Charles E. Hess

Rituximab Infusion Promotes Rapid Complement Depletion and Acute CD20 Loss in Chronic Lymphocytic Leukemia

Complement plays an important role in the immunotherapeutic action of the anti-CD20 mAb rituximab, and therefore we investigated whether complement might be the limiting factor in rituximab therapy. Our in vitro studies indicate that at high cell densities, binding of rituximab to human CD20+ cells leads to loss of complement activity and consumption of component C2. Infusion of rituximab in chronic lymphocytic leukemia patients also depletes complement; sera of treated patients have reduced capacity to C3b opsonize and kill CD20+ cells unless supplemented with normal serum or component C2. Initiation of rituximab infusion in chronic lymphocytic leukemia patients leads to rapid clearance of CD20+ cells. However, substantial numbers of B cells, with significantly reduced levels of CD20, return to the bloodstream immediately after rituximab infusion. In addition, a mAb specific for the Fc region of rituximab does not bind to these recirculating cells, suggesting that the rituximab-opsonized cells were temporarily sequestered by the mononuclear phagocytic system, and then released back into the circulation after the rituximab-CD20 complexes were removed by phagocytic cells. Western blots provide additional evidence for this escape mechanism that appears to occur as a consequence of CD20 loss. Treatment paradigms to prevent this escape, such as use of engineered or alternative anti-CD20 mAbs, may allow for more effective immunotherapy of chronic lymphocytic leukemia.

Glutathione synthetase deficiency as a cause of hereditary hemolytic disease.

Abstract Two enzymes are required for de novo glutathione synthesis: glutamyl-cysteine synthetase and glutathione synthetase. In a 32-year-old man with a well compensated hemolytic disorder, the er...

Double-blind randomized study of prophylactic trimethoprim/sulfamethoxazole in granulocytopenic patients with hematologic malignancies

In a double blind study, oral prophylactic trimethoprim/sulfamethoxazole was evaluated for its utility in preventing serious infections in patients with hematologic malignancy. Of 58 evaluated granulocytopenic episodes in 47 patients, acute leukemia was the underlying malignancy in 46 episodes. Trimethoprim/sulfamethoxazole prophylaxis resulted in fewer microbiologically documented infections (seven versus 15; p = 0.029). This was primarily the result of a reduction in episodes of bacteremia in the trimethoprim/sulfamethoxazole-treated group as compared with the placebo-treated group (three versus nine episodes; p = 0.05). The combined frequency of disseminated candidiasis, candidemia, and esophagitis of presumed fungal etiology was greater in the trimethoprim/sulfamethoxazole-treated group (six) than in the placebo-treated group (two) but not significantly so (p = 0.13). Similarly, there were no significant differences between groups in the overall incidence of infectious complications, number of febrile days, use of parenteral antibiotics, or number of days following randomization to first infectious episode. Throat and rectal surveillance cultures more frequently revealed trimethoprim/sulfamethoxazole-resistant gram-negative bacilli and yeasts in the trimethoprim/sulfamethoxazole-treated group. More frequent emergence of yeast isolates from previously culture-negative patients was documented (p = 0.033). Thus, in this study, trimethoprim/sulfamethoxazole prophylaxis during granulocytopenia reduced the incidence of microbiologically documented infections. However, the emergence of resistant bacteria and of fungi may limit the potential usefulness of this approach.

Residual tumor masses following treatment for advanced histiocytic lymphoma. Diagnostic and therapeutic implications

Forty percent or more of patients with advanced diffuse histiocytic (large cell) lyniphoma will achieve prolonged disease‐free survival with the use of intensive combination chemotherapy. These results are obtained only if complete resolution of all viable tumor is documented prior to the cessation of chemotherapy. Residual tumor masses at the time of re‐staging usually are excised or biopsied to confirm the presence or absence of viable tumor. Three patients are reported who had with advanced histiocytic (large cell) lymphoma, and who demonstrated residual intra‐abdominal tumor masses on CT scan following four courses of COPP chemotherapy. After two additional courses of a non‐cross‐resistant regimen and/or supplemental radiotherapy failed to reduce the size of the masses, abdominal exploration with removal of the tumors including splenectomy in one patient was performed, and in each instance no viable tumor was found. The patients have remained disease‐free for periods ranging from 24 to 48 months. The various options available to evaluate such patients are presented, and a systematic approach which should avoid the unnecessary prolongation of potentially harmful chemotherapy or radiotherapy is proposed.

Splenectomy in hematologic disorders: the ever-changing indications

A comparison between a series of splenectomics performed at the University of Virginia Medical Center for hematologie disorders between 1946 and 1962 (Series I) and 1963 and 1982 (Series II) is presented. Four hundred splenectomies (20 per year) were performed between 1963 and 1982 compared with 94 (5.5 per year) between 1946 and 1962. Also noted in Series II was a sharp decline in the number performed each year between 1974 and 1983. The major factor responsible for these observations was the evolution of the staging laparotomy for malignant lymphomas, particularly Hodgkins disease, and the decline in the average annual incidence of staging laparotomies since 1974. Staging laparotomy currently is rarely done for non-Hodgkins lymphomas. Also contributing to the changes noted was an increase in the total number but subsequent fall in the annual incidence of splenectomy for hereditary spherocyto-sis, idiopathic hypersplenism, and myeloproliferative disorders in Series II. The average number of splenectomies for idiopathic thrombocytopenic purpura increased from 1.1 per year in Series I to 3.6 per year in Series II; the annual incidence during the study period of Series II, however, remained constant. The total number of splenectomics for hairy cell leukemia and Fellys syndrome increased from zero in Series I to 12 and 17, respectively, in Series II, whereas the number of miscellaneous reasons dropped from 29 (1.7 per year) in Series I to 15 (0.75 per year) in Series II. The mortality rate in Series I was 6.3% compared with 4.0% in Series II. No deaths occurred in Series II after 1979. Indications for splenectomy in Series II were for diagnostic purposes in 3.2%, therapeutic in 56.5%, staging in 39.5%, and restaging in 0.8%. Accessory spleens were found in 49 (12.5%) in Series II.

