Drug-Eluting Bead, Irinotecan Therapy of Unresectable Intrahepatic Cholangiocarcinoma (DELTIC) with Concomitant Systemic Gemcitabine and Cisplatin.

BACKGROUND: Unresectable intrahepatic cholangiocarcinoma (ICC) carries a poor prognosis, and currently there are moderately established chemotherapeutic [gemcitabine/cisplatin (Gem/Cis)] treatments to prolong survival. The purpose of this study was to assess the efficacy of irinotecan drug-eluting beads (DEBIRI) therapy by transarterial infusion in combination with systemic therapy in unresectable ICC. PATIENTS AND METHODS: This is a prospective, multicenter, open-label, randomized phase II study (Clin Trials: NCT01648023-DELTIC trial) of patients with ICC randomly assigned to Gem/Cis with DEBIRI or Gem/Cis alone. The primary endpoint was response rate. RESULTS: The intention-to-treat population comprised 48 patients: 24 treated with Gem/Cis and DEBIRI and 22 with Gem/Cis alone (2 screen failures). The two groups were similar with respect to the extent of liver involvement (35% versus 38%) and presence of extrahepatic disease (29% versus 14%, p = 0.12). Median numbers of chemotherapy cycles were similar (6 versus 6), as were rates of grade 3/4 adverse events (34% for the Gem/Cis-DEBIRI group versus 36% for the Gem/Cis group). The overall response rate was significantly greater in the Gem/Cis-DEBIRI arm versus the Gem/Cis arm at 2 (p < 0.04), 4 (p < 0.03), and 6 months (p < 0.05). There was significantly more downsizing to resection/ablation in the Gem/Cis-DEBIRI arm versus the Gem/Cis arm (25% versus 8%, p < 005), and there was improved median progression-free survival [31.9 (95% CI 8.5-75.3) months versus 10.1 (95% CI 5.3-13.5) months, p = 0.028] and improved overall survival [33.7 (95% CI 13.5-54.5) months versus 12.6 (95% CI 8.7-33.4) months, p = 0.048]. CONCLUSION: Combination Gem/Cis with DEBIRI is safe, and leads to significant improvement in downsizing to resection, improved progression-free survival, and overall survival.

Safety and efficacy of irreversible electroporation in the treatment of obstructive jaundice in advanced hilar cholangiocarcinoma.

BACKGROUND: Irreversible electroporation (IRE) has successfully been used for palliation of pancreatic and liver cancers due to its ability to ablate tumors without destroying nearby vital structures. To date, it has not been evaluated in patients with advanced hilar cholangiocarcinoma (AHC). This study presents a single-institution experience with IRE for management of obstructive jaundice in AHC. METHODS: A single-institution database was queried for patients undergoing IRE for AHC after PTBD placement for relief of obstructive jaundice from 2010 to 2017 and compared to a control group treated with standard of care only (No IRE). RESULTS: Twenty-six patients underwent IRE for AHC after PTBD replacement. Three patients experienced complications, with two experiencing severe (≥ grade 3) complications. After IRE, median time to PTBD removal was 122 days (range 0-305 days) and median catheter-free time before requiring PTBD replacement was 305 days (range 92-458 days). In comparison, the 137 control patients had an admission rate of 59% (N = 80 patients) for PTBD infection, occlusion, or catheter related problem. CONCLUSION: IRE safely achieves biliary decompression via tumor electroporation and allows PTBD removal for an extended period of time. In appropriately selected patients with obstructive jaundice in the setting of AHC, IRE can be used to increase catheter-free days and optimize overall quality of life.

Total duplication of the small single copy region in the angiosperm plastome: Rearrangement and inverted repeat instability in Asarum.

PREMISE OF THE STUDY: As more plastomes are assembled, it is evident that rearrangements, losses, intergenic spacer expansion and contraction, and syntenic breaks within otherwise functioning plastids are more common than was thought previously, and such changes have developed independently in disparate lineages. However, to date, the magnoliids remain characterized by their highly conserved plastid genomes (plastomes). METHODS: Illumina HiSeq and MiSeq platforms were used to sequence the plastomes of Saruma henryi and those of representative species from each of the six taxonomic sections of Asarum. Sequenced plastomes were compared in a phylogenetic context provided by maximum likelihood and parsimony inferences made using an additional 18 publicly available plastomes from early-diverging angiosperm lineages. KEY RESULTS: In contrast to previously published magnoliid plastomes and the newly sequenced Saruma henryi plastome published here, Asarum plastomes have undergone extensive disruption and contain extremely lengthy AT-repeat regions. The entirety of the small single copy region (SSC) of A. canadense and A. sieboldii var. sieboldii has been incorporated into the inverted repeat regions (IR), and the SSC of A. delavayi is only 14 bp long. All sampled Asarum plastomes share an inversion of a large portion of the large single copy region (LSC) such that trnE-UUC is adjacent to the LSC-IR boundary. CONCLUSIONS: Plastome divergence in Asarum appears to be consistent with trends seen in highly rearranged plastomes of the monocots and eudicots. We propose that plastome instability in Asarum is due to repetitive motifs that serve as recombinatory substrates and reduce genome stability.

