Studies in vitro to discern the structural requirements for carcinogenicity in analogues of the carcinogen 4-dimethylaminoazobenzene (butter yellow)

4-Dimethylaminoazobenzene (butter yellow, DAB), is the parent member of a large family of 'azo-carcinogens'. Experiments have been conducted in vitro to determine the key structural requirements for carcinogenic activity in this chemical class, and it is suggested, based on the activity observed for 4-cyano-N,N-dimethylaniline, that the 4-phenylazo group of DAB is not an essential structural feature per se. The N-oxide derivative of DAB has been evaluated in vitro and the positive response observed related to its metabolic activation. It is concluded that cyclic amines, such as pyrrolidine, can replace the N-dimethyl group of DAB with a retention of biological activity. The confusion that exists in the literature concerning the chemical identity and carcinogenic status of 2-dimethylaminobenzo[c]cinnoline has been investigated, and it is concluded that it is a potential animal carcinogen. This observation also indicates that the phenylazo group of DAB can be incorporated within an aromatic ring system with a retention of biological activity. As observed earlier with a mixture of azobenzene and DAB, azobenzene also potentiates the cell transforming properties of the above cinnoline derivative in vitro. Two charts are presented. The first attempts to integrate DAB within a much larger family of carcinogens, and the second illustrates the usefulness of structure-activity studies in general.     

Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma.

PURPOSE: We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non-small-cell lung cancer (NSCLC), we conducted a phase I clinical trial. PATIENTS AND METHODS: Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 x 10(6), 4 x 10(6), or 1 x 10(7) cells, depending on overall yield, and were administered intradermally and subcutaneously at weekly and biweekly intervals. RESULTS: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 513 ng/10(6) cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed. CONCLUSION: Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC.     

Patterns and predictors of inpatient falls and fall-related injuries in a large academic hospital.

OBJECTIVES: Most research on hospital falls has focused on predictors of falling, whereas less is known about predictors of serious fall-related injury. Our objectives were to characterize inpatients who fall and to determine predictors of serious fall-related injury. METHODS: We performed a retrospective observational study of 1,082 patients who fell (1,235 falls) during January 2001 to June 2002 at an urban academic hospital. Multivariate analysis of potential risk factors for serious fall-related injury (vs no or minor injury) included in the hospital's adverse event reporting database was conducted with logistic regression to calculate adjusted odds ratios (aORs) with 95% confidence intervals (CI95) RESULTS: The median age of patients who fell was 62 years (interquartile range, 49-77 years), 50% were women, and 20% were confused. The hospital fall rate was 3.1 falls per 1,000 patient-days, which varied by service from 0.86 (women and infants) to 6.36 (oncology). Some (6.1%) of the falls resulted in serious injury, ranging by service from 3.1% (women and infants) to 10.9% (psychiatry). The most common serious fall-related injuries were bleeding or laceration (53.6%), fracture or dislocation (15.9%), and hematoma or contusion (13%). Patients 75 years or older (aOR, 3.2; CI95, 1.3-8.1) and those on the geriatric psychiatry floor (aOR, 2.8; CI95, 1.3-6.0) were more likely to sustain serious fall-related injuries. CONCLUSIONS: There is considerable variation in fall rates and fall-related injury percentages by service. More detailed studies should be conducted by floor or service to identify predictors of serious fall-related injury so that targeted interventions can be developed to reduce them.     

Immunogenicity, including vitiligo, and feasibility of vaccination with autologous GM-CSF-transduced tumor cells in metastatic melanoma patients.

PURPOSE: To determine the feasibility, toxicity, and immunologic effects of vaccination with autologous tumor cells retrovirally transduced with the GM-CSF gene, we performed a phase I/II vaccination study in stage IV metastatic melanoma patients. PATIENTS AND METHODS: Sixty-four patients were randomly assigned to receive three vaccinations of high-dose or low-dose tumor cells at 3-week intervals. Tumor cell vaccine preparation succeeded for 56 patients (88%), but because of progressive disease, the well-tolerated vaccination was completed in only 28 patients. We analyzed the priming of T cells against melanoma antigens, MART-1, tyrosinase, gp100, MAGE-A1, and MAGE-A3 using human leukocyte antigen/peptide tetramers and functional assays. RESULTS: The high-dose vaccination induced the infiltration of T cells into the tumor tissue. Three of 14 patients receiving the high-dose vaccine showed an increase in MART-1- or gp100-specific T cells in the peripheral blood during vaccination. Six patients experienced disease-free survival for more than 5 years, and two of these patients developed vitiligo at multiple sites after vaccination. MART-1- and gp100-specific T cells were found infiltrating in vitiligo skin. Upon vaccination, the T cells acquired an effector phenotype and produced interferon-gamma on specific antigenic stimulation. CONCLUSION: We conclude that vaccination with GM-CSF-transduced autologous tumor cells has limited toxicity and can enhance T-cell activation against melanocyte differentiation antigens, which can lead to vitiligo. Whether the induction of autoimmune vitiligo may prolong disease-free survival of metastatic melanoma patients who are surgically rendered as having no evidence of disease before vaccination is worthy of further investigation.     

Café-au-lait macules and pediatric malignancy caused by biallelic mutations in the DNA mismatch repair (MMR) gene PMS2

A 14-year-old male presented with a T4 sigmoid adenocarcinoma, <10 colonic adenomas and multiple café-au-lait macules. Family history was not suggestive of a dominant hereditary form of colorectal cancer. Evaluation of the tumor revealed abnormal immunohistochemical staining of the PMS2 protein and high frequency microsatellite instability. Germline analysis identified biallelic PMS2 missense mutations. A new cancer syndrome caused by biallelic mutations in the mismatch repair genes, including PMS2, is now emerging and is characterized by café-au-lait macules, colonic polyps and a distinctive tumor spectrum.     

A review of Kallmann syndrome: genetics, pathophysiology, and clinical management

Kallmann syndrome is a genetic disorder with the hallmarks of anosmia and hypogonadotrophic hypogonadism. It has a male preponderance. With the elucidation of the genetic pathways involved, affected females and inheritance patterns are becoming more clearly identified. It is an eminently treatable disorder, but it must first be recognized by the physician. With treatment, favorable reproductive outcomes can be attained in addition to maturation of secondary sex characteristics.