Charge delocalization through benzene, naphthalene, and anthracene bridges in π-conjugated oligomers: an experimental and quantum chemical study.

To understand the influence of orthogonal conjugation pathways fused directly to π-conjugated polymer backbones, we synthesized and studied three series of thiophene-based model compounds containing benzene, naphthalene, and anthracene peri-substituted central cores as representative acenes. These models were functionalized with methyl groups at the reactive thiophene positions in order to generate and observe oxidized species without complications from follow-up polymerization. The neutral monomers and their oxidized charged counterparts were subjected to cyclic voltammetry, spectroelectrochemistry, and EPR spectroscopy as appropriate, and these results were further corroborated with thorough density functional theory studies. This joint experimental and theoretical analysis allowed us to determine that benzene-based conjugated linkers led to more delocalized charge carriers on account of the quinoidal character maintained within the benzene core. In contrast, anthracene-based linkers displayed very localized carriers due to torsional strain between the adjacent aryl groups and to the local evolution of formal aromatic sextets on the benzo-fused rings orthogonal to the backbone in the quinoidal state. In some cases, the electronics of the thiophene-based substituent dominated the electronic properties of the oxidized species regardless of the nature of the central acene linker. These results highlight the dramatic influence that orthogonal conjugation pathways can exert on the electronic properties of π-conjugated materials.

DNA oxidation in anionic reverse micelles: ruthenium-mediated damage at Guanine in single- and double-stranded DNA.

One-electron guanine oxidation in DNA has been investigated in anionic reverse micelles (RMs). A photochemical method for generating Ru3+ from the ruthenium polypyridyl complex tris(2-2'-bipyridine)ruthenium(II) chloride ([Ru(bpy)3]Cl2) is combined with high-resolution polyacrylamide gel electrophoresis (PAGE) to quantify piperidine-labile guanine oxidation products. As characterized by emission spectroscopy of Ru(bpy)3(2+), the addition of DNA to RMs containing Ru(bpy)3(2+) does not perturb the environment of Ru(bpy)3(2+). The steady-state quenching efficiency of Ru(bpy)3(2+) with K3[Fe(CN)6] in buffer solution is approximately 2-fold higher than that observed in RMs. Consistent with the difference in quenching efficiency in the two media, a 1.5-fold higher yield of piperidine-labile damage products as monitored by PAGE is observed for duplex oligonucleotide in buffer vs RMs. In contrast, a 13-fold difference in the yield of PAGE-detected G oxidation products is observed when single-stranded DNA is the substrate. Circular dichroism spectra showed that single-stranded DNA undergoes a structural change in anionic RMs. This structural change is potentially due to cation-mediated adsorption of the DNA phosphates on the anionic headgroups of the RMs, leading to protection of the guanine from oxidatively generated damage.

Extensive necrosis in renal cell carcinoma specimens: potential clinical and prognostic implications.

BACKGROUND: Extensive necrosis is rare in primary renal cell carcinoma. This finding may reflect the biological characteristics of the carcinoma and therefore could be of prognostic and clinical value. OBJECTIVES: To assess the incidence of necrosis in renal cell carcinoma and its potential prognostic value. METHODS: We conducted a consecutive retrospective study of 173 patients after radical nephrectomy for renal cell carcinoma. Clinical and pathological data were collected from hospital medical records and compiled into a computerized database. RESULTS: Extensive necrosis was found in 31 tumor specimens (17.9%). Univariate analysis showed that the specimens with extensive necrosis were significantly larger and manifested more perirenal and venous extension than the tumors without necrosis. The size of the renal tumor was the only parameter that remained significant in multivariate analysis (P = 0.0001). Overall disease-free survival did not differ significantly between patients with necrotic tumors and those without (68% and 66% respectively). CONCLUSIONS: The finding of extensive necrosis in renal cell carcinoma specimens does not seem to be related to tumor biology but rather may reflect the relation between size and vascularity of the tumor.

Requirement of B7 costimulation for Th1-mediated inflammatory bone resorption in experimental periodontal disease.

