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Between October 1985 and March 1987, 92 patients were registered on a phase II study of the Northern California Oncology Group investigating the importance of dose intensity in the treatment of advanced non-small cell lung cancer (NSCLC). Treatment consisted of high-dose cisplatin in hypertonic saline (200 mg/m2 on a 28-day cycle) given in a divided day 1 and day 8 schedule. The response rate among 76 assessable patients was 36% (27/76), with complete response (CR) in 8% (6/76) and partial response (PR) in 28% (21/76). If all patients receiving any drug therapy were considered, the overall response rate was 31% (27/87), with CR in 7% (6/87) and PR in 24% (21/87). Median survival times for all assessable patients and all patients receiving any therapy were 37 and 35 weeks, respectively. With the use of a protocol design specifying dose delays rather than dose reduction for toxicity, the mean dose intensity delivered was 47.2 mg/m2 per week, or 94% of projected. Compared with other dose-intensive regimens of cisplatin, this day 1 and day 8 schedule was relatively well tolerated, with peripheral neuropathy as the dose-limiting toxicity. The data on response and median survival times among patients receiving this single-agent therapy are encouraging. They support the potential importance of cisplatin dose intensity in the treatment of NSCLC. Whether these results represent a positive dose-response effect in NSCLC will be tested in a randomized comparative trial of high-dose versus standard-dose cisplatin therapy.

Anthracyclines given by continuous infusion, as opposed to bolus administration, are associated with a reduced incidence of cardiac and gastrointestinal toxicity. Our study was developed to test the antileukaemic effect of anthracyclines given as a continuous infusion. Nineteen sequential patients admitted for treatment of acute nonlymphocytic leukaemia (ANLL) were managed with a regimen utilizing a 3 d continuous intravenous infusion of daunomycin (DNM), and the complete response rate was similar to this institution's past experience with antileukaemic regimens employing 3 d bolus DNM. In our studies, infusion DNM was at least as myelotoxic and antileukaemic as bolus DNM; thus this method of administration should be explored further in remission-induction regimens for ANLL.

The members of the RAS gene family of protooncogenes are of implied biological significance in oncogenesis. The precise role of these genes is unclear. One difficulty has been the inability to discriminate the individual p21 protein products of various ras genes in cell lines, de novo human tumors, and related normal tissues. In this report, specific proteins of the human c-Ha-ras-1, c-Ki-ras-2, and c-N-ras genes have been detected and discriminated by the differential use of various antisera recognizing these p21s. This enzyme-linked immunoblot assay utilizes a double antibody system in which monoclonal antibodies are initially used to immunoprecipitate the p21ras proteins. Immunoprecipitates are then subjected to one-dimensional Western blot analysis utilizing other antibodies raised against p21s, coupled with nonradiolabeled enzyme-linked colorimetric detection. By direct detection, the specific products of the three human ras genes can be discriminated. In addition, we describe the generation and characterization of a new anti-p21c-N-ras-specific antibody. The simultaneous expression into protein of multiple ras genes is unequivocally demonstrated in both homogeneous cell lines and heterogeneous human tissues. This new technique is also applicable for discrimination of the protein products of other gene families.

Thirty-five patients with superficial transitional carcinoma of the bladder were treated intravesically with escalating doses of recombinant alpha-2-interferon administered weekly for 8 weeks. Of the 19 patients with high-grade intraepithelial neoplasia (17 carcinoma in situ [CIS], two severe dysplasia, all cytology positive), six (32%) had complete resolution of all histologic and cytologic evidence of disease (complete response). An additional three patients (16%) had complete resolution of CIS, but the interval appearance of a low-grade transitional cell neoplasm. Five (26%) had a partial response (complete resolution of all evidence of CIS on multiple bladder biopsies but persistently positive cytologic preparations). Sixteen patients with recurrent papillary tumors and extensive prior therapy were also treated. Four (25%) had a complete response. Twenty-three of the 35 patients had prior intravesical therapy. Seven of the 23 (30%) patients with prior intravesical chemotherapy or immunotherapy had a complete or partial response to interferon, while eight of the 12 patients (67%) without prior intravesical treatment responded. These responses were achieved with minimal local and systemic toxicity. Of the ten complete responders, five remain in continuous unmaintained remission for 18+ to 37+ months. Intracavitary alpha-2-interferon is an effective new treatment for some patients with bladder cancer.

