Remission of paroxysmal atrial fibrillation with iron reduction in haemophilia A.

SUMMARY: Two male first cousins with mild haemophilia A had baseline factor VIII levels of 12-15% and experienced bleeding requiring coagulation factor infusion therapy with trauma and surgical procedures. Both the patients with haemophilia A also had electrocardiographically documented symptomatic paroxysmal atrial fibrillation (PAF) for several years that had become resistant to pharmacological suppression. Radiofrequency ablation was considered in both the cases but deferred considering refusal of consent by the patients to undergo the procedure. Remission of arrhythmias has been reported in patients with iron-overload syndromes. Body iron stores assessed by serum ferritin levels were elevated in both men but neither had the C282Y or H63D genes for haemochromatosis. Calibrated reduction of iron stores by serial phlebotomy, avoiding iron deficiency, was followed by remission of symptomatic PAF in both cases. Iron reduction may be an effective treatment for arrhythmias apart from the classic iron-overload syndromes and deserves further study particularly in patients with bleeding disorders who might be at risk for arrhythmias and other diseases of ageing.

Succinylcholine-induced hyperkalemia in a patient with mucositis secondary to chemotherapy.

OBJECTIVE: To report a case of fatal hyperkalemia owing to succinylcholine administration in a patient with mucositis secondary to chemotherapy. DESIGN: Case report. SETTING: Adult intensive care unit (ICU) at Dartmouth-Hitchcock Medical Center. PATIENTS: One patient with mucositis secondary to chemotherapy. MEASUREMENTS AND MAIN RESULTS: A 37-yr-old female with recently diagnosed acute myelogenous leukemia was admitted to the ICU with mental status changes and progressive dyspnea requiring intubation and mechanical ventilation. Before ICU admission, the patient had suffered from painful mucositis causing severe dysphagia and bleeding, which was thought to be the result of chemotherapy. By the 10th ICU day, the patient's respiratory and mental status improved and the patient was successfully extubated. However, 8 hrs after extubation, she gradually developed severe respiratory distress, requiring reintubation and mechanical ventilation. The patient was given 14 mg of etomidate and 100 mg of succinylcholine intravenously. Immediately after the intubation, she suffered cardiac arrest. Her serum potassium level was 13.1 mEq/L and HCO3- was 16 mEq/L. The resuscitation attempt was unsuccessful, and the patient was pronounced dead. CONCLUSION: Oral mucositis is a frequent and potentially severe complication of cancer chemotherapy. We believe that mucositis was a contributing factor to this case of fatal hyperkalemia after administration of succinylcholine, with a mechanism similar to that reported with thermal injury. Only nondepolarizing muscle relaxants should be used in patients who are at risk for mucositis. Mucositis should be added to the list of conditions in which succinylcholine is contraindicated.

Successful donation and transplantation of multiple organs after fatal poisoning with brodifacoum, a long-acting anticoagulant rodenticide: case report.

BACKGROUND: Successful organ donation has been reported after death from poisonings with cyanide, carbon monoxide, methanol, benzodiazepines, and tricyclic antidepressants. In this report, we describe a case of multiple organ donation from a previously healthy individual who died from poisoning with the long-acting anticoagulant rodenticide, brodifacoum. METHODS: Case report and review of the literature. RESULTS: All organs procured from the poisoned donor functioned adequately, and there were no hemorrhagic complications in any of the recipients. CONCLUSION: This case demonstrates that brodifacoum poisoning is not an absolute contraindication to organ donation from brain-dead patients who have sustained a fatal ingestion.

The differential diagnosis of posterior plagiocephaly: true lambdoid synostosis versus positional molding.

