell carcinoma?

ObjectivesRoutine panendoscopy is used to detect synchronous malignancies of the upper aerodigestive tract in staging of oral squamous cell carcinoma. The goal of this study was to investigate the occurrence of synchronous malignancies at time of diagnosis using panendoscopy. To challenge the role of panendoscopy as inherent part of routine staging procedures, we were especially interested in low risk patients.Materials and methodsRetrospectively, a cohort of 484 patients with pathologically confirmed diagnosis of primary oral and oropharyngeal squamous cell carcinoma was investigated. Electronically recorded findings of in-house conducted panendoscopy were retrieved and evaluated for the occurrence of pathological changes of the mucosa. In case of synchronous malignancies, findings were correlated to preoperative radiographic imaging. Patients were classified as high or low risk. Patients with lacking risk factors (no smoking, no drinking in history) were defined as low risk patients.ResultsOverall, we detected three synchronous malignancies of the upper aerodigestive tract (3/484; 0.6%). Two non-small cell lung cancers were detected in patients with a smoking history of 60 pack years. One esophageal carcinoma in situ was detected in a patient with reported alcohol consumption. No synchronous malignancy was detected in patients without risk factors and no malignancy was previously detected by diagnostic imaging.ConclusionPre-treatment panendoscopy can reveal synchronous malignancies of the upper aerodigestive tract in patients with primary oral squamous cell carcinoma. Risk stratification of patients can avoid unnecessarily conducted panendoscopy in patients without risk factors. This may lead to a higher cost-efficacy in public health system, less treatment-related complications and earlier treatment initiation.     

The 5q-anomaly

A deletion of the long arm of chromosome #5 (5q-) occurs nonrandomly in human malignancies. As a rule, the deletion is interstitial; the distal breakpoint by conventional techniques is usually in band q32, the proximal breakpoints in q12 or q14. Variant breakpoints occur in less than 10% of all cases. As the sole anomaly, 5q- is characteristically found in refractory anemia with or without excess of blasts. It can occur as the sole anomaly in de novo or secondary acute nonlymphocytic leukemia, but is usually accompanied in those disorders by other chromosome changes that are also nonrandomly distributed. In addition, it can be found in lymphoproliferative disorders, and occasionally, also in solid tumors. The 5q- myelodysplastic syndrome typically occurs in older age groups, particularly in females. Characteristic features are macrocytic anemia, normal or elevated platelets in the presence of megakaryocytic anomalies, and a mild clinical course. In cases with 5q- only, transformation into ANLL occurs rarely. Additional chromosome anomalies and male sex are prognostically unfavorable signs. Sex ratio is also at the disadvantage of females in de novo 5q- ANLL, and the latter disorder can occur without being preceded by a myelodysplastic phase. A myelodysplastic phase usually precedes 5q- secondary leukemia, in males as well as in females, and additional chromosome anomalies, especially of chromosome #7, are almost invariably present in those cases. We conclude that 5q- is the most frequently occurring single chromosome anomaly in secondary leukemia. Furthermore, the resemblance between de novo and secondary 5q- MDS and ANLL is striking; clinically, as well as cytogenetically, they are indistinguishable, suggesting that all de novo cases may be due to environmental (chemical) carcinogens. Response to treatment and prognosis are very poor with current therapeutic regimens in de novo as well as in secondary 5q- ANLL. Morphologically, these ANLLs fall into all FAB categories. There is considerable evidence to show that the 5q- anomaly occurs in a myeloid precursor stem cell. The occasional occurrence in lymphoid malignancies, of B cell as well as T cell type, suggests that, as in Ph-positive disorders, a common progenitor stem cell may be affected in 5q- also. The 5q- lymphoid malignancies, however, are much more rare; it is not clear at the present time whether or not a 5q- counterpart of Ph-positive ALL exists, and mixed lymphoid-myeloid 5q- disorders have not yet been documented.(ABSTRACT TRUNCATED AT 400 WORDS)     

Expression of the Ly49A gene in murine natural killer cell clones is predominantly but not exclusively mono-allelic