Multi-disciplinary Concurrent Management of Recurrent Hepatocellular Therapy is Superior to Sequential Therapy.

BACKGROUND: Recurrent hepatocellular carcinoma after a patient's initial therapy, whether it is transplantation, resection, or ablation, remains a challenging clinical problem. Since recurrence occurs in 70% of all initially treated disease within 5 years, optimal management to treat this recurrence is needed. Currently, a bias exists toward mono-therapy (i.e., ablation alone, hepatic arterial therapy alone, or sorafenib therapy alone) instead of concurrent sequential therapy-as is common in other primary and metastatic disease to the liver. Thus, the aim of our study was to evaluate the overall survival of recurrent HCC based on either mono-therapy or multimodality therapy. METHODS: A review of our prospective 2245 patient hepato-pancreatico-biliary database was performed for all patients who underwent treatment with curative intent for hepatocellular carcinoma and had complete recurrence treatment data from June 2002 to May 2015. Mono-therapy was defined as initiation of a solitary therapy until disease progression or intolerance. Multimodality therapy was defined as at least 2 therapies that occurred simultaneously or within 4 weeks of each therapy. RESULTS: A total of 281 patients underwent treatment with curative intent for hepatocellular carcinoma, in which 192 experienced recurrence. These patients were treated with either thermal ablation or liver resection (LR) (N = 51), transarterial chemoembolization (TACE) or radiation (N = 68), systemic therapy (N = 26), or multimodality therapy (N = 47). The extent of the first recurrence was similar in regard to the number of tumors (median 1), the type of radiologic HCC, gender, BMI, and percentage of liver involvement. They differed in regard to size (MMT largest, median 5.6 cm, p = 0.02), and MMT had higher Hepatitis C involvement (37% of patients, p = 0.001). In evaluation of first recurrence treatment, after a median follow-up of 24 months, multimodality therapy has a significant improvement in overall survival (median 40 months, range 8-85), when compared to LR/Ablation (27 months, range 4-75), TACE/XRT (13 months, range 4-68), and systemic (26 months, range 3-59) (p = 0.003). CONCLUSION: Multimodality therapy should be considered in all patients with recurrent HCC based on tumor biology and underlying hepatic reserve. Hepatocellular cancer should be treated like other hepatic malignancies in which concurrent therapies are utilized simultaneously to optimize oncologic effects (response rates and overall survival) and minimize quality-of-life side effects. Multimodality therapy can lead to far superior overall survival and is well tolerated in the majority of recurrent HCC patients.

Comparison of tumor response assessment methods in patients with metastatic colorectal cancer after locoregional therapy.

BACKGROUND: We evaluated the performance of the Response Evaluation Criteria in Solid Tumor (RECIST), modified RECIST, and the European Association for the Study of Liver (EASL) guidelines and correlated them with survival in patients with metastatic colorectal cancer (mCRC) treated with locoregional therapy (LRT). PATIENTS AND METHODS: Our LRT registry was evaluated from 2008 to 2013. 228 mCRC patients were treated with LRT (91% drug-eluting beads, 9% radioembolization) were evaluated. Cox regression and Kaplan-Meier (KM) statistics were utilized for survival analysis. RESULTS: Excellent inter-rater agreement between EASL/mRECIST (κ = 905) was seen. Correlations between RECIST/mRECIST (κ = 0.638) and EASL/RECIST were weaker (κ = 0.638 and 0.598, respectively). There were significant differences in KM and Cox regression survivals between responders and nonresponders with all three methods (all P < 0.0001). Multivariate analysis identified RECIST response, tumor extent, performance status, concomitant chemotherapy, and prior surgery/ablation as independent prognostic factors. EASL response and mRECIST response were not found to be independent prognostic factors. CONCLUSION: Imaging biomarkers are not efficient and do not represent ideal surrogates for survival; however, they all display prognostic significance. RECIST is superior to mRECIST/EASL given its ability to stratify survival benefit according to response category and demonstrate independent prognostic significance. J. Surg. Oncol. 2016;113:443-448. © 2016 Wiley Periodicals, Inc.

