Safety of apnea testing for the diagnosis of brain death: a comprehensive study on neuromonitoring data and blood gas analysis.

BACKGROUND AND PURPOSE: Here, we studied the safety of apnea testing (AT) for the determination of brain death with regard to intracranial pressure (ICP), cerebral perfusion and arterial blood gas parameters. We hypothesized that ICP only increases when cerebral perfusion pressure (CPP) remains positive during AT. METHODS: A total of 34 patients who fulfilled brain death criteria were identified by chart review (2009-2017). We analysed ICP, CPP and mean arterial pressure (MAP) prior to AT, during AT and after AT, as well as arterial pH, paCO2 , paO2 and arterial O2 saturation at the start and end of AT. RESULTS: Intracranial pressure was 87.9 ± 17.7 mmHg (mean ± SD) prior to AT, 89.9 ± 17.2 mmHg during AT and 86.4 ± 15.2 mmHg after AT (P = 0.9). CPP was -6.9 ± 12.8 mmHg prior to AT, -7.1 ± 13.7 mmHg during AT and -8.6 ± 13.0 mmHg after AT (P = 0.98), respectively. MAP was 82.9 ± 14.6 mmHg prior to AT, 84.7 ± 13.9 mmHg during AT and 79.7 ± 9.6 mmHg after AT (P = 0.57), respectively. A total of 10 patients had positive CPP (8.6 ± 4.3 mmHg), but ICP did not increase during AT. Arterial pH decreased from 7.43 ± 0.06 to 7.22 ± 0.06 (P < 0.05), paCO2 increased from 38.6 ± 4.2 to 69.6 ± 8.0 mmHg (P < 0.05), paO2 decreased from 416.3 ± 113.4 to 289.2 ± 146.5 mmHg (P < 0.05), and O2 saturation was stable at 99.8 ± 0.4% and 98.2 ± 3.2% (P = 0.39). CONCLUSIONS: Apnea testing had no detrimental effect on ICP, CPP, MAP or oxygenation, regardless of the presence of an initially positive CPP. The lack of further ICP elevations is presumably explained by critical closing pressures above individual CPP levels during AT.

Diagnosis and empirical treatment of fever of unknown origin (FUO) in adult neutropenic patients: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO).

Fever may be the only clinical symptom at the onset of infection in neutropenic cancer patients undergoing myelosuppressive chemotherapy. A prompt and evidence-based diagnostic and therapeutic approach is mandatory. A systematic search of current literature was conducted, including only full papers and excluding allogeneic hematopoietic stem cell transplant recipients. Recommendations for diagnosis and therapy were developed by an expert panel and approved after plenary discussion by the AGIHO. Randomized clinical trials were mainly available for therapeutic decisions, and new diagnostic procedures have been introduced into clinical practice in the past decade. Stratification into a high-risk versus low-risk patient population is recommended. In high-risk patients, initial empirical antimicrobial therapy should be active against pathogens most commonly involved in microbiologically documented and most threatening infections, including Pseudomonas aeruginosa, but excluding coagulase-negative staphylococci. In patients whose expected duration of neutropenia is more than 7 days and who do not respond to first-line antibacterial treatment, specifically in the absence of mold-active antifungal prophylaxis, further therapy should be directed also against fungi, in particular Aspergillus species. With regard to antimicrobial stewardship, treatment duration after defervescence in persistently neutropenic patients must be critically reconsidered and the choice of anti-infective agents adjusted to local epidemiology. This guideline updates recommendations for diagnosis and empirical therapy of fever of unknown origin in adult neutropenic cancer patients in light of the challenges of antimicrobial stewardship.

Cannabis and other illicit drug use in epilepsy patients.

