Short intensive sequential therapy followed by autologous stem cell transplantation in adult Burkitt, Burkitt-like and lymphoblastic lymphoma.

The feasibility and efficacy of up-front high-dose sequential chemotherapy followed by autologous stem cell transplantation (ASCT) in previously untreated adults (median age 33 years; range 15-64) with Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or lymphoblastic lymphoma (LyLy), both without central nervous system or extensive bone marrow involvement was investigated in a multicenter phase II study. Treatment consisted of two sequential high-dose chemotherapy induction courses incorporating prednisone, cyclophosphamide, doxorubicin, etoposide and mitoxantrone, without high-dose methotrexate or high-dose cytarabine. Patients with at least PR went on with BEAM and ASCT. Protocol treatment was completed by 23/27 (85%) BL/BLL and 13/15 (87%) LyLy patients. Median treatment duration until BEAM was 70 (range: 50-116) days. No toxic deaths occurred. Response to treatment was complete response (CR) 81% and partial response (PR) 11% for BL/BLL, CR 73% and PR 20% for LyLy. At a median follow-up of 61 months of patients still alive, six BL/BLL and eight LyLy patients have died. The actuarial 5-year overall and event-free survival estimates are 81 and 73% for BL/BLL vs 46 and 40% for LyLy patients. In conclusion, this short up-front high-dose sequential chemotherapy regimen, followed by ASCT is highly effective in adults with BL/BLL with limited bone marrow involvement, but less so in patients with LyLy.

Prognostic significance of activated cytotoxic T-lymphocytes in primary nodal diffuse large B-cell lymphomas.

Clinical outcome in diffuse large B-cell lymphoma (DLBCL) remains unpredictable, despite the identification of clinical prognostic parameters. Here, we investigated in pretreatment biopsies of 70 patients with DLBCL whether numbers of activated cytotoxic T-lymphocytes (CTLs), as determined by the percentage of CD3-positive lymphocytes with granzyme B (GrB) expression, have similar prognostic value as found earlier in Hodgkin's lymphoma and anaplastic large-cell lymphoma and whether loss of major histocompatibility complex (MHC)-I molecules or expression of the GrB antagonist protease inhibitor 9 (PI9) may explain immune escape from CTL-mediated cell death. Independent of the International Prognostic Index (IPI), the presence of >/=15% activated CTLs was strongly associated with failure to reach complete remission, with a poor progression-free and overall survival time. Downregulation of MHC-I light- and/or heavy-chain expression was found in 41% of interpretable cases and in 19 of 56 interpretable cases PI9 expression was detected. We conclude that a high percentage of activated CTLs is a strong, IPI independent, indicator for an unfavorable clinical outcome in patients with primary nodal DLBCL. Although in part of DLBCL expression of PI9 and loss of MHC-I expression was found, providing a possible immune-escape mechanism in these cases, no correlation with clinical outcome was found.

The influence of glycyrrhetinic acid on plasma cortisol and cortisone in healthy young volunteers.

Based on studies in laboratory animals and on measurements of the urinary metabolites (allo)tetrahydrocortisol and tetrahydrocortisone in human volunteers it has been claimed that liquorice-induced mineralocorticoid excess is caused by a unique defect in the conversion of cortisol to cortisone. To further evaluate this hypothesis we have investigated the influence of glycyrrhetinic acid (GA), the mineralocorticoid-active constituent of liquorice, on plasma cortisol and cortisone in 10 healthy young normotensive volunteers. Pure GA (500 mg/day), administered orally from days 3-10 of the study, exerted pronounced mineralocorticoid activity. Ingestion of GA resulted in an elevated urinary excretion of free cortisol and virtually unchanged plasma cortisol levels in the presence of markedly decreased levels of both plasma cortisone and urinary free cortisone. These results provide direct clinical support for the hypothesis that GA induces an inhibition of the activity of 11 beta-dehydrogenase, resulting in a blockade in the conversion of cortisol to cortisone.

