Bisphosphonate-associated osteonecrosis of the external auditory canal.

BACKGROUND: Osteonecrosis is a benign condition characterised by necrotic exposed bone, and is associated with bisphosphonate use. Osteonecrosis of the external auditory canal is rare, with only a few reported cases. METHOD: Two case reports of temporal bone osteonecrosis are presented. RESULTS: A 64-year-old man with a history of immunoglobulin G kappa multiple myeloma developed a right external auditory canal ulcer 6 years after commencement on clodronate. A 72-year-old woman taking alendronate for osteoporosis, initially diagnosed and treated for right-sided otitis externa, was found to have underlying exposed bone in the right external auditory canal, with a computed tomography scan confirming destruction of the temporal bone. CONCLUSION: With increasing use of both oral and intravenous bisphosphonates in the community for benign conditions such as osteoporosis and for malignant conditions such as breast cancer and multiple myeloma, the diagnosis of bisphosphonate-associated osteonecrosis should always be considered in patients with a temporal bone lesion, and a relevant drug history taken.

Prevention of venous thromboembolism in patients admitted to Australian hospitals: summary of National Health and Medical Research Council clinical practice guideline.

Each year in Australia, about 1 in 1000 people develop a first episode of venous thromboembolism (VTE), which approximates to about 20,000 cases. More than half of these episodes occur during or soon after a hospital admission, which makes them potentially preventable. This paper summarises recommendations from the National Health and Medical Research Council's 'Clinical Practice Guideline for the Prevention of Venous Thromboembolism in Patients Admitted to Australian Hospitals' and describes the way these recommendations were developed. The guideline has two aims: to provide advice on VTE prevention to Australian clinicians and to support implementation of effective programmes for VTE prevention in Australian hospitals by offering evidence-based recommendations which local hospital guidelines can be based on. Methods for preventing VTE are pharmacological and/or mechanical, and they require appropriate timing, dosing and duration and also need to be accompanied by good clinical care, such as promoting mobility and hydration whilst in hospital. With some procedures or injuries, the risk of VTE is sufficiently high to require that all patients receive an effective form of prophylaxis unless this is contraindicated; in other clinical settings, the need for prophylaxis requires individual assessment. For optimal VTE prevention, all patients admitted to hospital should have early and formal assessments of: (i) their intrinsic VTE risk and the risks related to their medical conditions; (ii) the added VTE risks resulting from surgery or trauma; (iii) bleeding risks that would contraindicate pharmacological prophylaxis; (iv) any contraindications to mechanical prophylaxis, culminating in (v) a decision about prophylaxis (pharmacological and/or mechanical, or none). The most appropriate form of prophylaxis will depend on the type of surgery, medical condition and patient characteristics. Recommendations for various clinical circumstances are provided as summary tables with relevance to orthopaedic surgical procedures, other types of surgery and medical inpatients. In addition, the tables indicate the grades of supporting evidence for the recommendations (these range from Grade A which can be trusted to guide practice, to Grade D where there is more uncertainty; Good Practice Points are consensus-based expert opinions).

HA14-1 selectively induces apoptosis in Bcl-2-overexpressing leukemia/lymphoma cells, and enhances cytarabine-induced cell death.

The Bcl-2 oncoprotein is commonly overexpressed in hematological malignancy, where it promotes the survival of neoplastic cells. Recently, a small molecule (HA14-1) was reported to bind the surface pocket of Bcl-2 that mediates antiapoptotic interactions, triggering apoptosis in a Bcl-2-transfected cell line. We investigated the activity of this compound in a panel of malignant hematopoietic cell lines. Consistent with its proposed role as a Bcl-2 inhibitor, HA14-1 was most cytotoxic in lines expressing high levels of Bcl-2. In addition, at lower concentrations (5-12.5 muM), the compound predominantly triggered apoptosis. However, at concentrations two-fold higher than this and above, increasing primary necrosis was observed, suggesting the onset of interactions supplementary to Bcl-2 inhibition. In experiments on primary cells, 25 muM HA14-1 induced extensive apoptosis in acute leukemic blasts, but also suppressed normal hematopoietic colony formation to <50% of baseline. Importantly, low-concentration HA14-1 (5 muM) was nontoxic to normal colony-forming cells, whereas it enhanced the cytotoxicity of the antileukemia drug cytarabine in Bcl-2-positive lymphoblastic leukemia cells. In conclusion, our results indicate that HA14-1 at low concentration selectively triggers apoptosis in malignant hematopoietic cells that overexpress Bcl-2. Agents of this class may have particular utility in combination with cytotoxic chemotherapy drugs.

