Toxicity and antitumor activity of cis-bis-carboxylato(trans-R,R-1,2-diaminocyclohexane) platinum(II) complexes entrapped in liposomes.

A new series of highly lipid-soluble cis-bis-carboxylato(trans-R,R-1,2-diaminocyclohexane)platinum(II) complexes were synthesized and characterized by their elemental analysis and by various spectroscopic techniques [infrared (IR), 195pt nuclear magnetic resonance (NMR)]. cis-bis-Neopentanoato(trans-R,R-1,2-diaminocyclohexane)platinum(II ) (NPDP), cis-bis-neodecanoato(trans-R,R-1,2-diaminocyclohexane)-platinum(II ) (NDDP), and cis-bis-n-decanoato(trans-R,R-1,2-diaminocyclohexane)-platinum(II) (DEDP) complexes were entrapped in multilamellar vesicles composed of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG) at a 7:3 molar ratio and tested for toxicity and antitumor activity. The entrapment efficiency of the liposomal platinum (L-Pt) complexes (L-NPDP, L-NDDP, L-DEDP) was greater than 95%, and the stability in 0.9% NaCl solution at 4 degrees C was greater than 95% at day 14 in each case. The LD50 values of L-NPDP, L-NDDP, and L-DEDP when injected i.v. were 30, 54, and 150 mg/kg, respectively. L-NPDP, L-NDDP, and L-DEDP had no significant nephrotoxicity [as evidenced by a lack of elevated blood urea nitrogen (BUN) levels]. The percentages of T/C obtained after a single i.p. injection of the optimal dose of L-NPDP, L-NDDP, and L-DEDP tested against L1210 leukemia were 175%, 187%, and 212%, respectively [160% for cisplatin (CDDP)]. When a multiple i.p. injection schedule was used (on days 1, 5, and 9), L-NPDP, L-NDDP, and L-DEDP were more active than CDDP (percentage of T/C: 312%, 312%, 277%, and 220%, respectively). When injected i.v., only L-NDDP showed significant activity against L1210 leukemia i.v. (percentage of T/C: 186%). L-NDDP and L-DEDP were markedly active against L1210 leukemia resistant to CDDP (percentage of T/C: 200% and 145% vs 112% for CDDP). L-NPDP, L-NDDP, and L-DEDP also had good activity against i.p. B16 melanoma when they were injected i.p. on days 1, 5, and 9 (percentage of T/C: 206%, 225%, and 306%, respectively). L-NDDP and L-DEDP were more effective than CDDP in inhibiting the growth of liver metastases of murine M5076 reticulosarcoma, whereas L-NPDP was not active. The results obtained to date suggest that L-NDDP is the best L-Pt-complex candidate for further developmental studies.

Soluble glucan and lymphokine-activated killer (LAK) cells in the therapy of experimental hepatic metastases.

Previous studies have indicated the efficacy of adoptive immunotherapy utilizing recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells in the treatment of advanced neoplastic disease. However, this therapeutic approach is associated with considerable toxicity, primarily due to the systemic administration of rIL-2. The present study was undertaken to determine the efficacy of a newly developed water-soluble glucan, when administered in combination with LAK cells, in the therapy of experimental hepatic metastases. Mice were challenged subcutaneously (1 X 10(4) cells) with reticulum cell sarcoma M5076 on day 0. Therapy was initiated on day 15, when a palpable primary tumor mass and hepatic micrometastases were evident, and continued at 3-day intervals up to day 54. Sarcoma-bearing mice received glucan (250 mg/kg) intravenously, either alone or in combination with LAK cells (1 X 10(7)/mouse). Control mice received 5% (wt/vol) dextrose in water. Glucan-LAK cell therapy significantly suppressed primary tumor growth, inhibited the progression of hepatic metastases and prolonged survival in sarcoma-bearing mice. Splenocytes, incubated with rIL-2 for 72 h, exhibited significant natural killer (NK) cell activity and were cytotoxic to sarcoma cells in vitro. Glucan-LAK cell administration resulted in significant increases in splenic NK cell activity and Kupffer cell-mediated tumoricidal activity. In addition, bone marrow proliferation was enhanced following the co-administration of glucan and LAK cells. Due to its nontoxic nature and immunostimulating properties, soluble glucan may prove to be an attractive biological response modifying agent for utilization in adoptive immunotherapy of advanced neoplastic disease.

Computed tomography of posterior pararenal and properitoneal metastases.