The Ly49 family of natural killer (NK) cell receptors are major histocompatibility complex (MHC) class I-specific inhibitory receptors that are distributed to overlapping NK cell subsets. Extending earlier studies of polyclonal NK cell populations, we have employed an analysis of short-term NK cell clones from Ly49A heterozygous mice, to demonstrate that the Ly49A gene is usually expressed from one or the other allele in each Ly49A⁺ cell. However, we also detected a small percentage of clones that expressed both Ly49A alleles. The possibility that the colonies exhibiting bi-allelic Ly49A gene expression had been inoculated with more than one cell was ruled out by parallel analysis of clones isolated from mixtures of NK cells from Ly49A homozygous mice. The frequency of bi-allelic Ly49A⁺ clones suggested that the two Ly49A alleles in an NK cell are chosen for expression independently. These data are consistent with the proposal that mono-allelic Ly49A gene expression may arise as a consequence of a stochastic Ly49 gene activation mechanism. Analysis of Ly49A⁺ clones from MHC-different mice demonstrated that class I-deficient mice harbored a greater number of bi-allelic Ly49A⁺ cells than did H-2^d mice, which express a Ly49A ligand. Although the numbers were insufficiently large for a clear assignment, H-2^b mice may harbor an intermediate number of bi-allelic Ly49A⁺ NK cells. The effects of MHC expression on the prevalence of bi-allelic Ly49A⁺ cells suggest that an MHC-dependent education process modifies the Ly49 repertoire.     

Identification of alpha1-adrenoceptor subtypes in the human prostatic urethra

To identify the α₁-adrenoceptor subtypes in the human prostatic urethra, we compared the potencies of various α₁-adrenoceptor agonists and antagonists in inhibiting [³H]tamsulosin binding to human prostatic urethral membranes with their potencies in inhibiting the binding of (+)-β-([¹²⁵I]iodo-4-hydroxyphenyl)ethylaminomethyl-tetralone ([¹²⁵I]HEAT) to cloned human α_1a, α_1b and α_1d subtypes. The α_1A-selective antagonists 5-methylurapidil and (+)niguldipine showed higher affinities for both cloned α_1a and urethral α₁-adrenoceptors than for cloned α_1b- and α_1d-adrenoceptors. NS-49, (R)-3′-(2-amino-1-hydroxyethyl)-4′-fluoromethanesulfonanilide hydrochloride, recently characterized as an α_1A-selective agonist, also showed high affinity for the cloned α_1a subtype and urethral α₁-adrenoceptors. Prazosin showed lower affinity for α₁-adrenoceptors in the human prostatic urethra than for any of the three cloned α₁-adrenoceptors. Comparison of the affinities of α₁-adrenoceptor agonists and antagonists for human prostatic urethral α₁-adrenoceptors to their affinities for the three cloned α₁ subtypes indicated a close correlation between the affinities for human urethral α₁ and the cloned α_1a-adrenoceptors. However, prazosin did not conform to this pattern. These findings suggest that the predominant α₁-adrenoceptor in the human urethra is the α_1A subtype, and that an α_1L subtype which has been characterised by its low affinity for prazosin, may also be present. Received: 2 August 1996 / Accepted: 17 October 1996     

Ulnar nerve entrapment neuropathy in the forearm

A 74-year-old male attorney developed rapidly progressive weakness of the fourth and fifth digits of the right hand with impairment of his grip and ability to perform cursive writing. Lancinating pain occurred spontaneously and was triggered by pressure along the ulnar border of the forearm about 5 cm proximal to the wrist crease. Nerve conduction studies revealed a complete electrical block to stimulation at a point 5 cm proximal to the wrist crease when recording from the abductor digiti minimi. Distal to this point, responses of normal amplitude and latency were recorded. Surgical exploration disclosed two fibrovascular bands coursing from the ulnar artery to the distal belly of the flexor carpi ulnaris, entrapping and grooving the ulnar nerve. Release of these bands resulted in reversal of the electrical block, complete relief of pain, and a full neurologic recovery during the ensuing six months.