The treatment of relapsed or refractory intermediate grade non-Hodgkin's lymphoma with autologous bone marrow transplantation followed by cyclosporine and interferon.

In an effort to decrease the relapse rate following autologous bone marrow transplantation for non-Hodgkin's lymphoma, patients were given cyclosporine and interferon following autologous marrow transplantation. Forty patients with intermediate grade non-Hodgkin's lymphoma that was relapsed or refractory to standard chemotherapy underwent autologous marrow transplantation. The preparative regimen consisted of cyclophosphamide 6.8 g/m2, etoposide 1600 mg/m2, and carmustine 400 mg/m2 over 4 days followed by reinfusion of bone marrow. Intravenous cyclosporine was started on day -1 as a 16 mg/kg loading dose followed by 3.6 mg/kg/day for 28 days after transplant. Patients were begun on alpha-interferon (starting dose, 0.5 million units s.c. every other day) following platelet engraftment (median day 24 post-transplant) and continued on 1.5 million units s.c. daily for 2 years. Regimen-related toxicities resulted in four (10%) deaths. Twenty-one (53%) patients developed marked erythema of the palms, soles, and arms. Biopsies of the erythema were consistent with grade I GVHD. Patients who did not develop rashes were not biopsied. The erythema persisted for a median of 10 days and resolved in all cases without treatment. Visceral GVHD was not apparent. All patients have been followed for a median of 24 months (range 12-54 months). To date, only five patients (13%) have relapsed after bone marrow transplant. Multivariant analysis could not identify risk factors for relapse post-transplant. Disease-free survival of all patients is 77% (95% confidence interval, 67-93%). The results of this pilot study suggest that the administration of cyclosporine and interferon may decrease the relapse rate of relapsed/refractory non-Hodgkin's lymphoma following autologous bone marrow transplantation.

Loin pain hematuria syndrome.

LPHS is a disorder of obscure etiology and inconsistent pathology whose most prominent clinical feature is severe flank pain. Were it not for the hematuria which nearly always accompanies the pain, there would be no specific objective correlate of the syndrome. In this sense, it is similar to a number of chronic conditions which have inspired heated controversy about their very existence as discrete diseases. As the foregoing discussion of pathogenesis, pathology and diagnosis illustrates, with respect to two important characteristics of a 'prototypical' disease--specificity and mechanism--LPHS falls far short. This, coupled with a rather unimpressive 'visible' concomitant of the symptoms (hematuria), has inspired skepticism and even suspicion in some physicians confronted with the demands for analgesia by these patients. On the part of physicians who have been involved in the care of these patients over time, however, there is no doubt that they suffer from a bona fide illness, if not a disease. The severity of the illness is evinced by the rather extreme measures that have been taken in its treatment; e.g., surgical denervation of the kidney, nephrectomy, autotransplantation. Only the last of these appears to offer the hope of enduring pain relief while preserving renal function, but the risk of pain recurrence in the autograft may limit the usefulness of this procedure. Accordingly, narcotic analgesics may need to be the treatment of first and last resort. Development of specific treatment will depend upon elucidating the pathogenesis of the disorder. The available data suggest further investigation of the role of vasoactive mediators, and the coagulation and immune systems.

Propranolol for the treatment of cyclosporine-induced headaches.

We studied whether small doses of propranolol given orally have an effect on headaches that are associated with intravenous cyclosporine therapy. In seven patients who had severe cephalalgia associated with intravenous cyclosporine post-bone marrow transplant, oral propranolol promptly relieved the symptoms in four patients. Intravenous propranolol was not effective in one patient who was unable to take oral medications. Propranolol should be considered as an alternative to chronic narcotics in patients with headaches due to cyclosporine.

The effect of changes in medical knowledge on examination performance at the time of recertification.

The purpose of this paper was to determine if the decline in performance with time since completion of training on the 1980 ABIM Recertification Examination can be explained by a difference in performance on items testing different types of knowledge. Results showed that candidates further out of training performed less well on items testing new or changing knowledge, while performance on items testing stable knowledge was relatively constant across age groups.