BACKGROUND AND PURPOSE: This study aimed to assess the prevalence of illicit drug use among epilepsy patients and its effects on the disease. METHODS: We systematically interviewed epilepsy outpatients at a tertiary epilepsy clinic. Predictors for active cannabis use were analysed with a logistic regression model. RESULTS: Overall, 310 subjects were enrolled; 63 (20.3%) reported consuming cannabis after epilepsy was diagnosed, and 16 (5.2%) used other illicit drugs. Active cannabis use was predicted by sex (male) [odds ratio (OR) 5.342, 95% confidence interval (95% CI) 1.416-20.153] and age (OR 0.956, 95% CI 0.919-0.994). Cannabis consumption mostly did not affect epilepsy (84.1%). Seizure worsening was observed with frequent illicit (non-cannabis) drug use in 80% of cases. CONCLUSIONS: Cannabis use does not seem to affect epilepsy; however, frequent use of other drugs increases seizure risk.

Phase II study of cetuximab in combination with docetaxel in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck after platinum-containing therapy: a multicenter study of the Arbeitsgemeinschaft Internistische Onkologie.

BACKGROUND: Cetuximab and docetaxel have single-agent activity in squamous cell carcinoma of the head and neck (SCCHN). The efficacy of their combination was evaluated in platinum-pretreated patients with recurrent and/or metastatic SCCHN. PATIENTS AND METHODS: A total of 84 patients were treated with docetaxel 35 mg/m(2) weekly for a maximum of 6 cycles and concomitant cetuximab 250 mg/m(2) weekly until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate and secondary endpoints included the response rate in relation to platinum sensitivity, progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: Nine (11%) patients achieved a partial response and 34 (40%) stable disease, resulting in a disease control rate of 51%. Response to treatment was 49% in previously platinum-sensitive and 50% in previously platinum-resistant disease. The median PFS was 3.1 months and the median OS 6.7 months. The most common grade 3 or 4 adverse events were mucositis (8%), pneumonia (8%), fatigue (8%) and skin reactions (14%). Sepsis occurred in 3 patients. CONCLUSION: Cetuximab plus docetaxel is an active treatment regimen with moderate toxicity in SCCHN patients. However, no superiority in comparison with monotherapy could be shown. Responsiveness and survival were independent of previous platinum sensitivity.

Status epilepticus induces increasing neuronal excitability and hypersynchrony as revealed by optical imaging.

In the wake of acquired brain insults such as status epilepticus (SE), time-dependent neuronal network alterations may occur resulting in cortical hyperexcitability and enhanced synchrony merging into chronic epilepsy. To better understand the underlying processes, we performed electrophysiological and optical imaging studies on combined hippocampal-entorhinal cortex slices. These were prepared from rats 1, 4 and 8 weeks after electrically-induced SE. Non-invasive imaging using intrinsic optical signal changes allowed detailed analysis of onset and spread patterns of seizure-like events (SLE) since coverage of the entire preparation is possible. The latency to occurrence of first SLEs after omission of Mg(2+) from the artificial cerebrospinal fluid was significantly reduced at 4 and 8 weeks after SE compared with all other groups indicating increased brain excitability. Optical imaging displayed multiregional onset and discontiguous propagation of SLEs 8 weeks after SE. Such patterns indicate neuronal hypersynchrony and are not encountered in naïve rodents in which SLEs commonly begin in the entorhinal cortex and display contiguous spread to invade adjacent regions. The electrophysiological and optical findings of the current study indicate evolving fundamental brain plasticity changes after the detrimental event predisposing to chronic epilepsy. The current results should be incorporated in any strategies aiming at prevention of chronic epilepsy.

Reduced intensity conditioning allows for up-front allogeneic hematopoietic stem cell transplantation after cytoreductive induction therapy in newly-diagnosed high-risk acute myeloid leukemia.

There is substantial need to improve the outcome of patients with high-risk acute myeloid leukemia (AML). The clinical trial reported here investigated a new approach of up-front allogeneic hematopoietic stem cell transplantation (HSCT), provided a median of 40 days (range 22-74) after diagnosis, in twenty-six consecutive patients with newly-diagnosed high-risk AML characterized by poor-risk cytogenetics (n = 19) or inadequate blast clearance by induction chemotherapy (IC, n = 7). The median age was 49 years (range 17-68). During IC-induced aplasia after the 1st (n = 11) or 2nd (n = 15) cycle, patients received allogeneic peripheral blood stem cells (PBSC) from related (n = 11) or unrelated (n = 15) donors following a fludarabine-based reduced-intensity regimen. Seventeen patients were not in remission before HSCT with a median marrow blast count of 34% (range 6-70). All patients achieved rapid engraftment and went into remission with complete myeloid and lymphatic chimerism. Grades II to IV acute GvHD occurred in 14 (56%) and extensive chronic GvHD was documented in 8 (35%) patients. The probability of disease-free survival was 61% with only three patients relapsing 5, 6 and 7 months after transplantation, respectively. Up-front allogeneic HSCT as part of primary induction therapy seems to be an effective strategy in high-risk AML patients and warrants further investigation.