The diagnosis and treatment of posterior plagiocephaly is one of the most controversial aspects of craniofacial surgery. The features of true lambdoid synostosis versus those of deformational plagiocephaly secondary to positional molding are inadequately described in the literature and poorly understood. This has resulted in many infants in several craniofacial centers across the United States undergoing major intracranial procedures for non-synostotic plagiocephaly. The purpose of this study was to describe the detailed clinical, imaging, and operative features of true lambdoid synostosis and contrast them with the features of positional plagiocephaly. During a 4-year period from 1991 to 1994, 102 patients with posterior plagiocephaly were assessed in a large multidisciplinary craniofacial program. During the same period, 130 patients with craniosynostosis received surgical treatment. All patients were examined by a pediatric dysmorphologist, craniofacial surgeon, and pediatric neurosurgeon. Diagnostic imaging was performed where indicated. Patients diagnosed with lambdoid synostosis and severe and progressive positional molding underwent surgical correction using standard craniofacial techniques. Only 4 patients manifested the clinical, imaging, and operative features of unilambdoid synostosis, giving an incidence among all cases of craniosynostosis of 3.1 percent. Only 3 among the 98 patients with positional molding required surgical intervention. All the patients with unilambdoid synostosis had a thick ridge over the fused suture, identical to that found in other forms of craniosynostosis, with compensatory contralateral parietal and frontal bossing and an ipsilateral occipitomastoid bulge. The skull base had an ipsilateral inferior tilt, with a corresponding inferior and posterior displacement of the ipsilateral ear. These characteristics were completely opposite to the findings in the 98 patients who had positional molding with open lambdoid sutures and prove conclusively that true unilambdoid synostosis exists as a specific but rare entity. Awareness of the features of unilambdoid synostosis will allow more accurate diagnosis and appropriate treatment of posterior plagiocephaly in general and in particular will avoid unnecessary surgical intervention in patients with positional molding.

Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes.

The myelodysplastic syndrome (MDS) comprises a group of clonal hematopoietic disorders derived from an abnormality affecting a multipotent hematopoietic stem cell. Despite trials testing numerous agents in patients with MDS, no single drug has yet emerged as the accepted standard of treatment. Observation and supportive care with blood products and antibiotics, when necessary, continue to be the mainstays of therapy. We administered 5-azacytidine, a cell-cycle specific ring analog of the pyrimidine nucleoside cytosine, as a continuous intravenous infusion, 75 mg/m2 per day for 7 days every 4 weeks. Patients had refractory anemia with excess blasts (RAEB) or refractory anemia with excess blasts in transformation (RAEB-T). Responses were seen in 21 (49%) of 43 evaluable patients: five (12%) in complete remission (CR, complete normalization of bone marrow and peripheral blood counts); 11 (25%) in partial remission (PR, > or = 50% restoration of the deficit from normal of all three peripheral blood cell lines, elimination of transfusion requirements, and a decrease in percentage bone marrow blasts by > or = 50% from prestudy values); five (12%) improved (> or = 50% restoration in the deficit from normal of one or more peripheral blood cell lines and/or a > or = 50% decrease in transfusion requirements). A trilineage improvement (CR and PR) occurred in 37% of the patients. The median survival for all patients was 13.3 months and the median duration of remission for those with CR and PR was 14.7 months. Mild to moderate nausea and/or vomiting was the most common side effect (63%). Myelosuppression, either bone marrow hypoplasia or drug related cytopenias requiring a reduction in the dose of azacitidine, occurred in only 33% of the patients. Prior to treatment, bone marrow erythroid progenitor cells were assayed in vitro. Colonies derived from erythroid burst-forming units (BFU-e) were undetectable in one patient and reduced in two. The number of colonies derived from erythroid colony-forming units (CFU-e)) were also reduced in two of the three patients. In the two patients with detectable colony growth prior to treatment, colony number decreased by day 8 of the first cycle, followed by a subsequent increase. Continued treatment with azacitidine led to normalization of the number of CFU-e derived colonies as well as an increase in the number of BFU-e derived colonies. This improvement in erythroid colony number correlated with the spontaneous rise in hemoglobin levels and red cell transfusion independence.(ABSTRACT TRUNCATED AT 400 WORDS)

Nitrogen mustard, vincristine, procarbazine, and prednisone as adjuvant chemotherapy in the treatment of medulloblastoma. A Pediatric Oncology Group study.

In a randomized postoperative trial, adjuvant post-irradiation chemotherapy, consisting of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP), was tested versus radiation therapy alone for newly diagnosed medulloblastoma in patients between 1 and 21 years of age. Patients treated with irradiation plus MOPP had a statistically significant increase in overall survival rate at 5 years posttreatment compared to patients treated with radiation therapy alone (74% vs. 56%; p = 0.06, adjusted for race and gender). Although the overall study failed to show a statistically significant advantage for irradiation plus MOPP in event-free survival (p = 0.18), statistical significance was attained in children 5 years of age or older (p = 0.05). More severe hematological toxicities occurred in the group with irradiation plus MOPP; however, this hematotoxicity appeared to be tolerable and acceptable. These results suggest that patients may benefit from combined irradiation and chemotherapy following surgery for medulloblastoma.

