Concomitant renal cell carcinoma and chronic myelogenous leukemia: use of a targeted approach.

Numerous therapeutic options have been introduced for metastatic renal cell carcinoma (MRCC) in recent years, including monoclonal antibodies such as bevacizumab and small-molecule tyrosine kinase inhibitors such as sunitinib and sorafenib. Similarly, several other small-molecule inhibitors-including imatinib, dasatinib, and nilotinib-have been approved for the treatment of chronic myelogenous leukemia (CML). The combination of these targeted agents is an area of intense clinical investigation. Here, we describe a patient diagnosed with MRCC)while on imatinib therapy for cml. Treatment of this patient with the combination of bevacizumab and imatinib led to a 6-month period of stable disease, with no treatment-related adverse events. More extensive clinical exploration of this combination of agents may therefore be warranted.

Efficacy of pegylated-liposomal doxorubicin in the treatment of AIDS-related Kaposi's sarcoma after failure of standard chemotherapy.

PURPOSE: To determine the efficacy and safety of pegylated-liposomal doxorubicin in patients with AIDS and Kaposi's sarcoma (AIDS-KS) who experienced failure of standard chemotherapy. METHODS: Fifty-three patients with advanced AIDS-KS who experienced disease progression or intolerable toxicities while receiving standard doxorubicin/bleomycin/vincristine (ABV) or bleomycin/vincristine (BV) chemotherapy were identified from a cohort of patients who were then treated with pegylated-liposomal doxorubicin. Patients received 20 mg/m2 pegylated-liposomal doxorubicin (Doxil; Sequus Pharmaceuticals, Inc, Menlo Park, CA) every 3 weeks. RESULTS: Nineteen patients (36%) had a partial response (PR) and one patient had a clinical complete response (CCR). The median duration of response and time (from study entry) to treatment failure were 128 and 134 days, respectively. Of 28 patients who experienced disease progression while receiving combination regimens that contained standard doxorubicin, the PR rate was 32%, which suggests that the pegylated-liposomal encapsulation increases the therapeutic effect of doxorubicin. Patients obtained clinical benefits such as flattening of lesions (48%), improved lesion color (56%), relief of pain (45%), and loss of edema (83%). Forty-nine percent of patients had more than one clinical benefit. The most common adverse effect was leukopenia, which occurred in 40% of patients. Only 15% of patients had nausea and/or vomiting, none of which was severe; 9% experienced alopecia, also generally mild. CONCLUSION: Pegylated-liposomal doxorubicin offers a new alternative for treatment of patients who have experienced failure of standard chemotherapy for AIDS-KS.

Detection of trisomy 8 by fluorescence in situ hybridization on bone marrow smears from patients with subtle myelodysplastic changes.

Trisomy 8 is the most common hyperdiploid numerical chromosomal abnormality that is found in myelodysplastic syndromes (MDSs). We explored the utility of combining fluorescence in situ hybridization interphase cytogenetics with routine morphologic analysis to characterize cases for which signs and symptoms were suggestive of MDS in which dysplastic changes were insufficient for a definitive diagnosis. Hybridization with a chromosome 8-specific centromeric probe was performed on bone marrow smears that were obtained from four patients with cytogenetically documented trisomy 8 and hematopoietic cell atypia that was suggestive but not diagnostic of MDS. Signals that corresponded to trisomy 8 were detected in 14.6% to 32.2% of the cells (detection threshold of trisomic clone, 5.0%). The conditions of two patients have remained hematologically stable with no disease progression, and these two patients are now considered to have refractory anemia. The conditions of the other two patients rapidly progressed to morphologically recognizable MDSs. This study demonstrates that the detection of trisomy 8 by fluorescence in situ hybridization can provide useful supplemental information in bone marrow specimens with morphologic changes that are suggestive of but not sufficient for a diagnosis of MDS. It should prove to be useful when standard cytogenetic analysis has not been performed or when it is not readily available.

Illness-related and treatment-related factors in psychological adjustment to breast cancer.

Seventy-eight breast cancer outpatients were interviewed and their medical records were reviewed to document illness-related and treatment-related factors associated with psychosocial adjustment. Poor prognosis and more radical surgery both independently predicted poor psychological adjustment. The effect of type of surgery appeared to be mediated by the patient's sense of disfigurement and by changes in the sexual and affectional patterns in the marriage, rather than by prognosis or disability. Degree of dysfunction and whether or not the patient had radiation therapy or chemotherapy had no independent effects on psychological adjustment. Results point to the problematic psychosocial outcomes associated with mastectomy and, more generally, to the illness- and treatment-related factors that may place a breast cancer patient at risk for psychosocial adjustment problems.