Rectally administered suspensions of 5-aminosalicylic acid (5-ASA) are topically effective in treating left-sided ulcerative colitis. The extent to which the contents of these enemas are distributed to inflamed mucosal linings has not previously been determined. This study was undertaken to validate a technique for labeling 5-ASA with 99mTc and to quantitate the distribution of [99mTc]5-ASA in eight patients with left-sided ulcerative colitis. Eight patients underwent three colonic scintigraphic exams within five days, receiving a 60-ml radiolabeled 5-ASA enema into the unprepared rectum for each study, with sequential anterior abdominal images obtained for 4 hr. Activity within the rectum, sigmoid, descending, transverse, and ascending colon was quantitated. Over 50% of the labeled enema had advanced beyond the rectum in five of eight patients and in six of eight patients by 30 min and 60 min, respectively. The distribution of [99mTc]5-ASA was quantitatively reproducible when repeated in the same patient on different days, despite apparent visual differences. By 2 hr, the amount of the enema present within the rectum decreased significantly (P less than 0.05) compared to the initial distribution. The amount of enema present within the descending colon was increased significantly at 0.5 hr (P less than 0.05) and at 2 hr (P less than 0.01). There were no significant changes in the distribution from initial values for the sigmoid, transverse, or ascending colon at any time. In each of these cases the spread of the enema to or beyond the extent of disease was documented. In patients with left-sided ulcerative colitis, small volume [99mTc]5-ASA enemas reliably reach the area of inflammation.

Screening examinations for so-called "early cancer" are popular methods to decrease cancer mortality. This report reviews current concepts in tumor biology that explain why screening for cancer succeeds and why it fails. From this review, three biologic subgroups emerge for many cancers. In only one of these groups will screening methods be successful in decreasing death from cancer. Breast cancer and prostatic cancer are specifically considered to support this hypothesis. Implications for future investigations and the impact on public policy are discussed.

Cellular proto-oncogenes are highly conserved genes thought to be critical in cell growth and differentiation. In this study, we used human sequence designed oligonucleotide primers to detect and discriminate c-Ha-ras-1, c-Ki-ras-2 and c-N-ras genes of dogs and cows by polymerase chain reaction (PCR) amplification of genomic DNA (DNA/PCR). Further, we have applied PCR for analysis of expressed mRNA transcribed from the RAS genes (RNA/PCR).

Relief of pain without drug toxicity can be achieved in cancer patients by adhering to basic pharmacologic principles. Agents should be chosen on the basis of potency and route of administration. Tolerance can be dealt with by combining different classes of drugs, such as phenothiazines and aspirin, and by using special routes of administration. Patients with severe pain from illnesses other than cancer can be effectively palliated in a similar manner.

All clinical studies in the English literature from 1976 to mid-1987 that address drug management of refractory or relapsed ANLL are reviewed and summarized. We conclude that, although many regimens may induce a CR, none is clearly superior. New drugs and or drug combinations must be sought if treatment outcomes are to be substantially improved. At present it appears that combination chemotherapy with VP-16 has not been extensively studied and may be active in non-cross-resistant regimens.

We report the efficacy and toxicity of combined cisplatin, methotrexate and vinblastine for the treatment of metastatic transitional cell carcinoma of the bladder in 50 evaluable patients. Of these 50 patients 17 had not undergone cystectomy and had residual invasive bladder cancer. Of these 17 patients 11 had complete response of the bladder lesions following cisplatin, methotrexate and vinblastine for metastatic disease, including 6 of 12 treated by cisplatin, methotrexate and vinblastine alone, and 5 of 5 treated with cisplatin, methotrexate and vinblastine plus palliative or preoperative pelvic irradiation. Complete response was confirmed in 10 of the 11 patients by endoscopy and biopsy, and in 1 by cystectomy. One patient whose liver metastasis responded to cisplatin, methotrexate and vinblastine had conversion to complete response by cystectomy for persistent bladder cancer. Of these 17 patients 7 are alive, including 5 without disease, 4 to 41 months after treatment. The bladder appears to be responsive to this combination chemotherapy for invasive transitional cell carcinoma. This experience underscores the need for regular pathological re-staging of the bladder cancer in patients receiving chemotherapy.

The author used blood flow measurements to guide partial splenic embolization procedures in five patients. The measurements were obtained by time density analysis of contrast medium injections in the splenic artery using digital subtraction angiographic techniques and modified software. The blood flow measurements demonstrated blood flow changes occurring as a result of the embolization. The embolization procedures continued until the blood flow in the splenic artery had been reduced to 50% of its original value. The blood flow measurements appear to predict the amount of parenchymal reduction achieved by embolization and show promise as a method of monitoring these procedures.