The CD28 costimulation at TCR signaling plays a pivotal role in the regulation of the T cell response. To elucidate the role of T cells in periodontal disease, a system of cell transfer with TCR/CD28-dependent Th1 or Th2 clones was developed in rats. Gingival injection of specific Ag, Actinobacillus actinomycetemcomitans 29-kDa outer membrane protein, and LPS could induce local bone resorption 10 days after the transfer of Ag-specific Th1 clone cells, but not after transfer of Th2 clone cells. Interestingly, the presence of LPS was required not only for the induction of bone resorption but also for Ag-specific IgG2a production. LPS injection elicited the induction of expression of both B7-1 and B7-2 expression on gingival macrophages, which otherwise expressed only MHC class II when animals were injected with Ag alone. The expression of B7 molecules was observed for up to 3 days, which corresponded to the duration of retention of T clone cells in gingival tissues. Either local or systemic administration of CTLA4Ig, a functional antagonist of CD28 binding to B7, could abrogate the bone resorption induced by Th1 clone cells combined with gingival challenge with both Ag and LPS. These results suggest that local Ag-specific activation of Th1-type T cells by B7 costimulation appeared to trigger inflammatory bone resorption, whereas inhibition of B7 expression by CTLA4Ig might be a therapeutic approach for intervention with inflammatory bone resorption.

Colon polyp registries and colorectal cancer control.

This cohort of 252 subjects in the Roger Williams Hospital Polyp Registry who had adenomatous polyps removed in 1990, was followed for 6 years. Thirty subjects died during that period. Follow-up rate for the 222 living patients (88.1% of total) was 85%. New adenomatous polyps were found in 59% of the endoscoped subjects. Risk factors for new polyps included family history of colorectal carcinoma (p = 0.00079), right-sided location (p = 0.0108), and (probably) prior adenomatous polyps (p = 0.0595). In addition, three colorectal carcinomas, two of which were Dukes stage A, were found 1, 1, and 6 years after index polypectomy. If, as is common practice, the two first-year cancers are excluded, the observed incidence of metachronous colorectal cancer was 0.8/1000 patient years, which is substantially less than the expected incidence of such carcinomas in reference populations. Compared to the 1984 and 1987 cohorts in the polyp registry, colonoscopy was used more frequently and sigmoidoscopy less so for surveillance. Within the sigmoidoscopy group, the flexible instrument continued to rise in popularity as compared with rigid sigmoidoscopy. In addition to helping reduce the incidence of metachronous colorectal carcinomas, the polyp registry also serves the educational function of sensitizing physicians and their patients to the need to detect and treat these premalignant lesions. Enrollees in the registry also provide a source for studies designed to evaluate possible inhibitory effects of dietary, chemopreventive, and other agents on colorectal neoplasias.

Lymphoepithelioma-like carcinoma of the colon in a patient with hereditary nonpolyposis colorectal cancer.

Tumors with features similar to those of nasopharyngeal carcinoma, so-called lymphoepithelioma-like carcinomas, have been described in several organs but are extremely rare in the colon. We describe a patient with a family history consistent with hereditary nonpolyposis colorectal cancer who had 3 malignant lesions in the right colon, namely, a mucinous cancer, a lymphoepithelioma-like carcinoma, and a well-differentiated adenocarcinoma with prominent lymphoid stroma. To the best of our knowledge, lymphoepithelioma-like carcinoma has not been described previously in hereditary nonpolyposis colorectal cancer.

Is laparoscopic radical nephrectomy with specimen morcellation acceptable cancer surgery?

Laparoscopic radical nephrectomy (LRN) for renal-cell carcinoma (RCF) with removal of the specimen by morcellation and suction remains controversial because precise pathologic tumor staging is lost, and there is a risk of tumor seeding. We assessed the theoretical impact of surrendering precise pathologic staging on the management of patients with low-stage RCC (T3a or less). In 22 patients who underwent open radical nephrectomy for RCC, the preoperative CT-based clinical stage was correlated with pathologic tumor staging. Possible clinical inclusion criteria for LRN were then correlated with pathologic tumor staging. When comparing clinical and pathologic staging, one patient was understaged and seven were overstaged by preoperative CT. However, if clinical stage T3a or lower was used as the inclusion criterion for LRN, 19 patients (86%) would have been so treated, none would have been underassigned, and future management would not have been compromised according to pathologic staging. Management of patients with low-stage RCC relying on clinical staging only is oncologically adequate. This would make LRN an acceptable option for this subset of patients.

Peritumoral and nodal muciphages.

Three patients who underwent surgery for cancer showed Alcian blue positive cells in the sinusoids of the regional lymph nodes and, in one case, extensive infiltration in the soft tissues around the tumor. The cells contained variably sized vacuoles that occasionally indented the nuclei, imparting a signet-ringlike appearance. They were interpreted as muciphages based on morphology, reactivity with mucin stains, positive immunohistochemical staining for KP-1 and Mac-387, and negative staining for cytokeratin, S-100, and leukocyte common antigen (LCA). The material contained in these cells was Alcian blue positive at pH 2.5 and pH 1, and was strongly periodic acid-Schiff positive after diastase digestion. Hyaluronidase only slightly reduced the intensity of the Alcian blue stain. These results indicate that the bulk of the material was epithelial-type mucin. To our knowledge, this is the first report of muciphages in lymph nodes. Careful attention to morphology and immunohistochemical findings is necessary to avoid confusion with metastatic or infiltrating signet ring or mucinous adenocarcinoma.

