James F. Holland

Treatment of invasive or metastatic thymoma: Report of eleven cases

The clinical presentation and therapeutic modalities of 11 patients with invasive or metastatic thymoma are presented. Two patients had myasthenia gravis, and five had extrathoracic metastases. Survival exceeded five years in five patients, and four patients remain free of recurrence between 2.1 and 9.0 years after diagnosis. Surgery, with an attempt at complete resection, is the first step of therapy. A second thoracotomy for local relapse or attempt at curative resection was carried out in four patients. Radiotherapy to the mediastinum and/or metastatic sites was given to ten patients with doses ranging from 3600–6000 rads (median = 4500 rads) in the nine nonmyasthenic patients. Inclusion of supraclavicular fossae in the radiotherapy field is recommended because it was a site of relapse in two patients. Systemic therapies were given to eight patients. Objective responses were seen with two of various chemo‐therapeutic regimens. A combination of bleomycin, Adriamycin, cisplatin, and prednisone (“BAPP”) produced a partial remission in two of five patients, during 12 and 4 months, respectively. Two of three patients responded to maytansine as a single agent after failure of other agents. Immunotherapy with intravenous Corynebacterium parvum or intradermal Methanol‐Extraction Residue of bacillus Calmette‐Guérin (MER‐BCG) was ineffective in one patient each. The importance of combined modalities in the management of the disease is emphasized.

Combination chemotherapy with adriamycin and cis-diamminedichloroplatinum in patients with neoplastic diseases

Forty‐eight patients with a variety of advanced solid tumors were treated with a combination of adriamycin 50 mg/m2, and cis‐diamminedichloroplatinum 50 mg/m2, every 2 to 4 weeks. Fifteen patients responded with a greater than 50% regression of measurable tumor: six with lung cancer; one, carcinoma of the breast; one, ovary; one, cervix; one, prostate; one, testis; one, maxillary sinus; and one, salivary gland, plus one patient with chemodectoma and one with adenocarcinoma of unknown primary. Responses lasted 1 to 18 months, with a median of 6 months. An additional six patients, including two with adenocarcinoma of the lung, three with carcinoma of the cervix, and one with embryonal cell testicular carcinoma improved (25–50% regression of the tumor). Toxicity encountered included myelosuppression, azotemia, alopecia, nausea, vomiting, and stomatitis. Severe hematologic toxicity occurred only in those with compromised marrow function or with concurrent active hepatitis. Major potentiation of toxicity by the combination does not appear to have occurred.

Case Report Metastatic Nonfunctioning Parathyroid Carcinoma: Ultrastructural Evidence of Secretory Granules and Response to Chemotherapy

A 69-year-old woman was admitted to the hospital because of recurrent cervical nodules, a large anterior mediastinal mass, and malignant left pleural effusion. Light and electron microscopy of the resected cervical nodules and cytology of the pleural fluid showed findings consistent with parathyroid carcinoma. There was no evidence of hyperparathyroidism on clinical evaluation, multiple serum calcium and phosphorus determinations, skeletal survey, intravenous pyelogram, or radioimmunoassay of intact and carboxy-terminal parathyroid hormones in the serum. Electron microscopy revealed secretory granules in the cytoplasma of malignant cells. A dramatic and complete resolution of the mediastinal mass and pleural effusion occurred after 18 months of chemotherapy with MACC (methotrexate, adriamycin, cyclophosphamide and CCNU).

One-Day VATH (Vinblastine, Adriamycin, Thiotepa, and Halotestin) Therapy for Advanced Breast Cancer Refractory to Chemotherapy

Twenty‐nine postmenopausal patients with metastatic breast cancer refractory to conventional combination chemotherapy underwent treatment with a combination of vinblastine, Adriamycin, thiotepa, and Halotestin given once every 21 days. Thirteen patients (45%) responded with a greater than 50% regression of measurable tumor. Responses occurred in nine of 12 patients (75%) with visceral dominant disease and were recognized in four of 15 (27%) with osseous dominant disease (another 5 improved for a total improvement of 60%). The median duration of response was 11 months. The median survival times were 16 months for responders and eight months for those with progressive disease. Response rate was not affected by age, number of years after menopause, number of metastatic sites involved, or number of systemic treatment modalities previously used, but may have been adversely affected by late stage at original diagnosis, short time from diagnosis, poor response to primary chemotherapy, and dose modification. This combination of drugs is a convenient, tolerable, and effective regimen for treating breast cancer refractory to primary chemotherapy regimens currently in use.

