Gary B. Weiss

Comparing survival of responders and nonresponders after treatment: A potential source of confusion in interpreting cancer clinical trials

The comparison of survival distributions between patients who respond to therapy and those who do not can present methodologic and interpretational difficulties. Since assignment of patients to the responder or nonresponder groups is not random, statistical procedures that test the equality of survival distributions only demonstrate association between response and survival, not cause and effect. This association may have no relevance to the efficacy of treatment. The assignment of patients to response categories also represents a methodologic problem. Variability in the definition of a nonresponder and the handling of early deaths can both lead to varying conclusions concerning survival. In spite of these problems, statistical comparisons of survival distributions of responders and nonresponders are reported in approximately 20% of phase II and phase III clinical trials. Descriptive statistics may be more useful than inferential statistics in this situation.

Megakaryoblastic transformation of chronic myelogenous leukemia

A 52‐year‐old man with Ph1‐positive chronic myelogenous leukemia (CML) developed a blastic transformation in which the predominant cell type was micromegakaryocytes. He did not respond to treatment. A review of the 15 previously reported cases of patients with circulating megakaryocyte abnormalities in association with either CML or a Ph1 chromosome positive myeloproliferative disorder suggests a female predominance rather than the usual male predominance of CML. Survival of the six patients reported as megakaryoblastic transformation of CML as well as this patient was poor.

Hla type and survival in lung cancer

A significant positive association between antigens HLA Aw 19 and/or HLA B5 and a disease‐free survival time of one year for patients with lung cancer has been reported but not confirmed. We have HLA‐typed 20 white patients with non‐oat‐cell bronchogenic carcinoma who have survived at least a year from the time of diagnosis. Half these patients possessed these antigens (P < 0.08). This highly suggests that the presence of these antigens is associated with prolonged survival time. Now may be the time for performing large scale clinical trials using these antigens as stratification factors. Cancer 46:38–40, 1980.

False data & the therapeutic misconception: two urgent problems in research ethics. False data and last hopes: enrolling ineligible patients in clinical trials.

A persistent ethical dilemma in research is the potential conflict between the patient-subjects best interests and the principles of scientific methodology. Vanderpool and Weiss discuss the problem in cancer research when a physician falsifies data in order to increase a patients chances of being selected to participate in a clinical trial. While raising the question of whether such lying is justified if it may prolong the life of a cancer patient for whom there are no other therapeutic options, the authors point out that the inclusion of ineligible subjects may render trial results invalid.

Comparison of direct harvest and cultures for karyotyping EDTA anticoagulated marrow.

Studies were undertaken to determine whether EDTA was a satisfactory anticoagulant for tissue specimens for cytogenetic analysis and to investigate a modification of a currently used culture technique for obtaining metaphases. The latter involved to prolonged exposure to very low-dose colcemid and was successful in qualitative or quantitative enhancement, or both, of the temperature yield over that obtained from direct harvest in 53% of the patients studied. EDTA is a suitable anticoagulant for cytogenetic studies of specimens from either direct harvest or short-term culture if the specimen is either processed within 24 hr after collection or diluted 1:1 with Eagles minimal essential media, supplemented with fetal bovine serum and refrigerated until processed. Success has been obtained with specimens stored up to 144 hr.

Inability of avian myeloblastosis virus RNA-directed DNA polymerase to transcribe poly(rU) due to instability of the oligo(dA): Poly(rU) complex

Abstract Avian myeloblastosis virus DNA polymerase is unable to transcribe poly(rU). When the random copolymer, poly(rI,rU), is used as template and oligo(dC)12–18 is used as primer, there is good incorporation of both dCMP and dAMP into product. In contrast, when oligo(dA)12–18 is used as primer, transcription is poor. This demonstrates that the problem with oligo(dA) as primer is in the initiation of DNA synthesis. This result, together with the observation of Martin and Tinoco that (dA:rU) duplexes are very unstable, suggests that it is the instability of the primer: template complex which results in the lack of transcription of poly (rU).

RNA-Directed DNA Polymerase Activity in Human Breast Cancer Biopsy Specimens

The expression of a mouse mammary tumor virus is inducible by hormones, and the virus contains a hormone-responsive element. Viral particles and RNA-directed DNA polymerase (RDDP, EC 2.7.7.7; reverse transcriptase) are both detectable in human breast tumors but the frequency and significance of these findings are unknown. Breast tumor biopsy specimens (from either the primary site or a metastasis), frozen in liquid nitrogen at the time of surgery, were routinely obtained to determine estrogen receptor (ERP) concentration. A sample of the tissue was pulverized, homogenized and centrifuged at low speed to remove nuclei and mitochondria. The supernate was then centrifuged at 225,000 g to obtain the cytosol fraction for estrogen and progestin receptor (PgR) assays. Partially purified membranes for the RDDP assays were prepared from the high-speed pellet by discontinuous sucrose density gradient centrifugation. The RDDP assay involved measuring primer-dependent poly(dT) synthesis in the presence of poly(A) as template and oligo-(dT)12-18 as primer. To date, we have studied biopsy specimens from 46 patients with breast cancer. 27 (59%) had ERP and 23 (50%) were RDDP-positive. There was no significant correlation between ERP concentration and RDDP activity. PgR data were available on 36 of the patients; 17 (47%) were positive. No correlation between RDDP and PgR was apparent. Similarly, there was no correlation between RDDP and clinical stage of the disease.

Template Specificities of a RNA-Directed DNA Polymerase from a Human Homologous Mixed Mesodermal Sarcoma

A RNA-directed DNA polymerase was partially purified from a human homologous, mixed mesodermal sarcoma by DEAE-cellulose chromatography after sucrose density centrifugation. The enzyme transcribed poly(rA) most effectively but also transcribed poly(rI), poly(dA) and poly(rG) and to a lesser extent, poly(rmC). It was unable to transcribe poly(rU). The product with poly(rA) as template contained large material (greater than 28S) in addition to some proper size product demonstrating a slippage reaction. This pattern of transcription, while similar to avian myeloblastosis virus DNA polymerase, reveals qualitative differences making direct extrapolation from studies with animal oncornaviruses to human cancer difficult. In this paper, the detection and purification of RNA-directed DNA polymerase from a patient with an uncommon uterine sarcoma is reported along with the template specificities of the enzyme.