Transcatheter embolic control of iatrogenic hematobilia

For the patient with hematobilia, a serious complication of liver injury, angiography is the definitive diagnostic procedure. In addition to localizing precisely the source of the hemorrhage, angiography also provides an effective alternative to surgery for the control of hemorrhage. In two cases of iatrogenic hematobilia discussed, the bleeding sites were identified by angiography, and the bleeding was controlled by transcatheter embolization.

A controlled study of ticarcillin plus clavulanic acid versus piperacillin as empiric therapy for fever in the immunocompromised host

Clavulanic acid, a potent beta-lactamase inhibitor, was studied in fixed combination with ticarcillin and used with tobramycin as empiric therapy for fever in the immunocompromised host. Fifty febrile episodes were evaluated in patients with hematologic malignancy and/or neutropenia. Eighty-one percent of evaluable infections treated with the study regimen of ticarcillin, clavulanic acid, and tobramycin responded. Seventy-four percent of evaluable infections treated with the control regimen of piperacillin, tobramycin, and vancomycin responded (p = 0.4). Resistance to piperacillin and ticarcillin were noted in 23.8 percent of 21 isolated organisms. Resistance to ticarcillin and clavulanic acid was noted in only one (4.7 percent) of the isolated organisms (p = 0.092). Untoward reactions, including rash, nephrotoxicity, and superinfection, were unusual and occurred with equal frequency in the study and control groups. Clavulanic acid in combination with ticarcillin was effective and safe in treating fever in the immunocompromised host.

Dilutional anemia of splenomegaly: an indication for splenectomy.

Dilutional Anemia of Splenomegaly: An Indication for Splenectomy Charles Hess;Carlos Ayers;Richard Wetzel;Daniel Mohler;William Sandusky; Annals of Surgery

Gamma heavy chain disease: Report of a case associated with trisomy of chromosome 7

A case of gamma heavy chain disease is reported in a 52-year-old white male who presented with fever and generalized lymphadenopathy. A lymph node biopsy showed malignant lymphoma. A partial transient response was obtained with cyclophosphamide, vincristine, prednisone, and doxorubicin. He died 3 months after diagnosis from disease progression and infectious complications. Chromosome analysis of cells from an involved lymph node showed the presence of trisomy 7. Chromosome abnormalities have been reported in three of ten previously published cases of gamma heavy chain disease. Trisomy of chromosome #7 has not previously been reported.

Intermittent Claudication as the Presenting Symptom in Primary Amyloidosis

B.F. Schneider, PhD, MD, Department of Radiology, Radiation Oncology – Box 383, University of Virginia Health Science Center, Charlottesville, VA 22908 (USA) Intermittent claudication is a symptom of circulatory insufficiency that develops primarily in muscles of the lower extremities. It is most frequently associated with atherosclerosis, but may also occur with other vascular disorders such as giant cell arteritis, thromboangiitis obli-terans, Takayasu disease and Raynaud disease, as well as with stenosis of the lumbar spinal canal [1]. Here we report on a patient whose symptoms of intermittent claudication appear to be due to amyloid angiopathy; moreover, this appears to be the first symptom of this patient’s previously unrecognized primary amyloidosis. A 77-year-old man presents with a 4-year history of exercise-induced pain in his calf muscles bilaterally, extending to his thighs and buttocks. These symptoms now occur after walking approximately 50 yards and are relieved completely by resting for a few minutes. He also has pain in both upper extremities with minimal exercise, relieved by rest. Approximately 18 months ago he underwent a la-minectomy of L4 and decompression of L3-4 and L4-5 for spinal stenosis, but his symptoms remained unchanged. Neurologic reevaluations indicate that his persisting symptoms of intermittent claudication are not due to spinal stenosis. Multiple peripheral vascular studies, including an angiogram and ankle brachial index with exercise, have all indicated no major vascular obstruction. On physical exam he is normotensive, with no bruits and nontender temporal arteries. The liver is moderately enlarged, and the spleen is not palpable. Straight leg raise is negative. Motor and sensory examinations are intact throughout. There is some degree of cyanosis of his feet, particularly in the dependent position, and the distal extremities are cool, but distal pulses and capillary refill are normal. Laboratory tests reveal a blood urea nitrogen of 28 mg/dl and a creatinine of 1.7 mg/dl. Blood count reveals a mild anemia with a hemoglobin of 11.9 g/dl and hematocrit of 36%. The white blood cell count is 4,300/ml with 22% lymphocytes, 17% monocytes, 5% eosinophils and 1% ba-sophils. The platelet count is 37,000/ml. Serum protein electrophoresis shows increased ß-glob-ulins (1.19 g/dl, normal 0.6-1.10) with normal levels of albumin, αr, α2and γ-globulins. Quantitative levels of IgG, IgA, IgM, k and λ