Poikilothermia in man: pathophysiology and clinical implications.

Poikilothermia, the inability to maintain a constant core temperature independent of ambient temperature, markedly influences both the mental and physical function of affected patients; furthermore, prolonged hypothermia can induce numerous complications. To establish the pathophysiology of thermoregulation underlying poikilothermia in man, we compared 4 women with acquired poikilothermia, with 9 female control subjects. The activity of the main thermoregulatory effector mechanisms was assessed in a thermoneutral environment, and during subsequent cold stress and heat exposure. At thermoneutrality the patients had a significantly lower rectal temperature and resting metabolic rate compared with the controls; no patient showed peripheral vasoconstriction or shivering. Cooling revealed markedly reduced peripheral vasoconstriction in 3 patients and failure of the metabolic response in 2 patients; unlike controls, no patient exhibited shivering. Heat challenge revealed severely reduced capacity for heat dissipation in all patients. We conclude that in patients with poikilothermia, the mechanisms for both heat conservation and heat dissipation are seriously attenuated. Careful monitoring of the core temperature and adequate measures to maintain normothermia are of great importance in patients with poikilothermia in order to provide adequate treatment, improve the quality of life, and prevent serious complications.

Effect of steady hypothermia and normothermia on multimodality evoked potentials in human poikilothermia.

OBJECTIVE: To assess the effects of steady-state spontaneous hypothermia on multimodality evoked potentials and on peripheral nerve conduction in human poikilothermia. DESIGN AND SETTING: Case series at a university hospital. PATIENTS: Four patients (four women, aged 28 to 37 years) with acquired poikilothermia. MAIN OUTCOME MEASURES: Short-latency somatosensory, brain-stem auditory, and visual evoked potentials as well as motor and sensory peripheral nerve conduction velocity during steady-state spontaneous hypothermia and normothermia. RESULTS: The marked latency prolongation of all evoked potentials and decreased peripheral nerve conduction velocity observed during steady-state spontaneous hypothermia (mean +/- SD core temperature, 33.5 +/- 0.3 degrees C) compared with normothermia (36.9 +/- 0.4 degrees C) agrees with previous findings during short-term induced hypothermia. CONCLUSIONS: The unequivocal effect of sustained mild spontaneous hypothermia on evoked potentials and peripheral nerve conduction velocity underlines the importance of meticulous attention to even small alterations in core temperature in interpreting neurophysiological investigations.

Sudomotor function in human poikilothermia.

Hypohidrosis predisposes to hyperthermia and may indicate generalized thermoregulatory failure. To assess the sweating capacity in human poikilothermia, we performed a quantitative analysis of the central and peripheral sudomotor pathways in four women with acquired poikilothermia (aged 29 to 38 years) and nine controls. Heat challenge in a climatic chamber (ambient temperature 40 degrees C, 50% relative humidity) for 180 minutes revealed that both sweat secretion and evaporative weight loss were significantly lower in the patients than in the controls (p < 0.01). Temperature thresholds for thermal sweating were markedly elevated in at least two patients, whereas a third patient showed no sweating response. Stimulation of the eccrine sweat glands by intradermally injected acetylcholine during reduced core temperature (34.9 +/- 0.7 degrees C) revealed a significantly reduced sweating response in all patients (p < 0.01); the sudomotor response to pilocarpine iontophoresis was reduced or absent in three patients. We conclude that the generalized thermoregulatory sudomotor failure in these patients was attributable primarily to disorders of the central sudomotor drive; the impaired postganglionic sudomotor response is temperature related and possibly secondary to (long-standing) poikilothermia. Quantification of heat-dissipating capacity is pivotal for diagnosing severe thermolability and may help to prevent serious heat illness.

An X;9 translocation, primary amenorrhea, and hypothalamic dysfunction.