Cyclophosphamide, etoposide, vincristine, adriamycin, and dexamethasone (CEVAD) regimen in refractory multiple myeloma: an International Oncology Study Group (IOSG) phase II protocol.

A 4- day continuous intravenous (CIV) infusion of vincristine and doxorubicin with high-dose dexamethasone (VAD) regimen is a standard refractory multiple myeloma (MM) regimen. A Phase II study of a CEVAD regimen, i.e., VAD plus etoposide administered as a 96-hr continuous infusion, was carried out with IV bolus cyclophosphamide. Thirty-six patients were treated on study and received a total of 114 cycles of CEVAD: median 2 cycles (range 1-8). No patient achieved a CR. The overall rate of PR was 15/36 (42%). Patients achieved maximal response after a median of 4 (range 3-6) courses. PR rates were 40% (4/10) in patients with primary refractory disease, 48% (11/23) in patients with secondary refractory disease, 31% (6/19) in patients who had failed previous VAD therapy, and 50% (7/14) in patients receiving 2nd or subsequent relapse therapy. Three patients died during their initial cycle of therapy from rapidly progressive disease and sepsis. Overall median survival was 24 weeks with a 1-year survival of 33.3% ¿95% confidence interval of 20-46%¿. Myelosuppression was the most frequent adverse event with NCI grade 2 neutropenia and/or thrombocytopenia in 15% of first cycles, grade 3 in 20%, and grade 4 in 65%. Two-thirds of patients had at least one episode of grade 3 or 4 sepsis. In 15% of septic episodes positive blood cultures were obtained. Overt cardiotoxicity was seen in two patients. CEVAD as used in this study was not more effective than VAD in terms of overall response rate or survival.

A prospective randomized study of Chop versus Chop plus alpha-2B interferon in patients with intermediate and high grade non-Hodgkin's lymphoma: the International Oncology Study Group NHL1 Study .

UNLABELLED: The addition of a brief alpha interferon regimen to each CHOP induction cycle, plus one year of alpha interferon thrice weekly maintenance therapy, has no early effect on response rates or survival in patients with Intermediate or High grade cell NHL. BACKGROUND: The CHOP (Cyclophosphamide, Adriamycin. Vincristine, Prednisone) regimen is the most widely used first-line therapy for patients with Intermediate or High Grade (IG/HG) non-Hodgkin's lymphoma (NHL). Alpha 2b interferon (INF) enhances response rates and improves survival in low-grade NHL. The International Oncology Study Group (IOSG) conducted a prospective randomized study comparing CHOP alone or combined with INF in patients with IG/HG-NHL. The primary study aim was to compare the objective response rates in these patient cohorts. PATIENTS AND METHODS: Patients with a confirmed diagnosis of measurable NHL of International Working Formulation (IWF) groups D to H histology were randomized to receive CHOP alone or CHOP with 5Mu INF s.c. for 5 days on days 22 to 26 of each 28 day cycle with INF 5 million units (Mu) given three times per week subcutaneously for 52 weeks in those patients who responded to CHOP plus INF. RESULTS: The overall response rates were equivalent in both groups: CHOP alone (214 patients) 81% (complete 55%, partial 26%); CHOP plus INF (221 patients) 80% (complete 54%, partial 26%). At 36 months, the actuarial survival rate was equivalent in both groups. CONCLUSIONS: There is no apparent early advantage in terms of response or survival conferred by adding the study INF regimen to CHOP therapy for patients with IG/HG-NHL.