Identification of the retroperitoneal fascial planes with modern computed tomographic scanners allows for precise localization of pathologic processes in the individual compartments of the retroperitoneum. Metastatic disease to the posterior pararenal space or properitoneal space in 6 patients is reported. Two patients had diffuse histiocytic lymphoma and 4 had metastatic melanoma.

Isolated radial nerve palsy due to metastasis from a primary malignant lymphoma of the brain.

A malignant lymphoma of the reticulum cell sarcoma variety developed in the right radial nerve of a 60-year-old man 3 years after he had presented with a primary malignant lymphoma of the brain. Serial evaluations and metastatic workups over several years failed to demonstrate evidence of extraneural metastasis.

The anti-tumor effect of recombinant interferon alpha or gamma is influenced by tumor location.

The in vivo anti-tumor effects of a recombinant human hybrid interferon alpha, rHuIFN-alpha A/D, and recombinant murine interferon gamma (rMuIFN-gamma) were evaluated against experimental hepatic metastases and s.c. tumor growth of the murine reticulum cell sarcoma M5076. The 2 interferons were equally active in preventing experimental hepatic metastases. However, the interferons differed in their relative ability to influence the growth of the same tumor when treatment was initiated following injection of tumor cells. Greater efficacy was obtained in the treatment of metastatic foci in the liver with rHuIFN-alpha A/D, while rMuIFN-gamma was more active in the therapy of an s.c. growing M5076 tumor. These results demonstrate that the same tumor growing at different sites can have different relative sensitivities to IFN-alpha and IFN-gamma.

Chemoimmunotherapy of experimental hepatic metastases.

Previous studies from our laboratory have demonstrated that particulate glucan is efficacious in the therapy of a syngeneic murine reticulum cell sarcoma (M5706), which specifically metastasizes from its primary site to the liver. The present study was undertaken to examine the therapeutic efficacy of a newly developed soluble glucan, in combination with cyclophosphamide in the treatment of hepatic metastatic disease. Male C57Bl/6J mice were injected subcutaneously on Day 0 with 1 x 10(4) sarcoma cells. Glucan (200 mg per kg i.v.), cyclophosphamide (45 mg per kg i.p.) or glucan and cyclophosphamide were administered beginning on Day 20, when hepatic metastases were evident, and continued at 3-day intervals up to Day 50. Combined therapy with glucan and cyclophosphamide resulted in reduction of hepatic metastatic lesions on Day 36, compared to control. Survival data revealed that the combination of glucan and cyclophosphamide significantly (p less than 0.001) extended median survival time and the time to 100% mortality in an additive fashion, when compared to either therapy alone. Glucan-cyclophosphamide therapy was also effective in decreasing primary tumor weight to a level that was significantly (p less than 0.05) less than when therapy was initiated. In vitro studies revealed that Kupffer cell tumoricidal activity against sarcoma was increased (p less than 0.05) following glucan and cyclophosphamide. Glucan and cyclophosphamide also enhanced bone marrow proliferation and splenocyte response to mitogens in vitro. Additionally, glucan was observed to exert a direct cytostatic effect on sarcoma in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Macrophage content of spontaneous metastases at different stages of growth.

The macrophage content of spontaneous metastases has been quantified morphometrically for a panel of rodent tumors at different stages of metastatic tumor growth. Using a histochemical technique to selectively stain macrophages, we have evaluated the relative content of macrophages in spontaneous pulmonary metastases from the 13762NF MTLn3 rat mammary adenocarcinoma and the B16-BL6 mouse melanoma, as well as in spontaneous hepatic metastases from the M5076 mouse reticulum cell sarcoma and from autochthonous reticulum cell sarcomas in SJL/J mice. Between 112 and 254 separate, individual metastases were evaluated for each of these tumors. The data show that the relative macrophage content of very small metastases is high. However, as metastases grow the relative macrophage content falls, reaching uniformly low levels by the time the metastases are 0.5 mm in diameter. These data are very similar to our previous observations on experimental metastases where the same pattern of high macrophage content in small metastases was seen. Finding the same pattern in more slowly growing, spontaneous metastases of tumors derived from several different tissues and in two species suggests that the fall in relative macrophage content is not a phenomenon isolated to experimental metastases, a particular site, or a tissue of origin for the tumor. The relative decrease in macrophage content may thus be a general phenomenon with important implications for immunotherapy directed to enhancing the tumoricidal activity of macrophages.