What is CD4+CD56+ malignancy and how should it be treated?

CD4+CD56+ malignancy is a rare neoplasm with a typical clinical pattern, an aggressive course and high early relapse rate despite good initial response to chemotherapy. In this review, the impact of different therapeutic approaches on clinical outcome has been studied. We evaluated 91 published cases and our own six patients in terms of clinical features, immunophenotype/cytogenetics and treatment outcome. Treatment was divided into four groups: (A) chemotherapy less intensive than CHOP; (B) CHOP and CHOP-like regimens; (C) therapy for acute leukemia; (D) allogeneic/autologous stem cell transplantation. The median overall survival was only 13 months for all patients. Patients with skin-restricted disease showed no difference in the overall survival from patients with advanced disease (17 and 12 months, respectively). Age >/=60 years was a negative prognostic factor. Age-adjusted analysis revealed improved survival after high-dose chemo/radiotherapy followed by allogeneic stem cell transplantation when performed in first complete remission. This therapeutic approach should be recommended for eligible patients with CD4+CD56+ malignancy. For older patients the best treatment option is still unknown.

Female patient with a history of Hashimoto's thyroiditis, diagnosed with MALT lymphoma of both breasts.

BACKGROUND: Mucosa-associated lymphoid tissue (MALT) lymphomas are a distinct subgroup of non-Hodgkin's lymphomas with preferable localization in the gastrointestinal tract. PATIENTS AND METHODS We describe the unusual case of a 48-year-old female patient, who was diagnosed with simultaneous MALT lymphoma of both breasts. Cervical, axillary and retroperitoneal lymph nodes were slightly enlarged, indicating an infiltration by the lymphoma. In her medical history the patient suffered from Hashimoto's thyroiditis. After 6 cycles of chemotherapy with CHOP regimen, the patient achieved complete remission. CONCLUSION: To our knowledge, this is the first case describing a patient with MALT lymphoma of the breast and a history of Hashimoto's thyroiditis. As patients suffering from autoimmune disorders, especially Sjögren's syndrome and Hashimoto's thyroiditis, are at a higher risk to develop B-cell lymphoma, we assume that Hashimoto's thyroiditis favored development of MALT lymphoma in our patient.

Cellular and humoral immune reconstitution after autologous peripheral blood stem cell transplantation (PBSCT).

Immune reconstitution after autologous peripheral blood stem cell transplantation (PBSCT) is of particular interest because of its importance for clinical outcome. Despite prolonged immunosuppression, especially of CD4(+) cells, few infections after neutrophil recovery occur. Only reactivation of varicella zoster virus (VZV) is more frequent in the first year after transplantation. From August 1997 to May 2001, we prospectively evaluated 38 patients prior to conditioning and during follow-up of 12 months post-transplant for virus antibodies [measles, mumps, rubella, polio, herpes simplex, varicella zoster, mononucleosis, cytomegalovirus (CMV)] and lymphocyte subpopulations by flow cytometry. CD3(+) T lymphocytes, CD8(+) T cells, and B-lymphocyte reconstitution in our study confirms previous reports. Complete CD4(+) lymphocyte reconstitution was not achieved in the 12 months post-transplant leading to a suppressed CD4/CD8 ratio. IgG antibody titers against measles, mumps, rubella, and polio were present in almost all patients pretransplant and during 12 months post-transplant, indicating persistent humoral immunity. CD3(+) and CD8(+) counts of patients with clinical VZV reactivation ( n=5) post-transplant were significantly higher (median: 1201/microl and 938/microl, respectively) than in patients without VZV reactivation (median: 594/microl and 482/microl, respectively) 6-12 months post-transplant. Positive CMV titers pretransplant ( n=19) were also correlated with higher CD3(+) and CD8(+) counts 3-6 months post-transplant (median: 1050/microl and 1056/microl, respectively) compared to CMV-negative patients (738/microl and 584/microl, respectively), although none of the patients suffered from CMV disease. Therefore, we conclude that persistent viral infections can contribute to the CD8(+) T-cell reconstitution after PBSCT by oligoclonal expansion of antigen-specific memory CD8(+) T cells.

