Immunologic Aberrations in the Di Guglielmo Syndrome

Immunologic studies were performed in 49 patients with the Di Guglielmosyndrome. Although altered immune reactivity has not been previouslythought to be a feature of myeloproliferative disorders, more than one-third ofthe cases showed immunologic aberrations. The abnormalities encounteredincluded overproduction of antibody protein (hypergammaglobulinemia) andan increased tendency to form rheumatoid factor, LE factor (including onecase with overt systemic lupus), positive serologic tests for syphilis, anderythrocyte autoantibodies and isoantibodies.

Possible pathogenetic mechanisms are considered. The underlying neoplasticprocess might directly involve the immunocytes, resulting in exaggerated andnonspecific responses, or in defective self-recognition and thus in the production of autoantibodies. Alternatively, preexisting but "hidden" antigens mightbe exposed by the proliferative disorder, thus stimulating an antibody response. Finally, and perhaps most likely, antigenic alteration of bone marrowtissue might accompany its neoplastic transformation. Such tissue could berecognized as "not-self" or "foreign" by a qualitatively normal immune system.This would result in the production of abnormal proteins, some of which wouldbe immunologically effective.

Submitted on February 1, 1966 Accepted on March 20, 1966     

Amifostine (WR-2721) shortens the engraftment period of 4- hydroperoxycyclophosphamide-purged bone marrow in breast cancer patients receiving high-dose chemotherapy with autologous bone marrow support

4-Hydroperoxycyclophosphamide (4-HC), a commonly used marrow-purging agent, is active against many tumors, but is also toxic to normal marrow progenitors. Amifostine (WR-2721) is a sulfhydryl compound with chemoprotectant activity. Preclinical studies using suspensions of bone marrow and breast cancer cells demonstrated that ex vivo treatment with amifostine followed by 4-HC resulted in protection of marrow progenitors, with no compromise in the antitumor effect of 4-HC. This fact stimulated the development of a clinical trial. Bone marrow was harvested from 15 poor-prognosis breast cancer patients and randomly assigned to ex vivo treatment with amifostine followed by 4-HC (amifostine + 4-HC), or treatment with 4-HC alone. High-dose chemotherapy was then administered followed by infusion of the purged autologous bone marrow support (ABMS). Leukocyte engraftment, defined as a white blood cell count > or = 1 x 10(9)/L, was achieved in an average of 26 days for patients whose marrow was purged with amifostine + 4-HC versus 36 days for patients whose marrow was purged with 4-HC alone (P = .032). The average number of platelet transfusions (12 v 29; P = .017) and days of antibiotic therapy (28 v 40; P = .012) were significantly less for patients whose marrow was exposed to amifostine + 4-HC, compared with 4-HC alone. Unpurged backup marrow fractions were infused into three patients whose marrow was purged with 4-HC alone, because of inadequate marrow recovery. None of the patients who received amifostine + 4-HC-purged marrow required a backup marrow fraction. Complete remissions were achieved in 83% of patients with measurable disease, with no difference between the two cohorts. Forty- three percent of patients remained alive and progression-free at a mean of 13 months posttransplant. There was no significant difference in the rate or pattern of relapse for patients whose marrow was purged with amifostine + 4-HC compared with those whose marrow was purged with 4-HC alone. Ex vivo treatment of marrow with amifostine significantly shortens the time to marrow recovery, thereby reducing the risk of myelosuppressive complications in breast cancer patients receiving high- dose chemotherapy and 4-HC-purged ABMS. Since supportive care requirements are also significantly decreased, amifostine may reduce the cost of such therapy.     

Ex vivo expansion with stem cell factor and interleukin-11 augments both short-term recovery posttransplant and the ability to serially transplant marrow

The characterization of many cytokines involved in the control of hematopoiesis has led to intense investigation into their potential use in ex vivo culture to expand progenitor numbers. We have established the optimum ex vivo culture conditions that allow substantial amplification of transient engrafting murine stem cells and which, simultaneously, augment the ability to sustain serial bone marrow transplantation (BMT). Short-term incubation of unfractionated BM cells in liquid culture with stem cell factor (SCF) and interleukin-11 (IL- 11) produced a 50-fold amplification of clonogenic multipotential progenitors (CFU-A). Following such ex vivo expansion, substantially fewer cells were required to rescue lethally irradiated mice. When transplanted in cell doses above threshold for engraftment, BM cells expanded ex vivo resulted in significantly more rapid hematopoietic recovery. In a serial transplantation model, unmanipulated BM was only able to consistently sustain secondary BMT recipients, but BM expanded ex vivo has sustained quaternary BMT recipients that remain alive and well more than 140 days after 4th degree BMT. These results show augmentation of both short-term recovery posttransplant and the ability to serially transplant marrow by preincubation in culture with SCF and IL-11.     