A white girl presented at age 16 yr with delayed puberty and primary amenorrhea. She had 46 chromosomes with a de novo reciprocal X;9 translocation. The normal X chromosome was found to be heterochromatic, thus preserving the function of the translocation portion of the 9. Her total estrogen and serum estradiol levels were low and her serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were at the lower end of the normal adult range. She had a reasonably good FSH and LH response to GnRH, but an inadequate response to 100 mg of clomiphene daily for 1 wk. This would suggest that the abnormality of function is probably hypothalamic, a hitherto unreported association. De novo translocations between X chromosomes and autosomes are rare and none identical to this case has been described. The breakpoint of the X chromosome was at p22, well outside the "critical region" for female reproductive function. It seems probable that her chromosome abnormality is responsible for her clinical state.

A case of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting with spontaneous splenic rupture: an extremely unusual presentation.

In a 22-year-old male with a 10-day history of fever, painful swelling in the left groin, and abdominal complaints, emergency surgery was performed because of spontaneous splenic rupture. At histology, a cellular infiltrate of intermediate-sized atypical lymphocytes was seen in the splenic white pulp, staining for T-cell markers. In addition, CD30 and anaplastic lymphoma kinase 1 (ALK) were diffusely positive, thus, representing a case of anaplastic large cell lymphoma (ALCL), T-cell, ALK-positive, small cell monomorphic variant. ALK-positive ALCL patients generally bear a much better prognosis than patients with T-cell lymphomas, unspecified, or ALK-negative ALCL. Therefore, besides the very unusual clinical presentation, this case highlights the importance of immunostaining for CD30 and ALK in all T-cell lymphomas. This report is the first extensive description of ALK-positive ALCL involvement of the spleen.

Pseudoplatelets: a retrospective study of their incidence and interference with platelet counting.

AIMS: Spurious platelet counts can be found in acute leukaemias, as a result of the fragmentation of blood cells. Microscopic examination of a blood smear should be performed to detect the presence of these so called pseudoplatelets. When present, the platelet count should be corrected because of the important clinical consequences that a lower platelet count may have in these patients. METHODS: K(3)EDTA anticoagulated blood was measured on an automated blood cell counter, and a blood smear was made and stained according the May Grünwald-Giemsa method for microscopic observation. A 500 cell/particle differentiation was performed and the automated platelet count was corrected. RESULTS: The incidence of pseudoplatelets in 169 patients with acute leukaemia was studied. Pseudoplatelets were detected in 43 patients (25.4%), and seven patients (4.1%) were re-classified as having a major bleeding risk (platelet count, < 15 x 10(9)/litre). CONCLUSIONS: Platelets should be determined morphologically in patients with acute leukaemia and a routine screening method for the detection of pseudoplatelets should be developed.

Follicular non-Hodgkin's lymphoma with refractory paraneoplastic pemphigus: case report with review of novel treatment modalities.

In this paper a patient with a non-Hodgkin's lymphoma (NHL) and paraneoplastic pemphigus (PNP) is described. PNP is a very rare, painful mucocutaneous intraepithelial blistering disease associated with occult or confirmed malignancy. Patients with PNP show severe, progressive mucocutaneous disease with a high mortality rate, because of drug-induced infectious complications. The patients sometimes benefit from high doses of oral corticosteroids. However, pulse therapy with high doses of prednisolone (or dexamethasone) in combination with other immunosuppressants induces variable and inconstant results. Intravenous immunoglobulin (IVIg) has been applied in different cases of PNP with encouraging results. Plasmapheresis or plasma exchange (PE) in combination with corticosteroids and/or cyclophosphamide or azathioprine showed similar rapid and beneficial results in association with decreasing auto-antibody levels in this group of refractory pemphigus. Another interesting therapeutic option is rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, which is found on the surface of normal and malignant B-lymphocytes. Administration of rituximab for patients with PNP in combination with follicular NHL is not always successful regarding oral lesions as we report in this case. PE leading to prompt depletion of autoreactive antibodies combined with immunosuppressants or synchronisation of PE with IVIg seems the best treatment modality for this refractory group, but the therapeutic value and appropriate timing of rituximab obviously deserve further evaluation in patients with low grade NHL and PNP.