Immunophenotypic characteristics of cerebrospinal fluid cells in children with acute lymphoblastic leukemia at diagnosis.

The presence of meningeal involvement in children with acute lymphoblastic leukemia (ALL) may have important prognostic and therapeutic implications. Conventional methods of diagnosing central nervous system (CNS) leukemia rely on the interpretation of cerebrospinal fluid (CSF) cell morphology, which may produce ambiguous results in the presence of minimal leukemic involvement. A methodology has been developed for immunophenotyping small numbers of CSF cells while preserving cell morphology. CSF samples from 33 children with CD10 (common ALL antigen [CALLA]) positive ALL were examined at initial presentation using both conventional morphology and this combined immunohistopathologic technique. Six (18%) of the samples contained lymphoblasts or cells considered morphologically suspicious for leukemic involvement. Nine additional samples (27% of the total) had normal CSF morphology, but contained increased numbers of CALLA positive cells. Twelve of the 33 samples were also examined for the simultaneous presence of nuclear terminal deoxynucleotidyl transferase (TdT) and demonstrated increased numbers of cells positive for both TdT and CD10. These data suggest that a large proportion of children with ALL may have abnormalities of CSF cells at initial diagnosis consistent with the presence of occult leukemic involvement.

Atherosclerosis and coronary bypass surgery in hereditary factor VII deficiency.

A 66-year-old man with homozygous deficiency of factor VII (less activity than 4 percent of normal) had a minimal hemorrhagic tendency and severe coronary atherosclerosis, and underwent aortocoronary saphenous vein bypass surgery. Although plasma factor VII coagulant activity and cross-reacting material were markedly reduced, comparable amounts of factor VII antigen were detected in peripheral blood mononuclear cells of both the patient and of a normal subject by Western blotting techniques. Accelerated coagulation was observed following brief exposure of the patient's phytohemagglutinin-stimulated peripheral blood mononuclear cells to low concentrations of ambient factor VII in vitro. Evidence indicates that factor VII plays a role in vivo in both hemostasis and atherogenesis and it might be assumed that factor VII deficiency would both predispose to excessive bleeding and forestall atherosclerosis. However, these observations suggest that factor VII-mediated thrombin generation may proceed by partitioning of small amounts of factor VII on tissue factor-expressing cells and that factor VII contained within monocytes may facilitate tissue factor-induced coagulation by these cells. These features may provide efficient coagulation activation despite a deficiency of the plasma coagulant protein. The current results may explain, at least in part, the minimal bleeding tendency, and also the occurrence of thrombosis and atherosclerosis in certain persons with factor VII deficiency.

Effect of mopidamol on survival in carcinoma of the lung and colon: final report of Veterans Administration Cooperative Study No. 188.

Mopidamol (RA-233), a derivative of dipyridamole, is a phosphodiesterase inhibitor that has been shown previously to limit progression of malignancy in certain experimental animal models and in a pilot study in humans. RA-233 plus chemotherapy was compared with chemotherapy alone in a 5-year double-blind trial involving 719 patients with advanced carcinomas of the lung and of the colon. RA-233 treatment was associated with a statistically significant prolongation of survival in patients with non-small cell lung cancer (N-SCLC) limited to one hemithorax and with reduction in mean plasma fibrogen concentration. RA-233 was not toxic. The favorable effects on survival could not be explained by any factor other than the RA-233 treatment. In other tumor categories tested, no differences in survival were observed. These results suggest that RA-233 is useful in the treatment of N-SCLC of limited extent. They also suggest that therapeutic intervention aimed at modified intracellular pathways might constitute a novel investigative approach to the treatment of cancer.

Mitoxantrone in relapsed or refractory acute nonlymphocytic leukemia.