One hundred forty-five men had undergone surgical correction of cryptorchid testes between 1936 and 1968. Eighty percent of 100 patients with unilateral cryptorchidism and 35% (16/45) of patients with bilateral cryptorchidism had reported fertility after 12 or more years of follow-up. There was no significant difference between the fertility rates of patients treated with or without preoperative human chorionic gonadotropin. These data serve to challenge other published series and the popular assumption that there is an inherent bilateral testicular defect in most patients with unilateral cryptorchidism.

We have adapted an enzyme-linked immunoblot assay (ELIBA) for the detection of a c-ras proto-oncogene and oncogene protein products in human cell lines and tumors of 21,000 daltons molecular weight (p21ras) to studies of tissues derived from sheep. In the ELIBA, a double antibody system is used in which p21ras proteins are initially immunoprecipitated from protein extracts with monoclonal antibodies, and subsequently identified using additional anti-ras antibodies. Binding is identified with a non-radioactive enzyme-linked colorimetric detection system. In the present study, the ELIBA system was used to study twenty-seven ovine lung specimens, representing normal lung, inflammatory, and neoplastic lesions. We detected p21ras protein expression in every tissue examined, but the nature and amount of the protein product varied significantly among the tissues examined. Some tissues expressed multiple ras species. Broncho-alveolar carcinoma specimens were most likely to express c-Ki-ras proteins. Mutant proteins of c-N-ras and c-Ki-ras were detected in several bronchoalveolar carcinoma specimens, based on migrational differences between mutant and normal proteins in 15% polyacrylamide gels. The results of this study demonstrate the utility of the ELIBA system for detection of c-ras expression in ovine lung tissues, and demonstrate the ability of the system to discriminate specific ras protein species. The prognostic significance of ras expression in sheep pulmonary carcinoma has yet to be determined.

A novel and successful undergraduate-level course in pharmacology has been established as part of the drug education program at California's San Quentin State Prison. The program was designed to create a two-way teaching--learning experience between former drug abusers and their teachers, all of whom were doctoral candidates and post-doctoral scholars in pharmacology at a nearby university medical center. In reviewing the pharmacology of psychoactive drugs, the emphasis was on the principles of drug action in the central nervous system, with additional attention to those factors that contribute a potential for abuse. An attempt was made to present information in a strictly objective and non-prejudical manner. An initial analysis has shown a possible change in attitude among the student-inmates toward drugs of abuse. It is likely that courses following a similar design would be well received and successful in any type of undergraduate program that addresses the subject of drug abuse.

A distinction between benign, preneoplastic, and malignant tissue, based upon the expression of surface antigens, would provide useful clinical information. Epithelial membrane antigen (EMA) has been reported in squamous cell carcinomas, but not in normal squamous epithelium. Twenty-nine specimens from 15 patients, representative of the spectra of changes seen in squamous cell epithelium from normal through dysplasia to squamous cell carcinoma, were fixed in B-5 and examined with anti-EMA monoclonal antibody in an immunoperoxidase technique. Normal squamous epithelium does express EMA. Squamous cell carcinoma also expresses EMA. Well-differentiated tumors stain more intensely and in greater numbers of cells than less-differentiated tumors. The presence or absence of EMA expression does not distinguish normal squamous epithelium from carcinoma. Investigations of membrane antigen content in fixed tissue must use methods of fixation that preserve antigenicity. While strict quantitation of immunoperoxidase preparations is not possible, quantitative differences in expression may be important.

A patient with end-stage congestive cardiomyopathy had progressive hemodynamic deterioration while awaiting orthotopic heart transplantation. Attempts to support cardiovascular function by high-dose dobutamine infusions were complicated by life-threatening cardiac arrhythmias. The addition of the noncatecholamine inotropic agent, amrinone, improved ventricular performance, enabling reduction of the dose of dobutamine and resolution of the cardiac arrhythmias. Beta receptor stimulation by dobutamine combined with phosphodiesterase inhibition by amrinone may additively or synergistically augment cardiac function despite severe congestive heart failure and also have an adrenergic "sparing effect."

We describe the detection and characterization of an activated c-N-ras allele from a gamma-radiation-induced canine acute nonlymphocytic leukemia (ANLL). The activated allele was detected by use of the NIH3T3 transfection/transformation assay. The leukemia DNA had a transforming activity of 0.0125 foci/microgram. By the use of a double anti-ras antibody enzyme-linked immunoblot assay, we have dissected the lesion within the activated c-N-ras allele. Aspartic acid has been substituted for the normal glycine at position 12 in the activated p21c-N-ras. The expression of the mutant p21ras has also been detected in an in vivo passage of the radiation-induced canine ANLL from which the activated c-N-ras allele was isolated. We have demonstrated sufficient homology between canine c-N-ras genes and the human cDNA c-N-ras clone, p6a1, that allows this probe to be used in Southern blotting of canine tissues. In addition, anti-ras antibodies generated against both murine and human ras antigens are capable of detecting canine p21ras species.