Breast self-examination among diagnosed breast cancer patients.

The practice of breast self-examination (BSE) was explored by personal interview in a sample of women with diagnosed breast cancer. Despite physician recommendations to practice BSE, only 43% of those interviewed were examining themselves regularly, a figure that is little different from that of the general population. Predictors of BSE were age (older women were less likely to practice) and practice of BSE before diagnosis. Factors contributing to nonpractice were judged to be: (1) the patients' beliefs that occasional examinations by physicians are a sufficient substitute for BSE; (2) the patients' perceptions that BSE is discretionary and not truly "medical"; and (3) the fact that BSE may raise patients' anxiety over cancer without affecting its likelihood. It was concluded that the practice of BSE among diagnosed patients could be increased if physicians stress its importance and provide systematic instruction or reinstruction in its practice.

Phase I study of L-alanosine using a daily x 3 schedule.

L-Alanosine is an antitumor antibiotic that inhibits adenine synthesis. It showed significant activity in animal tumor systems. Using a daily x 3 dose schedule every 3 weeks, we performed a phase I study to determine toxicity in man. Doses of 8-375 mg/m2/day x 3 were administered to 49 patients in 117 courses. The dose-limiting toxic effect was mucositis. Vomiting, infrequent myelosuppression, fever, headache, malaise, and blood pressure changes were detected at higher dose levels. No antitumor activity was noted. Toxicity with this regimen is acceptable. A phase II study with doses of 250 mg/m2/day x 3 every 3 weeks is feasible.

A rapid automated stathmokinetic method for determination of in vitro cell cycle transit times.

To provide a rapid method for examining cell cycle dynamics, we utilized continuous exposure of Chinese hamster ovary cells and human colon cancer cells to colcemid to block cycling cells in metaphase, suppressing re-entry into G1. Changes in cell cycle compartment distribution were monitored by DNA flow cytometry. Analysis of the rate of G2 + M compartment accumulation after addition of colcemid permitted calculation of all cycle transit parameters. These compared favorably with data in the same cell lines determined by the fraction of labeled mitoses technique. Serial assessment of DNA flow cytometry after addition of colcemid permits rapid quantitation of cycle traverse rates.

Predicting relapse of human leukemia by means of premature chromosome condensation.

We attempted to determine whether the technique of premature chromosome condensation (PCC) could be used to predict relapse in patients with acute leukemia in complete remission. Nineteen patients received chemotherapy and were studied serially with the PCC technique. Of the 19 patients in this pilot study, 14 relapsed, and the PCC technique predicted relapse in 11 of these 14. The median time from an elevation in the fraction of G1 cells in the late G1 phase (a high proliferative-potential index) to the development of clinical evidence of relapse was 3.5 months. On the other hand, the median time from a low proliferative-potential index to relapse or to the end of the study was eight months. The incidense of false-positive or false-negative measurements was low. Two patients had high index values just before chemotherapy, and remission was estimated to be prolonged by 2.5 and six months by our therapeutic protocol. These results suggest that the PCC technique is useful and accurate in the early prediction of relapse in human leukemia.

Flow cytometry of DNA content in human bone marrow: a critical reappraisal.

Because cytokinetic studies of the human bone marrow aspirate as a prognostic factor and as a monitor of drug perturbation are frequently inconsistent, we investigated reproducibility of DNA distribution measured by flow cytometry of DNA content in patients with morphologically normal bone marrow. In 15 patients, correlation was noted between DNA distributions simultaneously obtained on right and left iliac crest bone marrow aspirates (r = .588), although considerable variation in individuals was encountered. Much better reproducibility (r = .879) was achieved using bilateral core biopsy of bone marrow in these same patients. In 60 samples, comparison of DNA distribution between bone marrow aspirate and simultaneously obtained biopsy revealed higher relative proportions of S and G2 + M phase cells in biopsies (p less than 0.001), suggesting peripheral blood contamination of aspirate material. Brisk shaking of biopsy specimens in saline expelled a representative sample in the supernatant that could be subjected to simultaneous cytomorphological and cytokinetic analysis. To improve reproducibility of DNA content determinations in normal human bone marrow, bone marrow biopsy should be utilized.