Establishment of a colonic polyp registry in Rhode Island.

A colonic adenomatous polyp registry (PR) has been organized at the Roger Williams Medical Center whose main functions are to prevent the occurrence of colorectal cancer (CRC) in the enrollees, to provide a population of subjects for epidemiological and interventional studies, and to provide educational, including dietary, information to subjects and physicians. One hundred four and 202 patients with polyps, originally retrieved from the hospital pathology files, were enrolled in the 1984 and 1987 cohorts, respectively, of whom about 90% were followed for at least three years after polypectomy. Three carcinomas, all Dukes A, were found in the right colon in the follow-up period. New polyps identified in the first three years after polypectomy were generally small tubular adenomas with a greater predilection for the right colon than was found for the index polyps. Risk factors for new polyps included history of previous polyps and, probably, multiple index polyps. The use of colonoscopy for postpolypectomy surveillance increased between 1984 and 1987. About 25% of the subjects in each cohort were either lost to follow-up or received no endoscopic surveillance. On the other hand, some of those who were followed were probably subjected to excessive numbers of procedures. Defects in the PR include inadequacy of personal and family history data, and steady loss of patients during the three to six years after polypectomy. Despite the small size and limited resources of our hospital, its colonic polyp registry has already provided information that may help in the management of patients with this premalignant condition. The more widespread use of securely funded polyp registries would probably reduce the incidence of metachronous CRC in that population and would have significant epidemiological and educational functions.

Endoscopically removed malignant colorectal polyps: clinicopathologic correlations.

BACKGROUND/AIMS: Treatment options for patients with endoscopically removed malignant colorectal polyps are polypectomy alone vs. polypectomy followed by surgery. The aim of this study was to define histopathologic parameters that can be used for clinically relevant treatment decisions. METHODS: Five pathologists evaluated 140 polyps for the presence or absence of unfavorable histology. Unfavorable histology was tumor at or near (< or = 1.0 mm) the margin and/or grade III and/or lymphatic and/or venous invasion. Adverse outcome was recurrent and/or local cancer and/or lymph node metastasis. RESULTS: Adverse outcome was 19.7% (14 of 71), 8.6% (2 of 23), and 0% (0 of 46) when unfavorable histology was present, indefinite (lack of agreement), and absent, respectively (P < 0.0005, present vs. absent). Four patients with cancer > 1.0 mm from the margin had an adverse outcome (2 with lymphatic invasion and 2 indefinite for lymphatic invasion). Four patients with negative resections later developed distant metastases. Eight patients (6.3%) died of disease, and 2 of 69 without unfavorable histology (both indefinite for lymphatic invasion) had an adverse outcome. Interobserver strength of agreement was substantial to almost perfect for margin, grade, and venous invasion and fair to substantial for lymphatic invasion. CONCLUSIONS: This system is usable clinically. Patients with unfavorable histology are probably best managed by resection postpolypectomy, whereas in the absence of unfavorable histology, they probably can be treated by polypectomy only.

Neuroleptic malignant syndrome presenting without fever: case report and review of the literature.

The case of a patient with neuroleptic malignant syndrome (NMS) and delayed fever is presented. The patient was on lithium and trilafon before presentation to the emergency department with altered sensorium, rigidity, drooling, and tachycardia. The patient remained afebrile for 9 hours in the emergency department. He responded to treatment involving discontinuation of neuroleptics and bromocriptine. Typically NMS presents with a tetrad of fever, rigidity, altered sensorium, and autonomic dysfunction. This case is an example of NMS with delayed fever. A review of the literature on neuroleptic malignant syndrome is also presented.

Neutropenic enterocolitis. Two unusual cases with review of the literature.

Cases of neutropenic enterocolitis associated with Clostridium septicum infection have been reported with increasing frequency in the past decade. We report two such cases involving unusual hosts and briefly discuss possible pathogenetic mechanisms such as ischemia, mucosal damage related to chemotherapy and neutropenia, and immunosuppression. One case involved a young man with chronic Epstein-Barr infection who developed extensive gas gangrene of the right side of his trunk and thigh and who died within 12 hours of presentation to the emergency department. Diagnosis was only made at postmortem examination. The second, middle-aged patient was admitted with an acute abdomen shortly after he completed chemotherapy for pleural mesothelioma. A right hemicolectomy was performed, but the patient developed antibiotic-associated pseudomembranous colitis and died. These cases indicate that neutropenic enterocolitis may arise in a variety of underlying conditions and that prompt diagnosis and therapy will be required to salvage more patients with this disorder.