The hand in metastatic disease.

A review of the world literature shows 163 cases of tumors metastatic to the hand; we report three additional cases. The incidence of primary tumors elsewhere metastasizing to the hand is a little more than 0.1%. In over 16% of cases, a tumor of the hand was the first manifestation of a primary tumor elsewhere. The lung is the chief source, followed by the breast and the kidney. The terminal phalanges are the most frequent site of metastasis, followed by the metacarpals and the proximal phalanges. The mechanism of dissemination remains obscure.

Limbic lymphoma.

Two cases of metastatic malignant lymphoma confined to the limbic-hypothalamic region are presented. The non-specific nature of the neurological symptoms associated with these lesions such as memory loss, impotence and confusion made neurological localization of the disease process difficult. While non-contrast computed tomography (CT) was unremarkable, contrast CT was diagnostic, showing bilateral homogenous enhancement of specific limbic-hypothalamic structures without significant mass effect. Since lymphomatous involvement of the limbic-hypothalamic area tends to be infiltrative without attendant mass effect, detection of metastasis may be elusive unless special attention is directed to this region. As lymphoma is often chemoresponsive and highly radiosensitive, early recognition of limbic-hypothalamic involvement of this disease is important.

MACOP-B chemotherapy for the treatment of diffuse large-cell lymphoma.

Between April 1981 and May 1984, 61 patients with advanced diffuse large-cell lymphoma completed treatment with MACOP-B (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin), an innovative pilot chemotherapy program emphasizing weekly treatment, antibiotic prophylaxis, daily corticosteroid treatments, and brief duration (12 weeks). Fifty-one patients (84%) achieved a complete response and 10 patients (16%) had a partial response. Over a median follow-up after treatment of 23 months, the actuarial overall survival for the entire group has been 76%; for complete responders the relapse-free survival has been 90%. Toxicity was modest with one treatment-related death and seven episodes of serious infection. The most frequent toxicity was mucositis. Thus, MACOP-B is an effective treatment for large-cell lymphoma that can be delivered in 12 weeks with an acceptable incidence of toxicity. This regimen can achieve results similar and possibly superior to those of other presently used regimens of longer duration.

Therapeutic efficacy of glucan in a murine model of hepatic metastatic disease.

Glucan, a particulate beta-1,3-polyglucose immunomodulator, was evaluated for its ability to modify hepatic metastases and survival in mice with reticulum cell sarcoma. Sarcoma M5076 cells were injected subcutaneously (1 X 10(5) cells) into syngeneic C57BL/6J male mice. On Day 20, histopathological studies indicated the presence of hepatic micrometastases. At this time, glucan (0.45 mg per mouse) or dextrose was administered intravenously. Therapy was continued at 3-day intervals up to Day 50. By Day 36 postchallenge, the glucan-treated group, when compared to the control group, showed a marked decrease in hepatic metastases, both grossly and histopathologically. A significant inhibition in the growth of the primary tumor also occurred. Plasma clearance of bromosulfophthalein measured on Day 36, denoted that glucan therapy maintained hepatic parenchymal cell functional integrity, while a 4-fold impairment in bromosulfopthalein removal was observed in control mice. Glucan-treated mice showed a 28% (p less than 0.05) long-term survival. In contrast, control mice showed a 100% mortality by Day 42 postchallenge. Studies to evaluate the mechanism of the anti-metastatic action of glucan indicated that 8 days after glucan administration, isolated hepatic macrophages were significantly more cytotoxic to sarcoma cells in vitro than were normal Kupffer cells. At this time, the cytotoxic activity of peritoneal and splenic macrophages from glucan-treated mice were unaltered. Additionally, co-incubation of particulate glucan with diverse populations of normal or tumor cells in vitro indicated that glucan exerted a direct cytostatic effect on sarcoma and melanoma cells and, in contrast, had a proliferative effect on normal spleen and bone marrow cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary and secondary histiocytic lymphoma of the brain: CT features.

The authors examined 19 patients with diffuse histiocytic lymphoma of the brain, including 8 with primary disease and 11 with secondary disease. Both primary disease and secondary disease involving the brainstem and deep nuclei exhibited the characteristic CT appearance, consisting of a large, solid, homogeneously enhanced mass with varying amounts of edema. However, most secondary lymphomas outside the brainstem and basal ganglia contained large areas of low attenuation consistent with necrosis. Multifocal lesions were seen only in patients with secondary lymphoma. Systemic chemotherapy for extracranial lymphoma had no effect on the CT appearance of intracranial lesions. The authors suggest that these "unusual" CT patterns are actually typical of a distinct subset of histiocytic lymphomas.