Dosimetric verification of inverse planned step and shoot multileaf collimator fields from a commercial treatment planning system.

An inverse treatment planning (ITP) module on a commercial treatment planning system (TPS) (Helax AB, Uppsala, Sweden) is being used for an in-house clinical trial for treatment of nasopharyngeal cancer with contralateral parotid sparing. Intensity modulated radiation therapy (IMRT) fields are delivered by step and shoot multileaf collimator (MLC) with a DMLC enabled Varian 2300 CD (Varian Associates, Palo Alto, CA). A series of testing procedures have been devised to quantify the modeling and delivery accuracy of routine clinical inverse planned IMRT using Helax TMS and the Varian step and shoot MLC delivery option. Testing was done on specific aspects of the TPS modeling germane to DMLC. Measured relative dose factors (head scatter plus phantom scatter) for small MLC fields, normalized to a 10x10 cm2 non-MLC field, were found to differ by 2-3% from the TPS values for the smallest of the fields tested. Relative distributions for small off axis fields were found to be in good agreement. A process for the routine clinical verification of IMRT fields has been implemented. Each IMRT field in an inverse plan is imported into a flat water tank plan and a "beam's eye view" (BEV) dose distribution is generated. This is compared to the corresponding measured BEV dose distribution. The IMRT verification process has also been performed using an anthropomorphic phantom. Large clinical fields (i.e., greater than 14.5 cm in the leaf direction) caused difficulties due to a vendor specific machine restriction, and several techniques for dealing with these were examined. These techniques were (i) the use of static stepping of closed junctions, (ii) the use of two separate IMRT fields for a given gantry angle, and (iii) restricting the overall maximum field size used. The overall process has allowed implementation of an in-house protocol for IMRT use on an initial clinical site. Results of the verification measurements for the first ten patients treated at this center reveal an average maximum dose per IMRT field delivered of 71.0 cGy, with a mean local deviation from the planned dose of -1.2 cGy, and a standard deviation of 2.4 cGy.

Dissemination of Salmonella serotypes from raw feed ingredients to chicken carcases.

During a Salmonella survey in a large integrated poultry organization it was observed that a significant correlation existed between Salmonella serotypes isolated from the raw feed ingredients and those from finished carcases. A number of serotypes hitherto unrecognized in the organization were detected in the raw feed ingredients, and were later recognized in live birds and carcases from the processing plant. It appears that a significant reduction in carcase contamination rate could be achieved by minimizing Salmonella in the meal and grain constituents of poultry feed.

Tenosynovitis in chickens.

An adenovirus was isolated from the tendon fluid of broilers and meat breeders with clinical tenosynovitis. The viral infection was in many cases accompanied by a staphylococcal infection. The significance of the adenovirus is not yet known, although initial transmission studies indicate that it may play a role in the tendon thickening process.

Selenium-responsive myopathy in broiler breeder hens in Queensland.

A syndrome characterised by bilateral paralysis and associated with degenerative changes in skeletal musculature, has been noted in adult breeder hens, and their progeny broilers, in a commercial poultry organisation in Queensland. Paralysis occurred between the ages of 24 to 63 weeks in broiler breeder hens and at approximately 6 weeks in the broiler chickens. Onset is slow, taking up to 2-3 days from the time leg weakness if first noticed until paralysis was complete. Other than the paralysis the birds appeared normal. Histopathological and experimental observations indicate that the muscular dystrophy is caused by a selenium deficiency. Supplementation of the diet with selenium at a level of 0.1 ppm completely alleviated the symptoms such that the birds may be returned to the mating pens.

[Clinical thermometry. I. Historical developments]. / Klinische thermometrie. I. Historische ontwikkelingen.