Necrotizing colitis in patients with cancer.

Necrotizing lesions of the colon occur in patients with malignancy. We identified 26 patients with cancer (23 with acute leukemia and three with solid tumors) who died from necrotizing colitis. Autopsies revealed three pathologic categories: pseudomembranous colitis in 69 per cent, agranulocytic colitis in 19 per cent and ischemic colitis in 12 per cent. Most died from sepsis. A comparison of characteristics was made with a control population matched for diagnosis, age, cause of death and duration of neoplasia. Nearly all patients in both groups had fever and were granulocytopenic secondary to chemotherapy. Most received antineoplastic and antimicrobial regimens during the month prior to their terminal illness. Abdominal pain and distention, stomatitis and necrotizing pharyngitis were frequently associated with colitis. Hyperbilirubinemia was a frequent late complication in those with colitis and the control group. Single and multiorganism septicemia were found more frequently in patients with colitis. As antemortem diagnosis was unusual, aggressive attempts at diagnosis are necessary to assess the true incidence of this disorder and the best therapy.

Acute myelomonocytic leukemia following a chemotherapeutic regimen for metastatic sarcoma.

Acute myelomonocytic leukemia developed in a patient 18 months after treatment with cyclophosphamide, vincristine, adriamycin, and DTIC, a chemotherapeutic regimen used for the treatment of metastatic sarcoma. The patient had had no prior history of radiation. More than 400 patients received this treatment and none of them developed leukemia. The occurrence of leukemia in this relatively short period of time may have been caused by the combined chemotherapeutic agents. However, confirmation of this will require long-term followup studies in cancer patients receiving chemotherapy to determine the true risk of second malignancies.

Lethal and cytokinetic effects of anguidine on a human colon cancer cell line.

Anguidine is a fungal metabolite with antitumor activity in a murine colon cancer model. Because of disappointing results in clinical trials, we analyzed the lethal and cytokinetic effects of anguidine on cultured human colon cancer cells. The studies revealed a moderate reduction in survival only after prolonged drug exposure. Continuous incubation with anguidine for longer than 48 hr produced a moderate increase in the percentage of S-phase cells and a slight decrease in the proportion of cells in G1/0, by pulse cytophotometry. An immediate reduction in the cumulative labeling index for cells continuously exposed to tritiated thymidine and anguidine and a rapid decrease in the cumulative mitotic index for cells continuously exposed to Colcemid and anguidine indicated a block at the G1 into S and G2 into mitosis transitions. Tumoricidal activity of anguidine in a cultured human colon cancer line is poor and requires prolonged exposure. The kinetic data reflect an almost frozen state of the cell cycle.

Nephrotoxicity from cancer immunotherapy.

Because systemic intravenous immunotherapy with Corynebacterium parvum is an effective immunopotentiating and immunotherapeutic agent in animals, clinical studies of this agent have been undertaken. Toxicities in man have been noted, but most are treated symptomatically. Three patients with metastatic melanoma developed oliguria, edema, diffuse bilateral pulmonary infiltrates, azotemia, hypoalbuminemia and hypocomplementemia, while receiving intravenous C. parvum therapy. All had renal biopsies that showed a proliferative glomerulonephritis with subendothelial basement membrane deposits. Immunofluorescence showed glomerular IgG, IgA, IgM, and the C3 component of complement. A fourth patient was found in retrospective chart review of 87 patients registered on two C. parvum-containing protcols. The frequency of the complication in this group was 3/87. Renal failure resolved in all four patients spontaneously after the cessation of C. parvum immunotherapy. Serial evaluation of renal function should be carried out in all patients on systemic adjuvant immunotherapy.

Neuroblastoma in the adult: effective combination chemotherapy.

Although neuroblastoma occurs most frequently in children, it also may occur in adults and has been considered of poor prognosis. Six adult patients (greater than 16 years of age) with widespread neuroblastoma diagnosed between 1974 and 1976 are described. Five were treated with a combination of cyclophosphamide, vincristine, adriamycin and dimethyl triazeno imidazole carboxamide (CYVADIC). The sixth received a similar regimen in which actinomycin D was substituted for dimethyl triazeno imidazole carboxamide (CYVADACT). There were two complete responses and three partial responses. The median duration of survival is in excess of 11 months. The results indicate that effective chemotherapy is now available for these patients and the achievement of remission and prolongation of survival are realistic goals in neuroblastoma.