Patterns of Care and Efficacy of Chemotherapy and Radiotherapy in Skin-Involved Breast Cancers of All Sizes.

BACKGROUND: The management of small skin-involved (SI) invasive breast cancers is controversial because although they are considered unresectable, their prognosis is far better than their stage III classification. This study was undertaken to determine how SI lesions are treated in the United States and to discern the benefit of systemic therapy. PATIENTS AND METHODS: Data of patients diagnosed with stage I-III breast cancer in the National Cancer Data Base between 2004 and 2011 were reviewed. Treatment patterns were examined and overall survival assessed. RESULTS: A total of 3485 patients had SI and 456,287 patients had non-SI breast cancers. Chemotherapy was administered to 68.5% of SI and 45.9% of non-SI tumors (P < .001), including 77.2% of SI and 33% of non-SI tumors < 2 cm (P < .001). After adjusting for patient and tumor characteristics, SI patients were 19.4% more likely to receive chemotherapy than non-SI patients. Radiotherapy was provided to 61.1% of SI and 64.3% of non-SI tumors (P < .001), including 65.5% of SI and 66.5% non-SI tumors < 2 cm (P = .711). After adjusting for patient and tumor characteristics, SI patients were 76.6% more likely to receive radiotherapy than non-SI patients. Chemotherapy and radiotherapy provided an overall survival benefit for stage II and III SI and non-SI tumors. CONCLUSION: Despite controversy regarding staging and prognosis of SI tumors, the majority of patients are provided systemic therapy and radiotherapy. Varied patterns of chemotherapy administration for SI tumors suggests that further treatment guidance and standardization are required, especially because chemotherapy and radiotherapy are equally efficacious in SI and non-SI tumors alike.

Phantasmidine: an epibatidine congener from the ecuadorian poison frog Epipedobates anthonyi.

The skin of the Ecuadorian poison frog Epipedobates anthonyi contains the potent nicotinic agonists epibatidine (1) and N-methylepibatidine (3). In addition, a condensed tetracyclic epibatidine congener has been identified with activity at nicotinic acetylcholine receptors, but different selectivity than epibatidine. This rigid tetracycle has been named phantasmidine (4). Phantasmidine has a molecular formula of C(11)H(11)N(2)OCl, shares a chloropyridine moiety with 1, and also contains furan, pyrrolidine, and cyclobutane rings. A combination of GC-MS and GC-FTIR analysis with on-column derivatization, 1D NMR spectroscopy with selective irradiation, and spectral simulation, along with 2D NMR, were used to elucidate the structure from a total sample of approximately 20 microg of HPLC-purified 4 and its corresponding acetamide (5). After synthesis, this novel rigid agonist may serve as a selective probe for beta4-containing nicotinic receptors and potentially lead to useful pharmaceuticals.

N-methyldecahydroquinolines: an unexpected class of alkaloids from Amazonian poison frogs (Dendrobatidae).

The dominant alkaloids previously identified in skin extracts of Amazonian dendrobatid frogs of the genus Ameerega are histrionicotoxins and 2,5-disubstituted decahydroquinolines. Analysis of alkaloids in skin extracts of Ameerega picta from Bolivia revealed that the alkaloid 257A, previously reported as a 2,5-disubstituted decahydroquinoline, is an N-methyl-2,5-disubstituted decahydroquinoline. We characterized alkaloids of another 12 of the more than 25 species recently assigned to the genus Ameerega, and five additional N-methyldecahydroquinolines were identified. In some cases, the relative configuration of the N-methyldecahydroquinolines was determined by comparison with the N-methylated products prepared from the corresponding 2,5-disubstituted decahydroquinolines of known relative configuration. A dietary source for N-methyldecahydroquinolines is unknown; however, myrmicine ants are the likely source for the 2,5-disubstituted decahydroquinolines. The alkaloids in skin extracts of three species of another genus of Amazonian poison frog, Adelphobates, were also characterized, but N-methyldecahydroquinolines were not detected.

Indolizidine 239Q and quinolizidine 275I. Major alkaloids in two Argentinian bufonid toads (Melanophryniscus).

Alkaloid profiles in skin of poison frogs/toads (Dendrobatidae, Mantellidae, Bufonidae, and Myobatrachidae) are highly dependent on diet and hence on the nature of habitat. Extracts of the two species of toads (Melanophryniscus klappenbachi and Melanophryniscus cupreuscapularis) from similar habitats in the Corrientes/Chaco Provinces of Argentina have similar profiles of alkaloids, which differ considerably in profiles from other Melanophryniscus species from Brazil, Uruguay and Argentina. Structures of two major alkaloids 239Q (1) and 275I (2) were determined by mass, FTIR, and NMR spectral analysis as 5Z,9Z-3-(1-hydroxybutyl)-5-propylindolizidine and 6Z,10E-4,6-di(pent-4-enyl) quinolizidine, respectively. A third alkaloid, 249F (3), is postulated to be a homopumiliotoxin with an unprecedented conjugated exocyclic diene moiety.