THERAPEUTIC EFFECTIVENESS OF NEURAMINIDASE-TREATED TUMOR CELLS AS AN IMMUNOGEN IN MAN AND EXPERIMENTAL ANIMALS WITH LEUKEMIA*

The immunogenicity of leukemia L1210 in DBA/2 Ha and 6C3HED lymphosarcoma tumor cells in C3H/f mice was significantly increased after treatment with V. cholerae neuraminidase. DBA/2 Ha and C3H/f mice repeatedly immunized with neuraminidase-treated tumor cells rejected subsequent challenge of 10(7) or 10(6) untreated tumor cells, respectively. Based on the 51Cr microcytotoxicity assay, both strains of mice showed strong complement-dependent antibody titers and cell-mediated immunity. Sera and splenic lymphocytes from immunized C3H/f mice neutralized the tumorigenicity of 6C3HED lymphosarcoma and protected the recipient C3H/f mice against the disease. Immune lymphocytes pretreated with anti-theta sera lost their ability to neutralize the tumorigenicity of lymphosarcoma, and they failed to be stimulated by T-cell mitogens. We studied the effectiveness of chemoimmunotherapy in DBA/2 Ha mice with leukemia L1210. A single near optimal dose of BCNU 2 days after implantation of 10(6) tumor cells increased the survival time. A single immunization with 2 X 10(7) neuraminidase-treated L1210 tumor cells 4 days after cytoreductive therapy increased survival and resulted in cures for 50% of animals. Immunization of mice with neuraminidase-treated tumor cells and MER produced indefinite survival in a larger percentage of mice than did either treatment alone. AKR mice with spontaneous leukemia treated with combination chemotherapy sustained an 180% increase in life-span. Combination chemotherapy plus immunization with neuraminidase-treated syngeneic or allogeneic (Gross virus-induced) E2G leukemia cells were highly effective in prolonging the life-span of the immunized leukemic AKR mice. The experimental data led to clinical trials in acute myelocytic leukemia with neuraminidase-treated a-logeneic myeloblasts. Patients with acute myelocytic leukemia were randomized into two groups after remission induction. The median remission duration of patients on sustaining chemotherapy alone was 19 weeks (8 patients), whereas six of nine patients who received neuraminidase-treated allogeneic myeloblasts remain in remission 79-132 weeks. Statistical analysis of the remission duration and survival of patients who received chemoimmunotherapy versus the control group shows highly significant differences.

Vinblastine, adriamycin, thiotepa, and halotestin (VATH): therapy for advanced breast cancer refractory to prior chemotherapy.

Nineteen postmenopausal patients with metastatic breast cancer refractory to conventional combination chemotherapy were treated with monthly cycles with the combination of vinblastine, adriamycin, thiotepa and halotestin. Ten patients (52%) responded with a greater than 50% regression of measurable tumor. The median duration of response was 11.5 months, with 5/10 patients still responding at a mean follow‐up of 10 months. Only 2/10 responders have died with a mean follow‐up of 13.8 months. In contrast, 8/9 nonresponders have died (median survival 6.0 months). Response to therapy was neither in fluenced by site of disease, time interval from diagnosis to primary chemotherapy nor duration of response to primary chemotherapy. No patient was hospitalized because of drug induced toxicity. This combination of drugs is a tolerable effective regimen for patients relapsing after adjuvant chemotherapy or after primary combination chemotherapy for grossly metastatic disease. Cancer 42:2534–2537, 1978.

Phase I study with neocarzinostatin: tolerance to two hour infusion and continuous infusion.