Chromosomal aberrations during progression of chronic myeloid leukemia identified by cytogenetic and molecular cytogenetic tools: implication of 1q12-21.

To study the genomic abnormality underlying the acute transformation of chronic myeloid leukemia (CML), 15 CML patients in blast crisis (BC), 3 in accelerated phase (AP), and 20 in chronic phase (CP) were analyzed by conventional cytogenetics, comparative genomic hybridization (CGH), and dual-color chromosomal painting. Philadelphia (Ph) chromosome was identified in every case studied. Only 5 among 20 CP patients had additional abnormalities while 13 of 18 patients with disease progression (BC + AP) showed extra numerical and/or structural chromosomal aberrations. Cytogenetically, the most common chromosome gains during BC and AP were double or triple Ph chromosomes (5 of 14 cases) and trisomy 8 (5 of 14 cases). Trisomies 7 and 17 (1 of 14 cases each) were also observed. CGH analysis detected genetic imbalances in eight cases. Gains of chromosome 20 (3 cases) and 17q (2 cases) were observed, respectively. The recurrent chromosome loss was the deletion of the short arm of chromosome 17, seen in one case with i(17)(q10) and one case with an unbalanced translocation (1;17). In one case, a very complex chromosomal rearrangement, del(3),del(6),der(6)t(17;3;6),der(17)t(6;17), was seen. A novel finding of this work is the involvement of chromosome 1(q12-21qter) in CML disease progression. Overrepresentation of 1(q12-21qter) region was detected by CGH in one case which had a derivative chromosome 17. This abnormal chromosome was later confirmed by fluorescence in situ hybridization (FISH) painting to be a fusion between chromosome 1 and 17 to form the der(17)t(1;17) (q12-21;p11). Two other cases showed the same region being involved in translocations, t(1;10)(q12-21;q26) and t(1;11)(q12-21;p15). It is possible that one or more genes residing on chromosome 1q12-21 may be important in the acute transformation of CML. In conclusion, we find that the combined use of CGH, chromosome painting, and classic cytogenetic analysis allows a better evaluation of the genomic aberration involved in CML blastic transformation, and offers new directions for its further molecular investigations.

Combined morphological and interphase fluorescence in situ hybridization study in multiple myeloma of Chinese patients.

To gain insight into the real incidence of the numeric chromosomal aberrations and the cell lineage involvement of the neoplastic process in multiple myeloma (MM), we examined 18 Chinese MM patients by May-Grunwald-Giemsa (MGG) staining and fluorescence in situ hybridization using three DNA centromeric probes specific for chromosomes 3, 7, and 9. In this investigation, cytogenetic abnormalities were detected in plasma cells (PCs), myeloid cells (MCs), and lymphoid cells (LCs) in all of the MM patients studied. This is the first demonstration of the cytogenetic aberration involved in the myeloid series. Furthermore, the MCs and PCs of 16 MM patients had the same aneuploidies in one or more of the chromosomes analyzed. These data suggest that the neoplastic transformation of MM may occur early in the hematopoietic development. Chromosomal aberrations involving mainly subclones and considerable cellular heterogeneity with gain of a variety of copy numbers of the same chromosome were demonstrated within PCs, which may possibly be the result of an underlying defect of PCs in the control of their number of chromosomes. Whereas PCs showed evidence suggestive of increased polyploidization, MCs and LCs, which exhibited similar chromosomal patterns as the former, rarely did. Thus, the clonal evolution from LC to PC, if that happens in MM, is characterized by chromosomal instability favoring growth of tumor cells with polysomies and polyploidies.

Detection of chromosome over- and underrepresentations in hyperdiploid acute lymphoblastic leukemia by comparative genomic hybridization.