Relationship of polyps to cancer of the large intestine.

BACKGROUND: Pathologic and epidemiologic evidence indicates that patients with sporadic (nonfamilial) adenomatous polyps of the large intestine are at high risk of developing colorectal cancer. PURPOSE: Our primary goal in this study was to evaluate the colorectal cancer mortality rate among persons who have had a histologically confirmed benign colorectal polyp. METHODS: We used the retrospective follow-up method to evaluate the risk of death from colorectal cancer in 2872 Rhode Island men and women who were 24 through 79 years of age at the time of surgery for benign polyps in the years 1959 through 1975. RESULTS: Among 2872 subjects, the mortality from colorectal cancer, standardized for age, sex, and calendar time, was estimated as 1.74 (95% confidence interval = 1.44-2.09) times the rate in the general population of Rhode Island residents. Colorectal cancer mortality was higher in the first 5 years of follow-up than it was later. There was little relationship between the numbers of polyps and colorectal cancer mortality, and there was only a modest association between the size of polyps and mortality. Colorectal cancer mortality was more than twice as high in subjects whose polyps were proximal to the sigmoid compared with those with sigmoid or rectal polyps. The observed elevation of risk of colorectal cancer was almost entirely confined to subjects who had an adenomatous polyp. The risk increased strongly with the percentage of villous features in the polyp and was about twice as high in subjects with villous adenoma than in those with other adenomatous polyps. CONCLUSIONS: Our results support the suspected relationship between colorectal polyps and cancer incidence and extend the association to colorectal cancer mortality.

Oncogenic potential of tamoxifen on endometria of postmenopausal women with breast cancer--preliminary report.

Tamoxifen (TAM), a nonsteroidal antiestrogen, is used for pre- and postmenopausal patients with breast cancer. Recent reports suggest that TAM may cause endometrial neoplasia. This study is designed to evaluate the oncogenic potential of low-dose TAM on the endometrium. Initially, endometrial screening of patients with breast cancer who had received TAM therapy for at least 12 months was conducted. Seventy patients were interviewed and office endometrial biopsies were obtained from thirty-eight patients. Seven (18%) had hyperplastic changes, ranging from simple hyperplasia through complex hyperplasia with atypia. The following prospective study was conducted: after breast surgery and prior to initiation of TAM therapy, an office endometrial sampling was obtained as a control. After initiation of TAM therapy, biopsies were repeated every 4 to 6 months as long as the patients remained asymptomatic. Nineteen patients were interviewed. Twelve patients were biopsied and followed from 3 to 15 months. One patient refused additional biopsies. Eleven patients had repeat biopsies after initiation of TAM. New hyperplastic changes were found in 3/11 (27%) patients. The preliminary results of this study (although with a small number of patients) indicate that TAM may have some neoplastic effect on the endometrium of postmenopausal patients with breast cancer. This study is still in progress. Additional prospective studies are warranted before a significant correlation between TAM and endometrial neoplasia is confirmed.

Colonic oligosaccharide structures deduced from lectin-binding studies before and after desialylation.

Dolichos biflorus agglutinin (DBA) binds N-acetylgalactosamine (GalNAc), and peanut agglutinin (PNA) binds Gal beta(1-3)GalNAc residues (Gal = galactose). We used these lectins with neuraminidase to probe colonic oligosaccharides. Tissues included normal epithelium, adenocarcinomas (T) with contiguous transitional (TM) and normal mucosae (RM), and adenomatous polyps. Except for DBA binding in carcinomas, neuraminidase digestion increased DBA and PNA binding in all epithelia. In untreated specimens, reciprocal gradients for binding by DBA (T less than TM and TM less than RM) and PNA (T greater than TM and T greater than RM) were seen. After neuraminidase, all gradients were abolished except for T less than TM and T less than RM with DBA. We conclude that (1) qualitative as well as quantitative differences may exist between the mucins of benign and neoplastic colonic epithelium, (2) the NeuAc-GalNAc dimer is a widely prevalent terminal oligosaccharide in benign epithelium at all stages of differentiation (NeuAc = sialic acid), and (3) in contrast with evidence from recent biochemical studies, the Gal beta(1-3)GalNAc dimer is a common masked oligosaccharide in benign epithelium.