Randomized controlled trial of irinotecan drug-eluting beads with simultaneous FOLFOX and bevacizumab for patients with unresectable colorectal liver-limited metastasis.

BACKGROUND: Reports have demonstrated the superior activity of combining both irinotecan and oxaliplatin (FOLFOXIRI) therapy. An option for gaining similar benefits with less toxicity would be the administration of irinotecan through a hepatic artery approach. The aim of this study was to assess the response and adverse event rates for irinotecan drug-eluting beads (DEBIRI) with folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab as a first-line treatment for unresectable colorectal liver metastasis. METHODS: Patients with colorectal liver metastases were randomly assigned to modified FOLFOX (mFOLFOX) and bevacizumab or mFOLFOX6, bevacizumab, and DEBIRI (FOLFOX-DEBIRI). The primary endpoint was the response rate. The secondary endpoints were adverse events, the rate of conversion to resection, and progression-free survival. RESULTS: The intention-to-treat population comprised 70 patients: 10 patients in the pilot and then 30 patients randomly assigned to the FOLFOX-DEBIRI arm and 30 patients randomly assigned to the FOLFOX/bevacizumab arm. The 2 groups were similar with respect to the extent of liver involvement (30% vs 30%), but a greater percentage of patients in the FOLFOX-DEBIRI arm had an Eastern Cooperative Oncology Group performance status of 1 or 2 (57% vs 31%) and extrahepatic disease (56% vs 32%, P = .02). The median numbers of chemotherapy cycles were similar (10 vs 9), and there were similar rates of grade 3/4 adverse events (54% for the FOLFOX-DEBIRI group vs 46% for the FOLFOX/bevacizumab group). The overall response rate was significantly greater in the FOLFOX-DEBIRI arm versus the FOLFOX/bevacizumab arm at 2 (78% vs 54%, P = .02), 4 (95% vs 70%, P = .03), and 6 months (76% vs 60%, P = .05). There was significantly more downsizing to resection in the FOLFOX-DEBIRI arm versus the FOLFOX/bevacizumab arm (35% vs 16%, P = .05), and there was improved median progression-free survival (15.3 vs 7.6 months). CONCLUSIONS: The simultaneous administration of mFOLFOX6 (with or without bevacizumab) and DEBIRI through the hepatic artery (FOLFOX-DEBIRI) is safe and does not cause treatment delays or increase the systemic toxicity of chemotherapy. This strategy leads to improved overall response rates, improved hepatic progression-free survival, and more durable overall progression-free survival in patients downsized to resection.

Putative floral brood-site mimicry, loss of autonomous selfing, and reduced vegetative growth are significantly correlated with increased diversification in Asarum (Aristolochiaceae).

The drivers of angiosperm diversity have long been sought and the flower-arthropod association has often been invoked as the most powerful driver of the angiosperm radiation. We now know that features that influence arthropod interactions cannot only affect the diversification of lineages, but also expedite or constrain their rate of extinction, which can equally influence the observed asymmetric richness of extant angiosperm lineages. The genus Asarum (Aristolochiaceae; ∼100 species) is widely distributed in north temperate forests, with substantial vegetative and floral divergence between its three major clades, Euasarum, Geotaenium, and Heterotropa. We used Binary-State Speciation and Extinction Model (BiSSE) Net Diversification tests of character state distributions on a Maximum Likelihood phylogram and a Coalescent Bayesian species tree, inferred from seven chloroplast markers and nuclear rDNA, to test for signal of asymmetric diversification, character state transition, and extinction rates of floral and vegetative characters. We found that reduction in vegetative growth, loss of autonomous self-pollination, and the presence of putative fungal-mimicking floral structures are significantly correlated with increased diversification in Asarum. No significant difference in model likelihood was identified between symmetric and asymmetric rates of character state transitions or extinction. We conclude that the flowers of the Heterotropa clade may have converged on some aspects of basidiomycete sporocarp morphology and that brood-site mimicry, coupled with a reduction in vegetative growth and the loss of autonomous self-pollination, may have driven diversification within Asarum.