Chromosomal analysis of acute lymphoblastic leukemia (ALL) is often difficult because of the suboptimal in vitro growth of the immature lymphoid cell and the poor morphology obtained. In this study, we describe the application of comparative genomic hybridization (CGH) to investigate the genomic abnormalities in 14 patients with ALL, all of whom had cytogenetically identified numerical aberrations or gross chromosomal structural alteration. With the use of CGH, regional or whole chromosome overrepresentation or both were found to be more frequent than underrepresentation (52 gains vs. 6 losses), the most common gains being chromosomes 21 and X. The results of the comparison between CGH and conventional R-banding analysis could be classified into three categories: (1) in three cases, including two with trisomy, CGH and banding analysis gave identical results; (2) in six cases with hyperdiploidy and two cases presenting chromosome structural abnormalities, the results were consistent but with minor discrepancies; (3) in three cases, including two with triploidy and tetraploidy and one with chimeric karyotype together with +22, the data from CGH and cytogenetical analysis were discrepant. CGH could not find the triploidy and tetraploidy. Our results suggest that CGH has certain value in the detection of gains or losses of chromosome materials in hyperdiploid ALL. Nevertheless, the combination of CGH and conventional karyotyping provides more precise information on the genomic imbalance in ALL.

Haemostatic changes during surgery for primary brain tumours.

OBJECTIVE: Primary brain tumours may be associated with coagulation disorders which can pose intraoperative and postoperative management difficulties. The aim was to evaluate the coagulation profile of patients with brain tumours undergoing surgery using thromboelastography (TEG) in combination with simple laboratory tests. METHODS: Fifty adult patients with primary brain tumours larger than 4 cm in maximum diameter and no history of coagulation disorders were studied in a prospective, observational manner over a one year period. Preoperative, intraoperative, and postoperative measurements included haemoglobin concentration, platelet count, prothrombin and partial thromboplastin times, fibrin(ogen) degradation product concentration, D-dimer concentration, and TEG. RESULTS: Eleven patients (22%) had abnormal intraoperative TEGs, of whom six (12%) subsequently developed haematomas requiring surgical evacuation. The coagulopathy seemed to be hyperfibrinolysis in two cases (4%) and disseminated intravascular coagulation in four (8%). There was no preoperative difference in reaction time (R time) for clot formation between the non-haematoma and haematoma groups(mean 11.44 (SD 3.42) v 12.33 (2.50) min, P=0.46). However, when other preoperative indices were compared, in the non-haematoma group, K time (time to reach a clot amplitude of 20 mm) was shorter (6.72 (2.15) v 10.56 (3.50) min, P=0.001), rate of clot growth (å) was faster (43.67 degrees (7.53) v 27.11 degrees (5.42), P<0.0001) and maximum amplitude of clot strength (MA) was greater (52.64 (7.85) v 40.33 (6.59) mm, P<0.001). Intraoperatively, R time was significantly shortened in the non-haematoma group, (7.67 (1.78) min, P<0.0001) unlike the haematoma group (10.67 (1.58) minutes, P=0.11). CONCLUSIONS: Although these results indicate a general hypercoagulability during brain tumour surgery, in certain cases, a predisposition towards hypocoagulability may exist even before surgery, detectable only when the physical characteristics of clot formation are studied by TEG. Judicious replacement of clotting factors, platelets, and antifibrinolytic agents should be considered intraoperatively if the TEG is abnormal, without waiting for laboratory test results.

The spectrum of chronic lymphoproliferative disorders in Hong Kong. A prospective study.