A 28-year-old woman presented with acute leukemia. Surface antigen analysis showed monoclonal kappa immunoglobulin distribution. Morphology was consistent with either acute lymphoblastic leukemia or acute promyelocytic leukemia, hypogranular variant. This dilemma was resolved by examining the leukemic blasts for immunoglobulin gene rearrangement. None were found, ruling-out involvement of the B-cell lineage in this malignancy. Cytogenetic analysis showed a clonal abnormality diagnostic of acute promyelocytic leukemia. Immunoglobulin gene rearrangement in cytogenetics are invaluable in the care of patients with acute leukemia and can resolve ambiguities that result from phenotypic analysis.

A human prostatic-specific antigen was first purified in 1979 by M.C. Wang et al. In the years to follow, investigators have been able to develop antisera to prostatic-specific antigen. Using an immunoperoxidase technique to stain both fresh and archival specimens, tissue of prostatic origin can be identified. The stain in our experience has been both specific and sensitive as an indicator of extraprostatic spread of carcinoma. We describe five cases where this technique has been useful in clinical practice.

Based on experimental data suggesting synergy between cisplatin and cytosine arabinoside, 17 patients with recurrent squamous cancer of the head and neck were treated with this combination. The response rate was 18% with no complete responses, and the partial responses were of brief duration. There were moderate hematologic and gastrointestinal toxicities and two therapy-related deaths. The study was stopped early because of low response. When compared to results reported for cisplatin alone, the combination of cisplatin and cytosine arabinoside offered no clear advantage.

A precise cause for normocytic anemia can be determined through applied pathophysiology. Examination of the peripheral blood smear may yield evidence of renal disease, liver disease, hemolysis or megaloblastic anemia. A reticulocyte count is performed next; then the creatinine clearance is determined. Bone marrow aspiration with iron stain should further narrow the cause. Physical examination and family history remain important in determining the etiology of normocytic anemia.

A 29-yr old woman developed urticaria pigmentosa which subsequently progressed through systemic mastocytosis to Philadelphia chromosome negative (Ph neg) chronic myelogenous leukemia (CML) with t(8;17). Further cytogenetic evolution occurred at the time of transformation to the aggressive phase of the disease. Unlike Ph-positive CML, chromosome number 9 was not involved, nor was the breakpoint cluster region located at band 22q11. This clearly separates this case from other Ph-negative CML patients who do have involvement of 9q34 or the breakpoint cluster region. Since this is the first case of its type to be reported with cytogenetic abnormalities, the clinical relevance of the unique chromosomal rearrangement t(8;17)(p11;q25) in the setting of systemic mastocytosis is unclear. Additional cases need to be reported to determine if this genetic rearrangement is a nonrandom marker of leukemia evolving in a setting of malignant mast cell disease.

Carbon disulfide (CS2), tetraethyl lead (TEL), tetraethyl tin (TeET), dithiothreitol (DTT), and gossypol acetic acid (GAA) significantly decreased brain norepinephrine (NE) in rats. The central dopamine (DA) increased after ip administration of CS2, TEL, and DTT, but decreased after TeET and GAA. The brain serotonin decreased only after TeET. Two doses of DTT decreased the NE longer than one dose (24 vs 2 hr) but did not increase DA. L-DOPA, given SC with DTT, delayed the decrease in NE by 24 hr. The similar behavioral and autonomic effects of each of these compounds suggest a central sympatholytic effect and an antipsychotic type of sedation and rigidity. A possible mechanism is reversible inhibition of dopamine beta-hydroxylase through the reduction of the copper ion of the enzyme. Each of these reducing agents, together with the boranes previously studied, has similar behavioral and autonomic effects and a common effect on NE concentration, suggesting that the agents act through a physicochemical property rather than by combination with a cellular component. These data have applications to the toxicity of the single agents. They also provide an index of activity, previously lacking, of systemic antioxidant effect.

Forty-two evaluable endomyocardial biopsies were obtained from 29 patients treated with epirubicin, the 4'-epimer of doxorubicin in cumulative doses ranging from 147 mg/m2 to 888 mg/m2. In this study of the Northern California Oncology Group, myofibrillar loss and sarcoplasmic vacuolization were identified and shown to be identical to those previously described for doxorubicin. However, when these biopsies were compared to 119 biopsies obtained from 98 patients treated with doxorubicin, milligram for milligram, epirubicin caused less endomyocardial injury than doxorubicin (P = 0.0013). Age, sex, type of primary malignancy, prior cardiac disease, and hypertension did not influence the degree of histologically demonstrated anthracycline injury induced by epirubicin.