Subcutaneous panniculitis-like T-cell lymphoma during pregnancy with successful autologous stem cell transplantation.

We report a 35-year-old pregnant woman with progressive subcutaneous panniculitis-like T-cell lymphoma (SPTCL). During pregnancy chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) stabilized the disease for 4 months before new manifestations appeared. After delivery of a healthy girl, myeloablative radiochemotherapy followed by autologous stem cell transplantation could be performed leading to complete remission.

Aseptic necrosis of both femoral heads as first symptom of chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is a disease of the elderly; in rare cases it occurs in childhood or adolescence. One complication at primary diagnosis is leukostasis, which usually causes respiratory, retinal, or central nervous symptoms. In this report we describe the case of a 24-year-old woman who developed aseptic necrosis of both femoral heads, which was successfully treated by bore holes in the femoral heads. This is a very rare complication of severe leukostasis, leading to the diagnosis of CML in this case. To our knowledge, this is the first case of an adult patient showing aseptic necrosis of femoral heads caused by leukostasis.

Decreased transfusion requirements for patients receiving nonmyeloablative compared with conventional peripheral blood stem cell transplants from HLA-identical siblings.

Red blood cell (RBC) and platelet transfusion requirements in patients given nonmyeloablative versus conventional peripheral blood stem cell (PBSC) transplants from HLA-matched siblings were compared. Between December 1997 and March 2000, 40 patients, aged 21 to 67 years (median 51), with hematologic malignancies underwent nonmyeloablative allografts after either 2 Gy total body irradiation alone (n = 30) or 2 Gy total body irradiation preceded by fludarabine 30 mg/m(2)/d on days -4, -3, and -2 (n = 10). All received postgrafting mycophenolate mofetil and cyclosporine. Controls included 67 concurrent patients, aged 23 to 66 years (median, 46 years), given conventional PBSC transplants following high-dose conditioning and postgrafting methotrexate and cyclosporine. Among patients given nonmyeloablative transplants, 23% required platelet transfusions compared with 100% among patients given conventional grafts (P <.0001). Further, the number of platelet units given to nonmyeloablative recipients was reduced, with a median of 0 (range, 0 to 214) compared with a median of 24 (range, 4 to 358) after conventional transplantation (P <.0001). Sixty-three percent of nonmyeloablative recipients required RBC transfusions compared with 96% of those with conventional grafts (P =.0001). The number of RBC units transfused was also reduced, with a median of 2 (range, 0 to 50) compared with 6 (range, 0 to 34) after conventional transplantation (P =.0001). High transfusion requirements before transplantation and donor-recipient ABO incompatibility increased transfusion requirements in both patient groups, though neither significantly influenced the outcome of the analysis. Neither patient age, splenomegaly at transplantation, development of graft-versus-host disease, nor posttransplantation cytomegalovirus antigenemia or cytomegalovirus disease had statistically significant influences on posttransplantation transfusions.

Idiopathic CD4+ T cell lymphocytopenia evolving to monoclonal immunoglobulins and progressive renal damage responsive to IL-2 therapy.