We report the incidence of the chronic lymphoproliferative disorders evolving with leukaemia in Hong Kong. Our findings demonstrate that B cell malignancies are significantly more frequent than mature T cell neoplasms, a picture similar to that seen in Western countries but different from other Eastern countries, eg Japan, where T cell malignancies are more frequent. In contrast to the West, where chronic lymphocytic leukaemia (CLL) is the most common disorder, in Hong Kong there is a clear predominance of B cell lymphomas in leukaemic phase accounting for two-thirds of the cases and particularly those displaying lymphoplasmacytic features or with villous lymphocytes. CLL in Hong Kong has similar clinical and laboratory features to the disease in patients from the West. Distinct disease categories, rare in the West such as the variant form of hairy cell leukaemia and T cell prolymphocytic leukaemia, are also documented. It is unclear whether the differences in prevalence of disease subtypes between Hong Kong and the West relate to different genetic background or environmental factors determinant of the development or progression of the leukaemia. Further studies investigating the genetic/molecular lesions may help to clarify whether the aetiopathogenesis of the lymphoid disorders in Hong Kong is similar to that of Western countries.

Fatal Penicillium citrinum pneumonia with pericarditis in a patient with acute leukemia.

We report here a case of fatal Penicillium citrinum infection. The patient, who suffered from acute myeloid leukemia, developed signs and symptoms typical of fungal pneumonia and pericardial tamponade after undergoing standard induction chemotherapy. Despite attaining complete remission of her leukemia, the patient succumbed 8 weeks after presentation. At autopsy, multiple nodular cavitary pulmonary lesions with invasion by fungal hyphae were found. Pericardial and lung tissue obtained at autopsy grew P. citrinum, a fungus ubiquitous in the environment but seldom reported as a pathogen. The microbiological findings were consistent with the histopathological features and confirmed this as a case of true P. citrinum infection causing fatal pulmonary and pericardial complications in an immunocompromised host.

Frequent hypermethylation of p16 and p15 genes in multiple myeloma.

Both p16 and p15, encoded by the genes located on chromosome 9p21, are inhibitors of cyclin-dependent kinases (CDK4/6) and the upstream regulators of Rb function. In hematopoietic malignancies, deletion of p16/p15 locus has been shown to be highly specific to lymphoid, and more particularly from B-lineage malignancies except multiple myeloma (MM). To investigate whether these genes are inactivated by deletions, mutations, and hypermethylation of the 5' CpG islands, we examined 12 MM patients by Southern hybridization and polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis. No deletions nor mutations of the p16 and p15 genes were found. However, hypermethylation was observed in 75% for p16 and 67% for p15 in our group of MM patients. Such high frequencies of involvement of these genes in MM make them hitherto the most common genetic abnormalities in this disease. Concomitant hypermethylation, uncommon thus far in the literature of the study of these genes, is a rather common phenomenon, occurring in 67% of our patient group. Moreover, hypermethylation of p16/p15 was associated with blastic disease and concomitant hypermethylation of both genes may be pathogenetically related to plasmacytoma development. These results indicate that these genes are important in MM pathogenesis. Here we report, for the first time in the literature, the high incidences of p16 and p15 alterations in MM, not by homozygous deletions or mutations, but solely by hypermethylation of the 5' CpG islands, which may be a specific mechanism in this disease.

Pressure area care in A&E.

Although the literature specific to A&E and pressure sores is scant, Nicola Wickham argues that the treatment of pressure sores is fundamental to nursing care in any work area. In this first of a two part series she reviews the literature available in pressure area care, and discusses the importance of early intervention in treating this highly preventable condition.

Monoclonal gammopathy of unknown significance and malignant paraproteinemia in Hong Kong.