Determination of human core temperature has a long history. Since Antiquity, the significance of normal and abnormal body temperatures has been the subject of various interpretations. In this respect, theories based on humoral pathology were replaced by more scientific concepts in the 19th and 20th centuries. Objective measurement and comparison could be performed only after the invention of the thermometer and the introduction of temperature scales. Sanctorius and subsequently Boerhaave and others emphasized the use of measurement of body temperature in the clinic, but its importance was not accepted generally until the late 19th century. Many physicians and scientists have contributed to the progress of thermometry; however, the creation of a firmer scientific basis for clinical thermometry is usually attributed to Wunderlich.

[Clinical thermometry. II. Current dilemmas]. / Klinische thermometrie. II. Huidige dilemma's.

The relevance of measuring core temperature for diagnosis and treatment of various diseases is generally acknowledged nowadays. Despite introduction of new techniques and markedly improved understanding of body temperature regulation and the pathophysiology of fever, several dilemmas remain to be elucidated in clinical thermometry. In the measurement and interpretation of body temperature, the many variables that influence core temperature, the site of temperature registration and the significance of an elevated or decreased core temperature should be taken into account. With every type of thermometer, good calibration and an adequate recording technique remain pivotal to obtain reliable and reproducible results.

[Patient with refractory celiac disease and secondary lymphoma]. / Een patiënt met refractaire coeliakie en een secundair lymfoom.

A 50-year-old woman who had suffered from well-regulated coeliac disease for 16 years, presented with weight loss, soft stools and abdominal cramps. She had ulcers in the oesophagus and stomach, and in biopsies localisations of so-called enteropathy-associated T-cell lymphoma (EATL) were detected. During a staging investigation she suffered an enteric perforation and later on repeated haemorrhages, from which she eventually died. Patients with coeliac disease who do not respond to a gluten free diet or who relapse after an initial response should be investigated for the presence of a gastrointestinal malignancy. Weight loss is an important symptom. The most frequently occurring malignant complication is an EATL. This is often difficult to diagnose and the prognosis is poor, with frequent complications such as haemorrhages and perforations.

X-linked sideroblastic anaemia due to ALAS2 mutations in the Netherlands: a disease in disguise.

BACKGROUND: X-linked sideroblastic anaemia (XLSA; OMIM#300751) is the most common inherited form of sideroblastic anaemia and is associated with several mutations in the erythroid specific 5-aminolevulinate synthase gene (ALAS2). This gene encodes for aminolevulinic acid synthase 2 (ALAS2), the catalytic enzyme involved in the first en rate-limiting step of haem biosynthesis.1-3 The disorder is characterised by mostly mild hypochromic microcytic anaemia with bone marrow ring sideroblasts. Even untransfused patients with mild or no anaemia are at risk for severe systemic iron overload due to ineffective erythropoiesis. To date, 61 different ALAS2 mutations have been reported in 120 families with XLSA. Descriptions of molecularly confirmed case series from the Netherlands, however, are lacking. METHODS: We reviewed age of presentation, clinical and biochemical features, ALAS₋2 defects and treatment characteristics of 15 Dutch patients from 11 unrelated families diagnosed with XLSA. RESULTS AND CONCLUSIONS: In one family a novel pathogenic c.1412G>A (p.Cys471Tyr) mutation was found. All other families shared the previously described c.1355G>A (p.Arg452His) mutation. Haplotype analysis in seven probands with the p.Arg452His mutation strongly suggests that six of them were ancestrally related. Nevertheless, their phenotype was very different. Our patients illustrate the phenotypical heterogeneity in the presentation of XLSA patients, the effectiveness of treatment regimens and the various pitfalls associated with the diagnosis, follow-up and treatment of the disease. A timely diagnosis avoids unnecessary investigations and allows adequate treatment that can prevent systemic iron load with subsequent severe life-threatening complications. Therefore, we suggest considering XLSA in both male and female patients with unexplained iron overload and÷or (mild) microcytic anaemia, also at older age.