Phylogenetic relationships in Asarum: Effect of data partitioning and a revised classification.

PREMISE OF THE STUDY: Generic boundaries and infrageneric relationships among the charismatic temperate magnoliid Asarum sensu lato (Aristolochiaceae) have long been uncertain. Previous molecular phylogenetic analyses used either plastid or nuclear loci alone and varied greatly in their taxonomic implications for the genus. We analyzed additional molecular markers from the nuclear and plastid genomes, reevaluated the possibility of a derived loss of autonomous self-pollination, and investigated the topological effects of matrix-partitioning-scheme choice. METHODS: We sequenced seven plastid regions and the nuclear ITS1-ITS2 region of 58 individuals representing all previously recognized Asarum s.l. segregate genera and the monotypic genus Saruma. Matrices were partitioned using common a priori partitioning schemes and PartitionFinder. KEY RESULTS: Topologies that were recovered using a priori partitioning of matrices differed from those recovered using a PartitionFinder-selected scheme, and by analysis method. We recovered six monophyletic groups that we circumscribed into three subgenera and six sections. Putative fungal mimic characters served as synapomorphies only for subgenus Heterotropa. Subgenus Geotaenium, a new subgenus, was recovered as sister to the remainder of Asarum by ML analyses of highly partitioned datasets. Section Longistylis, also newly named, is sister to section Hexastylis. CONCLUSIONS: Our analyses do not unambiguously support a single origin for all fungal-mimicry characters. Topologies recovered through the analysis of PartitionFinder-optimized matrices can differ drastically from those inferred from a priori partitioned matrices, and by analytical method. We recommend that investigators evaluate the topological effects of matrix partitioning using multiple methods of phylogenetic reconstruction.

Discovery of unusual anatomical and continuous characters in the evolutionary history of Conostegia (Miconieae: Melastomataceae).

Conostegia has been traditionally defined to consist of 42 species in the tribe Miconieae. Recent phylogenetic studies have cast doubt on the monophyly of the genus and highlighted the need for a phylogenetic study focused on Conostegia. The purpose of this study was to test the monophyly of Conostegia and address relationships in the genus. We addressed the evolutionary history of Conostegia using DNA sequences from six loci. Difficulty in finding discrete characters that support clades prompted an anatomical survey of leaves and flowers as well as the exploratory use of some continuous characters. We coded as many species as possible for fifteen characters. Lastly, field work was conducted to document floral traits at anthesis due to the poor quality of preservation of flowers on herbarium specimens. Conostegia was found to be paraphyletic and composed of three main clades. The historically important characters of a calyptrate calyx and pleiostemony were found to have evolved more than once inside the Conostegia clade. Several other characters were found to support the clades we identified. The most unusual characters were mucilage inside the ovary which is here reported in the Melastomataceae for the first time, a stele inside the style which is mostly restricted to one clade of Conostegia and known only in this clade of the Melastomataceae, and herkogamy which has been lost in two clades within Conostegia. A combination of molecular phylogenetic analyses and broad morphological surveys allowed the better understanding of the evolutionary history in a clade of mostly cloud forest Neotropical trees. The need to include anatomical studies and tackle continuous characters is here demonstrated.

Phylogeny and infrageneric classification of Symplocos (Symplocaceae) inferred from DNA sequence data.

Symplocos comprises ∼300 species of woody flowering plants with a disjunct distribution between the warm-temperate to tropical regions of eastern Asia and the Americas. Phylogenetic analyses of 111 species of Symplocos based on the nuclear ribosomal internal transcribed spacer (ITS) region and the chloroplast genes rpl16, matK, and trnL-trnF yielded topologies in which only one of the four traditionally recognized subgenera (Epigenia; Neotropics) is monophyletic. Section Cordyloblaste (subgenus Symplocos; eastern Asia) is monophyletic and sister to a group comprising all other samples of Symplocos. Section Palura (subgenus Hopea; eastern Asia) is sister to a group comprising all other samples of Symplocos except those of section Cordyloblaste. Symplocos wikstroemiifolia (eastern Asia) and S. tinctoria (southeastern United States), both of subgenus Hopea, form a clade that groups with S. longipes (tropical North America) and the species of subgenus Epigenia. The remaining samples of subgenus Hopea (eastern Asia) form a clade. Section Neosymplocos (subgenus Microsymplocos; Neotropics) is well nested within a clade otherwise comprising the samples of section Symplocastrum (subgenus Symplocos; Neotropics). Section Urbaniocharis (subgenus Microsymplocos; Antilles) groups as sister to the clade comprising Symplocastrum and Neosymplocos. The data support the independent evolution of deciduousness among section Palura and S. tinctoria. The early initial divergence of sections Cordyloblaste and Palura from the main group warrants their recognition at taxonomic levels higher than those at which they are currently placed. An inferred eastern Asian origin for Symplocos with subsequent dispersal to the Americas is consistent with patterns from other phylogenetic studies of eastern Asian-American disjunct plant groups but contrary to a North American origin inferred from the earliest fossil occurrences of the genus.