The incidence of multiple myeloma is lower in Southeast Asia than in the West. However, there are few reports on the overall incidence of paraproteinemia and its disease-associations in the Chinese. Therefore, the authors have correlated the laboratory features with the eventual clinical diagnosis in patients with paraproteinemia in a Hong Kong general/teaching hospital. Over 18 months, 1,600 patients were investigated for the presence of paraproteinemia. Paraproteinemia was detected in 157 (10%) patients. In 11 patients, investigations could not be completed. The remaining 146 patients were subjected to detailed clinical, radiologic, and laboratory investigations. Eighty-seven (59.6%) had monoclonal gammopathy of unknown significance (MGUS), 44 (30.1%) myeloma and 15 (10.3%) other lymphoproliferative disorder (LPD). There was no significant difference in the paraprotein concentration, frequency of hypogammaglobulinemia of Bence Jones proteinuria (BJP) or concentration of nonparaprotein immunoglobulin (Ig) between the myeloma and LPD groups. The overall kappa:lambda light chains ratios were 2.9, 1.6 and 3.3 in the MGUS, MM and LPD groups, respectively. Polyclonal Ig elevation was rare with myeloma (4.5%) but was detected in 33% of patients with LPD (P < .02) and 40% of those with MGUS (P < .0001). Biclonal (and one triclonal) gammopathy was detected in 11.5% of patients with MGUS, 11% with LPD and 4.5% with myeloma. In the MGUS group, infection was the commonest associated clinical disorder (29.3%). Moreover, 70% of patients with biclonal gammopathy and MGUS had an infection. Five of 15 patients with LPD had a T-cell malignancy, including 3 lymphomas and 2 large granular cell leukemias. Only one patient had primary systemic amyloidosis. It is concluded that the high frequency of biclonality and its association with infection, of paraproteinemia in association with T-cell malignancy and of kappa light chains in the MGUS and LPD groups are at variance with reports from the West and probably reflect local differences.

Upper airway obstruction caused by acquired inhibitor to factor VIII.

Bleeding caused by inhibitors to factor VIII is a rare medical emergency requiring immediate specialist investigation and management. Urgent initiation of therapy with high dose factor VIII concentrates may be life saving. Successful management of acute upper airway obstruction from uncontrolled haemorrhage into the oropharyngeal tissues should be achieved with fibreoptic guided nasotracheal intubation.

Campath-1G in vivo confers a low incidence of graft-versus-host disease associated with a high incidence of mixed chimaerism after bone marrow transplantation for severe aplastic anaemia using HLA-identical sibling donors.

We have evaluated the effect of in vivo Campath-1G on engraftment and GVHD in 23 patients with severe aplastic anaemia transplanted from HLA-identical sibling donors. In 14 patients Campath 1g was given pre-transplant for up to 9 days in an attempt to overcome graft rejection (group 1). In nine patients Campath-1G was given pre-transplant, but also continued post-transplant until day +5 to reduce GVHD (group 2). There were three patients with late graft failure in group I following initial neutrophil engraftment, and four cases of grade II+ GVHD. In group II, two patients had early graft failure (no take), and there were no cases of acute GVHD out of seven evaluable patients. One patient in group I developed chronic GVHD of the liver, and two patients (one in each group) had transient localised chronic GVHD. PCR of short tandem repeats was used to evaluate chimaeric status in 13 patients. Of 11 patients with initial neutrophil engraftment, only one had 100% donor haemopoiesis at all times. The remaining patients had either transient mixed chimaerism or persistence of recipient (< 20%) cells. We conclude that in vivo Campath-1G is associated with a high incidence of mixed chimaerism which tips the balance away from GVHD but towards graft rejection.

Small cell variant of Ki-1 lymphoma associated with myelofibrosis and a novel constitutional chromosomal translocation t(3;4) (q13;q12).

An unusual case of small cell variant of Ki-1 non-Hodgkin's lymphoma diagnosed one year after an original diagnosis of idiopathic myelofibrosis is reported. On the second occasion, the patient presented with fever, lymphadenopathy and hepatosplenomegaly. A lymph node biopsy specimen confirmed a diagnosis of small cell variant of Ki-1 lymphoma. A repeat bone marrow biopsy specimen showed myelofibrosis with no evidence of lymphomatous infiltration, but cytogenetic studies on blood, bone marrow and skin fibroblasts revealed a novel chromosomal translocation t(3,4)(q13;q12).