Promotion of lung tumor colonization in mice by the synthetic thrombin inhibitor (no. 805) and its reversal by leech salivary gland extracts.

The role of anticoagulation per se in the reduction of experimental or spontaneous metastasis still remains to be determined, as shown by the conflicting results reported by the literature using different conventional anticoagulants. A new compound has been synthesized (compound no. 805) which prolongs or suppresses coagulation via specific inhibition of thrombin and its possible use in a model of experimental metastasis to clarify the role of anticoagulants in tumor spread was investigated. Contrary to our expectations, this compound increased rather than decreased the number of lung colonies induced by intravenous injections of a variety of murine neoplasias. Studies of the mechanism of this effect indicated that the compound increases retention of tumor cells by the lung without apparent impairment of the natural cell immune system, suggesting that the synthetic thrombin inhibitor may enhance vascular attachment of tumor cells. The promoting effect of compound no. 805 on metastasis was totally reversed by the administration of leech salivary gland extracts, which appear to protect capillaries from damage produced by cyclophosphamide, as revealed by other studies.

Leech salivary gland extract from Haementeria officinalis, a potent inhibitor of cyclophosphamide- and radiation-induced artificial metastasis enhancement.

Studies were designed to determine whether salivary gland extract (SGE) from the leech Haementeria officinalis could inhibit enhancement of lung tumor colonization induced by pretreatment of mice with cyclophosphamide (CY) or local thoracic irradiation (LTI). Tumor nodules in the lung were generated by i.v. injections of T241 sarcoma and FSA fibrosarcoma cells into syngeneic C57BL/6 and C3Hf/Kam mice, respectively. CY (200 mg/kg) was given i.p. 1 or 4 days prior to i.v. injection of tumor cells. In other mice, a single dose of 1000 rads of LTI was given 1 day before tumor cells. Three i.v. or i.p. injections of SGE at doses of 600 to 800 micrograms of protein per injection given at 2-hr intervals between 2 hr before and 4 hr after CY, LTI, or tumor cell injection strongly inhibited and, in some cases, abolished the artificial metastasis enhancing effect of CY and LTI. SGE was similarly effective in inhibiting the enhancement of lung colonization when given before or after cytotoxic agents. Using [125I]iododeoxyuridine-labeled tumor cells, it was observed that SGE did not affect the initial lodgement of tumor cells in the lung, but it greatly facilitated their subsequent release from the lung. In normal mice, the SGE was active when given on the day or 1 day before but not when given 4 days before tumor cells. The antimetastatic effect of SGE was ascribed to its anti-platelet-aggregating, anticoagulant, and antiproteolytic enzyme activities.

Crystallocryoglobulinemia resulting from human monoclonal antibodies to albumin.

Two patients had a previously unrecognized form of crystallocryoglobulinemia. Their clinical presentations were similar, consisting of necrotizing vasculitis and purpura involving the legs. Analysis of each cryoglobulin complex showed that two components, albumin and a monoclonal IgG-lambda, were present, and both components were needed in a fixed ratio for precipitation. In addition, cryoprecipitation occurred in serum, but not plasma, due to citrate inhibition of complex formation. Our findings suggest that the monoclonal IgGs have the properties of antibodies directed specifically against a calcium-dependent antigenic site on human albumin, and that the resultant IgG-lambda-albumin immune complexes crystallized in the cold.

Inhibition of lung tumor colonization by leech salivary gland extracts from Haementeria ghilianii.

Salivary gland extract from the South American leech Haementeria ghilianii, administered i.v. on the same day as the i.v. inoculation of T241 sarcoma cells, completely suppresses colonization of the mediastinal lymph nodes and markedly reduces the number and size of lung tumor colonies produced by this tumor. Additional studies indicate that the extract contains various types of proteinase inhibitors and has the capacity to inhibit clotting and platelet aggregation by tumor material and collagen. Although not yet proved by direct evidence, these activities may be involved in the inhibitory effect of lung tumor colonization by the leech extract.