Seventeen patients with relapsed or refractory acute nonlymphocytic leukemia were treated with 14 mg/m2 of mitoxantrone given in a 30-minute infusion daily for three days. If the day fourteen bone marrow showed residual leukemia, a second course was given at the same dose for two days. Eight patients (47%) entered complete remission. Three patients (17%) had a partial response, four (24%) did not respond, and two (12%) died with hypoplastic marrows during treatment. Seven of the 12 relapsed patients entered a complete remission, as did one of the five refractory patients. Toxicity was acceptable; prolonged myelosuppression, moderate hepatic toxicity, and stomatitis were the only problems. Several dose schedules of mitoxantrone have been studied by other investigators with varying results. The three-day schedule in the present study is similar to the schedule used for common induction regimens employing anthracycline drugs. On the basis of its activity and acceptable toxicity in relapsed and refractory ANLL patients, we feel that this schedule could be safely combined with other agents in future studies.

Abnormalities of blood coagulation tests in patients with cancer.

Routine blood coagulation tests were performed on 431 consecutive patients enrolled in a study of the role of anticoagulation in cancer treatment (VA Cooperative Study #75). Two hundred sixteen control patients were treated with standard therapy, and 215 patients were treated with standard therapy plus sodium warfarin. At the time of entry into the study, the most common abnormalities were elevated fibrinogen levels, platelet counts, and fibrinopeptide A levels. Serial studies demonstrated a steady increase in platelet count and fibrinogen levels before death. Anticoagulation lowered FPA levels but had no significant effect on fibrinogen levels, platelet counts, or euglobulin clot lysis times. An unexpected finding was a dramatic increase in fibrin split product levels after institution of anticoagulation (means +/- SEM = 42.6 +/- 116.4 vs. 2.9 +/- 7.0 mg/L in control subjects; P less than 0.02). This study supports the presence of subclinical activation of blood coagulation in most patients with cancer. Moreover, the preferential activation of fibrinolysis in anticoagulated patients suggests a role for a vitamin K-dependent factor(s) in the regulation of fibrinolysis in patients with cancer.

Bleeding complications from warfarin anticoagulation in patients with malignancy.

Bleeding complications from warfarin anticoagulants were analyzed in 431 patients with carcinoma of the lung, colon, prostate and head and neck who were admitted to a randomized, controlled therapeutic trial of this agent. A total of 215 patients were randomized to the warfarin-treated group and 216 to the control groups. The mean prothrombin time was significantly prolonged (p = 0.0001) for warfarin-treated patients. The duration of warfarin administration was 64.9% of the total followup period providing 101 patient-years of experience with warfarin in cancer. Both the overall incidence of bleeding episodes (58% of warfarin-treated versus 30% of control) and the incidence of major bleeding episodes (42% versus 14%, respectively) were significantly increased in the warfarin-treated group (p = less than 0.001). The incidence of major bleeding was 1.86 per patient-year on warfarin. The most common sites of bleeding (in descending order) were the gastointestinal tract, the urinary tract, the nasal passages and skin. Hemorrhage occurred in association with the terminal event in 10 warfarin-treated and 12 control patients. Warfarin anticoagulation may have contributed to terminal bleeding in 3 (1.4%) patients. There was no difference in mean hemoglobin or hematocrit values for patients with versus patients without bleeding episodes.

Comparison of local versus central tumor measurements in a multicenter cancer trial.

Four hundred nineteen solid tumors from 92 patients were measured by a local team consisting of a physician and nurse oncologist or physician's assistant, and centrally by one radiologist. The central radiologist also remeasured 137 tumors on 30 patients to assess intraexaminer agreement. Tumor measurements at specific points in time as well as changes in tumor measurements over time were evaluated. When signed differences were calculated, there was little overall difference between local and central examiners, although three of the eight centers did show a significant difference. However, when absolute differences were calculated, the relative errors of the width times length products ranged from 35 to 55%. Although local and central examiners agreed 75% of the time on change in disease, there was only 42% agreement on the subset of patients who had a remission. In general, the intraexaminer agreement was slightly better than the interexaminer agreement. This study suggests that solid tumor measurements are not particularly reliable, and that survival time remains the most satisfactory endpoint in a cancer clinical trial.

Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA Cooperative Study #75.