Deficiency of platelet membrane glycoprotein Ia associated with a decreased platelet adhesion to subendothelium: a defect in platelet spreading

A bleeding disorder with absent collagen-induced platelet aggregation and adhesion has been described in a patient whose platelets failed to express surface glycoprotein Ia. We studied the interaction of her platelets with subendothelium in an annular perfusion chamber and the interaction with purified human collagen type III in a rectangular perfusion system under flow conditions. Platelet adherence was almost completely absent both at low and high shear rates. The few platelets which adhered remained in the contact stage without subsequent spreading and aggregate formation. Addition of a monoclonal antibody, which was directed against the von Willebrand moiety of FVIII-VWF, to the blood, completely abolished platelet adherence at high shear rates and had a partial effect at low shear rates. These data indicate that von Willebrand factor plays a role in the initial attachment (contact stage) of platelets to subendothelium. We conclude that the bleeding disorder and excessively prolonged bleeding time in our patient are caused by a new specific defect of the platelet-vessel wall interaction.     

Aortopulmonary window lesions: detection with chest radiography

A retrospective morphologic study of 80 cases was undertaken to determine factors affecting detectability of computed tomographically (CT) proved aortopulmonary (AP) window lesions on conventional posteroanterior (PA) and lateral chest radiographs. Criteria used for determining abnormality were: solitary lymph node enlargement over 1.5 cm or three or more 1-cm nodes and obvious large masses or vascular anomalies. CT scans and corresponding PA and lateral radiographs were analyzed for lesion detectability, size, and location. In 49% of cases there was no detectable lesion in the AP window on radiographs; a definite AP window lesion was seen in 41%, and 10% were equivocal. Major contributing factors to low detectability of AP window lesions on radiographs include size and, more important, location of the lesion. An additional 45 cases of CT-proved normal AP windows were retrospectively reviewed to determine the false-positive rate of PA and lateral radiographs in detection of AP window lesions: 43 (96%) were classified as negative, the remaining two (4%) as equivocal. Although the AP window is a small space, it is the site of many pathologic conditions; the study results indicate that CT may be an essential procedure for its evaluation.     

Colorectal neoplasms: accuracy of US in demonstrating the depth of invasion

Six normal and 16 neoplastic colorectal specimens were examined with 8.5-MHz ultrasound (US). An articulated system facilitated precise spatial correlation between US and histologic sections. Images were blindly interpreted and then compared with histologic results. All six normal specimen showed five distinct echo layers and were distinguished from neoplastic specimens by all the observers. The central echogenic layer, corresponding to the submucosa, is useful in determining the depth of origin of a neoplasm and the presence of submucosal invasion. US had an accuracy of 92.5% in demonstrating invasion of the submucosa and 77% for invasion of the muscularis externa. For mucosal neoplasms with invasion through the muscularis externa and extension into the subserosal tissues, nearly 90% of US interpretations were correct. High-frequency US may be useful in determining the depth of invasion of mucosal tumors with respect to the submucosa and in differentiating mucosal from extramural masses.     

Annular Array Technology: Application to Cardiac Imaging

Annular array imaging combines desirable features of both phased-array and mechanical transducer technology. Its major advantage is dual-plane electronic focusing, which contributes to deeper penetration, improved lateral resolution, and a thinner tomographic slice. All of these features help to improve image quality in the majority of patients. Areas of improvement observed with annular array imaging in the clinical setting include increased depth of field, better endocardia1 definiton, greater detail of valvular structures, more accurate recording of intracardiac masses, and generally improved signal-to-noise ratio. These aspects of improved image quality make annular array technology an important advance in ultrasonic cardiac imaging.