Assessment of mazindane, a pro-drug form of mazindol, in assays used to define cocaine treatment agents.

The current studies compared mazindane (5-(4-chlorophenyl)-2,3-dihydro-5H-imidazo [2,1a] isoindole) hydrogen sulfate, a water soluble pro-drug of mazindol (5-(4-chlorophenyl-2,3-dihydro-5H-imidazo [2,1-a] isoindol-5-ol), with mazindol in assays used to define cocaine treatment agents. Both compounds enhanced motor activity (LMA) in Swiss Webster mice with ED(50) values of 2.5 mg/kg i.p. for mazindane and 3.9 mg/kg i.p. for mazindol. At 25 mg/kg mazindane displayed toxic effects and death while mazindol was effect/death free at 50 mg/kg. In Sprague-Dawley rats trained to discriminate cocaine from saline both compounds fully substituted for cocaine with mazindane being fourfold more potent in the total session (0.33 vs. 1.3 mg/kg i.p.) and first reinforcer (0.29 vs. 1.2 mg/kg i.p). Complete substitution was observed in rhesus monkeys trained to discriminate cocaine from saline with ED(50) values for mazindane (0.134 mg/kg i.m.) and mazindol (0.119 mg/kg i.m.). Mazindol exhibited little or no activity at 10(-5) M in inhibiting radioligand binding at 14 neurotransmitter sites while mazindane gave weak activity at the histamine H(1) and 5-hydroxytryptamine 5-HT(3) sites. These results demonstrate that mazindane could be a useful alternative to mazindol as a pharmacological tool because of its similar profile of activity and enhanced water solubility.

Mazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter.

A series of mazindol (2) and homomazindol (3) analogues with a variety of electron-donating and electron-withdrawing groups in the pendant aryl group and the benzo ring C, as well as H, methoxy, and alkyl groups replacing the hydroxyl group were synthesized, and their binding affinities at the dopamine transporter (DAT) on rat or guinea pig striatal membranes were determined. Several active analogues were also evaluated for their ability to block uptake of DA, 5-HT, and NE and inhibit binding of [(125)I] RTI-55 at HEK-hDAT, HEK-hSERT, and HEK-hNET cells. Mazindane (26) was found to be a pro-drug, oxidizing (5-H --> 5-OH) to mazindol on rat striatal membranes and HEK-hDAT cells. The 4',7,8-trichloro analogue (38) of mazindol was the most potent and selective ligand for HEK-hDAT cells (DAT K(i) = 1.1 nM; SERT/DAT = 1283 and NET/DAT = 38). Experimental results strongly favor the cyclic or ol tautomers of 2 and 3 to bind more tightly at the DAT than the corresponding keto tautomers.

Benzo- and cyclohexanomazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter.

A series of mazindol (1), homomazindol (2), and bishomomazindol (3) derivatives with a benzo or cyclohexano ring fused at various sites were prepared as part of an SAR study to determine the effect of increased aliphatic and aromatic lipophilicity on selected in vitro assays used to identify potential cocaine-like and cocaine antagonism activity. Very good (IC(50) = 2-3 nM) inhibition of [(3)H] WIN 35,428 and [(125)I] RTI-55 binding on rat or guinea pig striatal membranes and HEK cells expressing cDNA for the human dopamine transporter (HEK-hDAT) was shown by the 8,9-benzomazindol 25 and 9,10-benzohomomazindol 28. All new compounds were weaker inhibitors of [(3)H] DA uptake in HEK-hDAT cells than 1 and 2. No improvement in the binding selectivity ratio (SERT/DAT and NET/DAT) was found when compared to 2. Compounds 25and 28 showed a considerable increase versus 1 in uptake/binding discrimination ratios at the DAT (311.0 and 182.1 vs 0.9), SERT (33.6 and 127.3 vs 1.9), and NET (7.3 and 10.0 vs 0.3).