VA Cooperative Study #75 was established to test in a controlled, randomized trial the hypothesis that warfarin anticoagulation would favorably affect the course of certain types of malignancy. No differences in survival were observed between warfarin-treated and control groups for advanced non-small cell lung, colorectal, head and neck and prostate cancers. However, warfarin therapy was associated with a significant prolongation in the time to first evidence of disease progression (P = 0.016) and a significant improvement in survival (P = 0.018) for patients with small cell carcinoma of the lung, including the subgroup of patients with disseminated disease at the time of randomization (P = 0.013). A trend toward improved survival with warfarin treatment was observed for the few patients admitted to this study with non-small cell lung cancer who had minimal disease at randomization. These results suggest that warfarin, as a single anticoagulant agent, may favorably modify the course of some, but not all, types of human malignancy, among which is small cell carcinoma of the lung. Further trials of warfarin may be indicated in patients with limited disease who have cell types that failed to respond when advanced disease was present.

Accrual of patients into a multihospital cancer clinical trial and its implications on planning future studies.

Little information exists on the population of cancer patients from which individual patients are selected for admission to a clinical trial. In fact, most reports of clinical trials of cancer chemotherapeutic agents begin by describing samples of treated patients but neglect to collect data and describe the population from which the samples were taken. In a multi-institutional VA Cooperative Study in which two different cancer treatments were compared, an attempt was made to screen all lung, colorectal, prostate, and head and neck patients seen at participating hospitals prior to randomization to a therapeutic regimen. Of a total of 2687 patients screened, 437 (16.3%) were randomized and 2250 (83.7%) were excluded for 2981 reasons. Protocol reasons were the basis for 68.6% of all exclusions, 21.3% were physician refusals, and 10.1% were patient refusals. The number of patients randomized did not correlate well with number of patients screened across participating centers. Patients admitted to the study tended to be younger and in better health than excluded patients. Overestimates of randomization rates projected initially from published information point to the need for improved screening data in the planning of future studies. Factors such as screening methods, physician acceptance of the experimental approach, number of competing protocols within each center, and cooperation among medical center departments and personnel all are important ingredients in any screening effort.

Platelets and malignancy. Rationale and experimental design for the VA Cooperative Study of RA-233 in the treatment of cancer.

Considerable evidence has accumulated in recent years which implicates blood coagulation reactions in the growth and spread of malignancy. In particular, platelets may accumulate on embolic tumor cells and facilitate their adhesion to the endothelium at distant sites perhaps by enhancing blood coagulation reactions. Alternatively, platelets may promote tumor cell proliferation by contributing a growth-promoting factor or through interactions mediated by prostaglandins. Inhibition of tumor growth and spread by platelet-inhibitory drugs has been demonstrated in several experimental tumor systems. Preliminary data suggest that similar effects may be seen in human malignancy. The purpose of this paper is to review relevant literature which provides the rationale for therapeutic trials of platelet-inhibitory drugs in human malignancy and to describe the experimental design for a trial involving one such drug, RA-233, in a recently established VA Cooperative Study.

Chronic granulocyte leukemia with respiratory distress. Efficacy of emergency leukapheresis.

In the absence of preexisting pulmonary disease, progressive respiratory failure caused by leukostasis associated with uncontrolled chronic granulocytic leukemia developed in two patients. The conditions of both patients improved dramatically with aggressive leukapheresis. Clinical improvement correlated with decreased pulmonary wedge pressure, while vascular volume remained constant. Continuous-flow cell separation removed numerous immature myeloid cells, replaced them with oxygen-carrying erythrocytes, and maintained a constant blood volume. The course of these two patients demonstrates the use of continuous-flow leukapheresis in an intensive care unit to reduce leukocyte count and manifestations of leukostasis rapidly, while improving the oxygen-carrying capacity of blood, without exposing the patients to dangerously large shifts in fluid volume.

Effect of warfarin on survival in small cell carcinoma of the lung. Veterans Administration Study No. 75.

In a controlled, randomized study, survival of patients with small cell carcinoma of the lung (SCCL) was prolonged on addition of warfarin sodium to combination chemotherapy plus radiation therapy. Median survival for 25 control patients was 24 weeks and for 25 warfarin-treated patients was 50 weeks. This difference could not be accounted for by differences between groups in performance status, extent of disease, age, or sex. The survival advantage associated with warfarin administration was observed both for patients with extensive disease and for those who failed to achieve complete or partial remission. The warfarin-treated group also demonstrated a significantly increased time to first evidence of disease progression. These results suggest that warfarin may be useful in the treatment of SCCL and also support the hypothesis that the blood coagulation mechanism may be involved in the growth and spread of cancer in man.