A human cell line has been established from a renal adenocarcinoma rib metastasis of a 58-y-old male. This cell line has been maintained in continuous culture for 20 mo. through more than 50 passages. It displays simultaneous expression of the intermediate filaments cytokeratin and vimentin. Flow cytometric analysis of DNA content reveals a major hyperdiploid population.

Blue Cross of North Dakota, Blue Cross of Massachusetts, and the Blue Cross and Blue Shield Association, along with 10 hospitals, developed and implemented the Hospital Capitation Payment Project as a novel approach for containing escalating hospital costs. The hospital is paid a prospective, fixed amount for each person covered; in exchange, it assumes responsibility to provide or pay for all covered services needed by that individual. This responsibility extends to payment for covered care provided by other hospitals. The new tools and incentives created by the program, notably an innovative management information system, are designed to help hospitals better manage the health care needs and related costs of a defined population.

Indium-111-labeled monoclonal antibody directed against prostate-specific antigen was injected into ten patients with known prostatic carcinoma, nine with metastatic disease. The monoclonal antibody scan was compared to the standard technetium bone scan, and both were correlated to clinical status and to 2-year follow-up. The ratio of target-to-nontarget activity and pharmacokinetics of the radiolabeled antibody were determined. Based on these findings we are hopeful that modifications of this radiolabeled antibody approach may be used for staging and may be developed as a therapeutic adjuvant.

A child with an extensive periorbital hemangioma developed an endophthalmitis caused by Staphylococcus aureus after her second strabismus surgical procedure. Treatment with vitrectomy and intraocular antibiotics and steroid resulted in preservation of her eye. Despite previous successful treatment for amblyopia in that eye, her visual acuity improved from hand motion during the acute episode of endophthalmitis to 20/40 -2.

Published studies of delta 9-tetrahydrocannabinol (THC) and marihuana in the control of nausea and vomiting in cancer patients leave many unanswered questions about dosage, time of administration, technique of use, use in pediatric and geriatric patients, and continuous use for extended periods. Four separate protocols are described which will determine optimal dosage of oral THC in adults and children receiving cyclic chemotherapy and adults receiving chronic chemotherapy or radiotherapy, and the optimal dose for smoked marihuana. Side effects and efficacy will be assessed by chemotherapeutic agent or combination, type of cancer, age, sex, etc. How well THC is tolerated in the elderly and very ill are important questions to be answered. Research goals are combined with widespread therapeutic access of cancer patients to marihuana and THC. The problems of designing and sponsoring a very large-scale Phase III collaborative study involving community practitioners are outlined. The design stresses uniformity and simplicity to obtain compliance by the more than 200 investigators.

Two patients with poorly differentiated metastatic cancer were shown to have metastatic thyroid carcinoma. Each patient had poorly differentiated cancer and remaining thyroid tissue in the neck. The diagnosis was secured using the immunoperoxidase technique with an antibody against thyroglobulin. The proper evaluation of patients with carcinoma of unknown primary involves specific tissue identification using special techniques in pathology.

Members of the ras family of proto-oncogenes code for 21,000-dalton molecular weight protein products (p21s). Transformation of cells from the normal to the malignant phenotype in experimental studies has been associated with point mutations within the coding region for these ras proteins. Recent reports demonstrate that 40% of human colon cancers and 20% of acute leukemias contain ras mutations in the twelfth or thirteenth codon that can result in amino acid substitutions at these positions in the p21 products. Similarly, studies of ras mRNA detected 40% of human colon tumors with twelfth codon c-Ki-ras mutant mRNA. The authors previously developed a nonradioactive double-antibody enzyme-linked immunoblot assay (ELIBA) for detection of normal and mutant ras p21. They have adapted that technology to specifically detect twelfth codon activated ras p21 utilizing mutation-specific antisera. In this report the authors show that one of seven de novo human bladder cancers and four of seven colon cancers express a twelfth codon activated ras p21. These results document that mutations at both the DNA and mRNA levels are ultimately translated into an abnormal protein product present in human tumors.

The sleeping time of mice given pentobarbital was found to be significantly shortened by the injection of eserine or amphetamine. When both eserine and amphetamine were given with pentobarbital the sleeping time, though much shortened, was significantly longer than with the addition of amphetamine alone. Though possessing an analeptic effect of its own, eserine appears to antagonize the analeptic effect of amphetamine.