Spatial and temporal patterns of alkaloid variation in the poison frog Oophaga pumilio in Costa Rica and Panama over 30 years.

A total of 232 alkaloids, representing 21 structural classes were detected in skin extracts from the dendrobatid poison frog Oophaga pumilio, collected from 53 different populations from over 30 years of research. The highly toxic pumiliotoxins and allopumiliotoxins, along with 5,8-disubstitiuted and 5,6,8-trisubstituted indolizidines, all of which are proposed to be of dietary mite origin, were common constituents in most extracts. One decahydroquinoline (DHQ), previously shown be of ant origin, occurred in many extracts often as a major alkaloid, while other DHQs occurred rather infrequently. Histrionicotoxins, thought to be of ant origin, did not appear to possess a specific pattern of occurrence among the populations, but when present, were usually found as major components. Certain 3,5-disubstituted pyrrolizidines and indolizidines, known to be of ant origin, did occur in extracts, but infrequently. Alkaloid composition differed with regard to geographic location of frog populations, and for populations that were sampled two or more times during the 30-year period significant changes in alkaloid profiles sometimes occurred. The results of this study indicate that chemical defense in a dendrobatid poison frog is dependent on geographic location and habitat type, which presumably controls the abundance and nature of alkaloid-containing arthropods.

Oribatid mites as a major dietary source for alkaloids in poison frogs.

Alkaloids in the skin glands of poison frogs serve as a chemical defense against predation, and almost all of these alkaloids appear to be sequestered from dietary arthropods. Certain alkaloid-containing ants have been considered the primary dietary source, but dietary sources for the majority of alkaloids remain unknown. Herein we report the presence of approximately 80 alkaloids from extracts of oribatid mites collected throughout Costa Rica and Panama, which represent 11 of the approximately 24 structural classes of alkaloids known in poison frogs. Forty-one of these alkaloids also occur in the dendrobatid poison frog, Oophaga pumilio, which co-occurs with the collected mites. These shared alkaloids include twenty-five 5,8-disubstituted or 5,6,8-trisubstituted indolizidines; one 1,4-disubstituted quinolizidine; three pumiliotoxins; and one homopumiliotoxin. All but the last of these alkaloid classes occur widely in poison frogs. In addition, nearly 40 alkaloids of unknown structure were detected in mites; none of these alkaloids have been identified in frog extracts. Two of these alkaloids are homopumiliotoxins, five appear to be izidines, four appear to be tricyclics, and six are related in structure to poison frog alkaloids that are currently unclassified as to structure. Mites are common in the diet of O. pumilio, as well as in the diets of other poison frogs. The results of this study indicate that mites are a significant arthropod repository of a variety of alkaloids and represent a major dietary source of alkaloids in poison frogs.

Geographic and seasonal variation in alkaloid-based chemical defenses of Dendrobates pumilio from Bocas del Toro, Panama.

Poison frogs contain an alkaloid-based chemical defense that is derived from a diet of certain alkaloid-containing arthropods, which include mites, ants, beetles, and millipedes. Variation in population-level alkaloid profiles among species has been documented, and more than 800 different alkaloids have been identified. In the present study, we examine individual alkaloid variation in the dendrobatid poison frog Dendrobates pumilio among seven populations and between two seasons on Isla Bastimentos, located in the Bocas del Toro archipelago of Panama. Alkaloid profiles vary among populations and between seasons, illustrating that chemical defense in this species can vary on a small spatial and temporal scale. Alkaloid variation among populations is marginally correlated with geographic distance, and close populations have profiles more similar to each other than to distant populations. Individuals within populations also vary in alkaloid profiles. Differences are attributed to both spatial and temporal variations in the availability of alkaloid-containing arthropods. Many of the alkaloids present in the skin of D. pumilio appear likely to be of ant origin, supporting the importance of myrmecophagy in chemical defense among poison frogs. However, a variety of frog skin alkaloids was recently detected in mites, suggesting that mites may also play an important role in chemical defense.

Bioassay-guided isolation of epiquinamide, a novel quinolizidine alkaloid and nicotinic agonist from an Ecuadoran poison frog, Epipedobates tricolor.

Analytical HPLC fractionation, combined with an off-line 96-well fluorescent bioassay screen, has been developed and used for the separation and screening of a natural product extract. This method was used to guide the isolation of a novel quinolizidine alkaloid from the methanolic skin extracts of an Ecuadoran frog, Epipedobates tricolor. The structure was determined on the basis of MS, IR, and NMR analysis as (1R,10R)-1-acetamidoquinolizidine (alkaloid 196). We have named this compound epiquinamide, reflecting its origin and structure. The activity of the isolated compound was determined in five cell lines expressing various nicotinic acetylcholine receptor subtypes. The bioactivity of epiquinamide was evaluated on the basis of membrane potential fluorescence and was found to be beta2 selective. This compound represents a new structural class of nicotinic agonists and a potential lead compound for the development of new therapeutics and pharmacological probes for nicotinic receptors. The off-line screening technique was found to be very sensitive for the detection of compounds active at nicotinic receptors.