Neocarzinostatin (NCZ), an acidic polypeptide antibiotic, was given to 47 patients with cancer and leukemia, and tolerance to two schedules, a single dose given as a 2 hour infusion and a continuous infusion over 5 days, was investigated. Immediate reactions, including fever, chills, rigor, hypertension and mental confusion, were dose‐limiting for the 2 hour infusion schedule, occurring at 3000 U/m2 and higher. Continuous administration for 5 days eliminated the immediate reactions and then hematological toxicity—often prolonged leukopenia and thrombocytopenia—became dose‐limiting. Other toxicities of NCZ at both dose schedules included anemia, fever and chills, anorexia, nausea and vomiting, hepatic dysfunction, azotemia, hypophosphatemia, aminoaciduria, stomatitis, phlebitis and/or cellulitis at the venous infusion site and pruritus. Patients with solid tumors who had received little or no prior chemotherapy and had good bone marrow reserve tolerated up to 6000 U/m2/24 hours × 5 days. One patient with previously treated acute myelocytic leukemia was induced into a good partial remission lasting 10 weeks. Cancer 42:1670–1679, 1978.

Comparison of the interaction of antineoplastic aminoanthraquinone analogs with DNA using competitive fluorescence polarization

1,4-dihydroxy-5-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione one (NSC 287836) and 1,4-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione diacetate (NSC 287513) have shown activity against solid tumors and are now in Phase I clinical trials. Fluorescence polarization was used to determine the extent of inhibition of the binding of acridine orange to DNA (Richardson, Boboz, Holland, Res. Comm. Chem. Pathol. Pharmac. 27, 497, 1980). Displacement of 50% of acridine orange from calf thymus DNA was obtained with 0.18 micro M of NSC 287836 while 0.52 micro M of NSC 287513 was needed to displace an equivalent amount of acridine orange. NSC 287513 showed preference for polynucleotides of high adenine + thymine content while NSC 287836 did not. Analogs lacking both hydroxyethylaminoethyl-amino side chains did not displace acridine orange.

Implications of 5′-Nucleotidase and its Inhibitor for Cellular Aging and Cancer

The concept of using neoplastic cells as a control to study cellular aging has been generally accepted and become very popular in recent years. Using this approach to study the change of 5′-nucleotidase during the aging of normal cells in vitro has led us to a number of consistent findings, including the discovery of an inhibitor for 5′-nucleotidase (Sun et al., 1975; Sun, et al., 1979; Sun, et al., 1982; Sun, et al., 1983, Lee, et al., 1985). In this article we review our study of using neoplastic cells as a control to study 5′-nucleotidase and its inhibitor in cellular aging and the previous work of others on 5′-nucleotidase related to cancer and cell proliferation. The criteria for using cancer cells as a control to study cellular aging are defined. A hypothesis is proposed on the biochemical role of 5′-nucleotidase and its inhibitor in the control of the proliferation and aging of normal cells and the lack of this control in neoplastic cells.

Future prospects in lymphoma and leukemia.

Possible advances in leukemias and lymphomas can, in my opinion, derive from continued consideration of viral etiopathogenesis, possibly demonstrated by therapeutic impact of antiviral therapy. Terminology is in constant flux, and a classification based on biochemical (such as asparagine dependence) and immunologic (such as surface marker) characteristics should displace older terms such as chronic and acute. There is a constellation of neoplasms of lymphoid cells and their derivatives—leukemias, lymphomas, and plasmacytomas which need an integrated taxonomy. New diagnostic tests, new strategies of adapting therapy to tumor cell kinetics perturbed by the preceding treatment, and interesting clinical and preclinical combinations of drugs provide new basis for favorable expectations. Immunotherapy is just emerging as a potent therapeutic tool. A technique for standardizing clinical results of different institutions to the age and sex of the population who develop the disease in question is much needed. Controls in trials of leukemias and lymphomas are found to be dispensable if one is measuring qualitative differences; for quantitative assessment of remission frequency or response duration, however, controls are requisite.