Idiopathic CD4+ T cell lymphocytopenia was unexpectedly detected in a 33-year-old, otherwise healthy young woman with no HIV or other viral infection, autoimmune, or neoplastic disease or increased susceptibility to infection. CD4+ T cell levels were 60-140/microl over a 3.5-year period. Following an uneventful pregnancy, the patient developed anemia and interstitial nephritis associated with a plasma cell dyscrasia with a monoclonal IgA gammopathy and a shifting immunoglobulin pattern that included IgG and IgA monoclonal proteins and increased urinary light chains. Osteolytic lesions were never detected and bone marrow aspirations revealed up to 10% atypical plasma cells. Various therapies often used in treating multiple myeloma only temporarily controlled the increasing renal damage. IL-2 therapy of 600,000 to 1 million units subcutaneously daily resulted in increased CD4+ T cells to normal levels, a decrease in the gammopathy, a return of renal function, energy, and weight gain, and apparently normal health status sustained for 2 years. The findings are compatible with a potentially fatal but nonmalignant immunoregulatory disorder that can be controlled by IL-2 administration.

Optical imaging reveals characteristic seizure onsets, spread patterns, and propagation velocities in hippocampal-entorhinal cortex slices of juvenile rats.

We have combined recordings with extracellular microelectrodes or ion-sensitive electrodes and imaging of intrinsic optical signal changes to study the spatiotemporal pattern of seizure onset and spread during development. We have employed the entorhinal cortex-hippocampus brain slice preparation of juvenile rats at different stages of postnatal maturation. Three age groups were analyzed: 4-6 days (age group I), 10-14 days (age group II), and 20-23 days (age group III). Seizure-like events were induced by perfusion of slices with Mg(2+)-free artificial cerebrospinal fluid thereby removing the Mg(2+) block of the N-methyl-d-aspartate receptor. Seizure susceptibility was highest in age groups II and III. In age group I seizure-like events originated mainly in the hippocampus proper. Seizure-like events in age group II originated mainly in the entorhinal cortex and this tendency was even more pronounced in age group III. Invasion of the hippocampal formation via the perforant path-dentate gyrus and via the subiculum was seen in age groups I and II. In contrast, in age group III the hippocampus was invaded exclusively via the subiculum pathway. The velocity of spread at which seizure-like events propagated within different regions of the slice increased with postnatal age. The characteristics of onset, spread patterns, and propagation velocities as revealed by this study allow insight into the evolving properties of the developing brain.

Persistent polyclonal B-cell lymphocytosis--an important differential diagnosis of B-cell chronic lymphocytic leukemia.

Over the last 17 years, 83 cases of polyclonal B-cell lymphocytosis (PPBL) have been published. This rare hematological disorder of unknown etiology is characterized by morphologically atypical lymphocytes, polyclonal immunoglobulin M production in association with smoking, female gender, and HLA-DR7 phenotype. We studied another male patient with PPBL. In contrast to normal B-cells, PPBL cells showed no response to interleukin-4 with regard to CD23 and human leukocyte antigen-DR expression. F2mu antibodies failed to co-stimulate interleukin-4-mediated CD23 expression. Crosslinking membrane immunoglobulin M receptors by F2mu resulted in elevated human leukocyte antigen-DR expression but did not induce in vitro proliferation of PPBL cells. This indicates a different activation and differentiation status than normal B-cells.

Stimulation of gammadelta T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma.

Bisphosphonates are well-known inhibitors of osteoclastic bone resorption, but recent clinical reports support the possibility of direct or indirect antitumor effects by these compounds. Because bisphosphonates share structural homologies with recently identified gamma delta T-cell ligands, we examined the stimulatory capacity of bisphosphonates to gamma delta T cells and determined whether gamma delta T-cell stimulation by bisphosphonates could be exploited to generate antiplasma cell activity in multiple myeloma (MM). All tested aminobisphosphonates (alendronate, ibandronate, and pamidronate) induced significant expansion of gamma delta T cells (V gamma 9V delta 2++ subset) in peripheral blood mononuclear cell cultures of healthy donors at clinically relevant concentrations (half-maximal activity, 0.9-4 mcmol/L). The proliferative response of gamma delta T cells to aminobisphosphonates was IL-2 dependent, whereas activation of gamma delta T cells (up-regulation of CD25 and CD69) occurred in the absence of exogenous cytokines. Pamidronate-activated gamma delta T cells produced cytokines (ie, interferon [IFN]-gamma) and exhibited specific cytotoxicity against lymphoma (Daudi) and myeloma cell lines (RPMI 8226, U266). Pamidronate-treated bone marrow (BM) cultures of 24 patients with MM showed significantly reduced plasma cell survival compared with untreated cultures, especially in cultures in which activation of BM-gamma delta T cells was evident (14 of 24 patients with MM). gamma delta T-cell depletion from BM cultures completely abrogated the cytoreductive effect on myeloma cells in 2 of 3 tested patients with MM. These results show that aminobisphosphonates stimulating gamma delta T cells have pronounced effects on the immune system, which might contribute to the antitumor effects of these drugs. (Blood. 2000;96:384-392)