Persistent Epstein-Barr virus infection and a histiocytic sarcoma in a renal transplant recipient.

Lymphomas occurring in renal transplant recipients are mostly large cell non-Hodgkin's lymphomas (B-cell-derived). A sarcoma with all morphologic, immunohistochemical, and ultrastructural characteristics of a tumor of the mononuclear phagocytic system (MPS) developed in a 23-year-old woman 1 year after renal transplantation. Anti-Epstein-Barr-virus antibody titers proved to be exceptionally high, even in pretransplant sera. Tumor-derived cells proved to be positive for Epstein-Barr nuclear antigen (EBNA), and hybridization showed multiple copies of Epstein-Barr virus (EBV)-DNA, suggesting a relationship between this tumor and EBV. More widespread use of immunochemical and histochemical diagnostic techniques might detect more cases, which, until now, have probably been diagnosed as B-cell-derived immunoblastic lymphomas.

Computed tomography of malignant lymphoma of the brain.

Correct diagnosis of malignant lymphoma of the brain and differentiation from malignant glioma, metastases, meningeoma and infection is often difficult. With the aim of finding characteristics pointing to the correct diagnosis all CT examinations from 16 patients with primary or secondary lymphoma of the brain were analysed. In 3 of 10 patients with primary lymphoma and 4 of 6 with secondary lymphoma the tumors were multiple. No differences between the CT appearance of primary and secondary lymphoma were found except that secondary lymphomas were generally smaller and more often multiple. The lymphomas were most often well demarcated, had a density equal to or slightly higher than normal brain tissue, were surrounded by no or slight edema and showed a moderate to marked contrast enhancement. The tumors were situated in the basal ganglia, corpus callosum or cerebellum in high frequency and were always in contact with either the ependyma of the ventricles or the superficial subarachnoid space. A tumor with widespread infiltration of the surroundings of the ventricles seen in 6 patients in the material is highly characteristic of lymphoma.

Non-Hodgkin lymphoma: computed tomographic demonstration of unusual extranodal involvement.

With the advent of computed tomography, lymphomatous involvement of sites other than lymph nodes is being seen with increasing frequency. Review of computed tomographic scans in 400 patients with newly diagnosed or recurrent non-Hodgkin lymphoma revealed 37 patients to have involvement of 56 unusual sites below the diaphragm: psoas/iliacus muscle (16 patients), kidney (13 patients), pancreas (5 patients), adrenal (4 patients), skin/subcutaneous tissue (4 patients), abdominal wall musculature (4 patients), peritoneum (4 patients), omentum (3 patients), and female reproductive tract (3 patients). These were mostly seen in patients with lymphomas of diffuse architecture, especially diffuse histiocytic lymphoma. Concomitant retroperitoneal and/or mesenteric adenopathy was very common; extranodal involvement was rarely the only site of initial or recurrent lymphoma.

Cerebral disorders detected by EEG and missed by CAT scan.

EEG recordings of the electrical seizure activity during unilateral non-dominant (right) hemisphere electroconvulsive therapy reveal three phases of activity: (1) Phase I initial 14-22 Hz rhythmic activity; (2) Phase II arhythmic polyspike activity; and (3) Phase III rhythmic 2 1/2-3 1/2 Hz. spike/polyspike-wave activity. The Phase II polyspike activity appears as an orderly march beginning in the right anterial temporal area. The Phase II activity is of higher voltage on the right side compared to the left side. The Phase III activity ends abruptly with a nearly isoelectric tracing (the "fit switch").

[Intra-thyroid metastases (author's transl)]. / Les métastases intrathyroïdiennes.

Four cases with intra-thyroid metastases which simulate a primary tumor of the gland are reported. These metastatic lesions are probably more frequent than generally accepted. Their clinical discovery is quite frequent in patients with a renal neoplasm and is in those cases often the presenting feature of the primary tumor. Ablation of the thyroid gland is often necessary to make a correct diagnosis and to prevent local compression symptoms. This intervention is indicated whenever deemed necessary unilateral thyroid lobectomy is preferable to total ablation since it achieves its goal with a lower mortality. Postoperative radio- and chemotherapy might be added as indicated.