Comparison of intrinsic optical signals associated with low Mg2+-and 4-aminopyridine-induced seizure-like events reveals characteristic features in adult rat limbic system.

PURPOSE: To analyze the intrinsic optical signal change associated with seizure-like events in two frequently used in vitro models-the low-Mg2+ and the 4-aminopyridine (4-AP) models-and to monitor regions of onset and spread patterns of these discharges by using imaging of intrinsic optical signals (IOS). METHODS: Combined hippocampal-entorhinal-cortex slices of adult rats were exposed to two different treatments: lowering extracellular Mg2+ concentrations or application of 100 microM 4-AP. The electrographic features of the discharges were monitored using extracellular microelectrodes. Optical imaging was achieved by infrared transillumination of the slice and analysis of changes in light transmission using a subtraction approach. The electrographic features were compared with the optical changes. Regions of onset and spread patterns were analyzed in relevant anatomic regions of the slice. RESULTS: Both lowering extracellular Mg2+ concentrations and application of 4-AP induced seizure-like events. The relative duration of the intrinsic optical signal change associated with seizure-like events in the low-Mg2+ model was significantly longer compared with that seen with those occurring in the 4-AP model, although duration of field potentials did not differ significantly in the two models. Seizure-like events of the low-Mg2+ model originated predominantly in the entorhinal cortex, with subsequent propagation toward the subiculum and neocortical structures. In contrast, no consistent region of onset or spread patterns were seen in the 4-AP model, indicating that the seizure initiation is not confined to a particular region in this model. CONCLUSIONS: We conclude that different forms of spontaneous epileptiform activity are associated with characteristic optical signal changes and that optical imaging represents an excellent method to assess regions of seizure onset and spread patterns.

A lymphohistiocytic variant of anaplastic large cell lymphoma with demonstration of the t(2;5)(p23;q35) chromosome translocation.

Cytogenetic investigations were performed in a case of a nodal malignant non-Hodgkin's lymphoma. Histopathological analysis from an involved lymph node as well as from a skin biopsy revealed a lymphohistiocytic variant of CD30-positive anaplastic large cell lymphoma (ALCL). A t(2;5)(p23;q35) chromosome translocation could be observed in all metaphases analysed. This finding was confirmed both by RT-PCR analysis of the NPM/ALK fusion protein and by positive staining with the p80(NPM/ALK) antibody. To the best of our knowledge, this is the first report of a t(2;5) documented by classic cytogenetics in the lymphohistiocytic variant of ALCL.

[High dose chemotherapy with autologous stem cell transplantation]. / Hochdosis-Chemotherapie mit autologer Stammzelltransplantation.

Subsequent stem cell transplantation makes it possible to increase the dose of oncological chemotherapy by a factor of between three- and ten-fold. For primary treatment, the superiority of this approach vis-a-vis standard doses seems to be highly likely in the case of recurrent highly malignant lymphomas, metastatic mamma carcinomas and plasmacytomas. To date, however, the most favorable time point for high-dose chemotherapy has not yet been definitively established-not has the patient group most likely to benefit or the most effective combination of cytostatics to be used. For this reason, such treatment, even of these diseases, should not be applied outside of controlled studies, and must be viewed even more critically in the case of other diseases for which data from randomized studies are not yet available. Despite a relatively low overall level of toxicity, peripheral blood stem cell transplantation (PBSCT) still has a mortality rate--even in large centers--of 2 to 5%. Any such treatment should therefore be given only in controlled studies and in suitable centers.