SWOG 1815: A phase III randomized trial of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin in newly diagnosed, advanced biliary tract cancers

Background: Biliary tract cancers (BTCs) are a heterogeneous group of malignancies with a dismal prognosis. Gemcitabine-based regimens are the standard of care in advanced disease, but median overall survival (OS) is roughly 12 months. The addition of albumin-bound paclitaxel to gemcitabine and cisplatin (GAP) demonstrated promising efficacy in a 60 patient, single-arm phase II study (Shroff et al, JAMA Oncol 2019), with observed median OS of 19.2 months. Methods: SWOG 1815 is a randomized, open-label, phase III trial comparing GAP to gemcitabine/cisplatin (GC). The study included newly diagnosed advanced BTC patients (pts), randomized 2:1 to GAP vs. GC. GAP included gemcitabine at 800 mg/m2, cisplatin at 25 mg/m2 and albumin-bound paclitaxel at 100 mg/m2 on days 1 and 8 of a 21-day cycle. GC included standard dosing of gemcitabine at 1000 mg/m2 and cisplatin at 25 mg/m2 on days 1 and 8 of a 21-day cycle. Pts were treated until progression. The primary endpoint was overall survival (OS) with a target hazard ratio of 0.7 with 90% power and a 1-sided alpha of 0.025; randomization was stratified by disease site (intrahepatic cholangiocarcinoma [CCA] vs gallbladder adenocarcinoma [GBC] vs extrahepatic CCA), disease stage (locally advanced vs metastatic), and Zubrod PS 0 vs 1. Results: Of 441 eligible pts randomized, 55% were female. 67% of patients had intrahepatic CCA, 16% had GBC and 17% had extrahepatic CCA. Most pts had metastases (73%). Median OS with GAP vs. GC was 14 vs. 12.7 mo respectively (HR 0.93, 95% CI 0.74-1.19, p=0.58), ORR (confirmed and unconfirmed) 34% vs25% (p=0.11) and median PFS 8.2 vs 6.4 mo (HR 0.92, 95% CI 0.72-1.16, p=0.47), respectively. Grade 3 and 4 treatment related adverse events (TRAEs) in ≥10% of pts for GAP and GC were anemia, neutropenia, and thrombocytopenia. GAP had more ≥ grade 3 hematologic AEs compared to the GC arm (60% vs. 45%, p=0.003). Discontinuation due to toxicity was at 24% vs 19% (p=0.26) with GAP vs GC. In exploratory subset analyses, GAP vs GC improved OS in pts with locally advanced disease (medians 19.2 vs 13.7 mo; HR 0.67, 95% CI 0.42- 1.06, p=0.09) and in GBC pts (medians 17.0 vs 9.3 mo; HR 0.74, 95% CI 0.41-1.35, p=0.33). ORR for GAP vs GC in GBC was 50% vs 24% (p=0.09) and for locally advanced disease 28 vs 21% p=0.74. Conclusions: SWOG 1815 did not result in a statistically significant improvement in median OS with GAP vs. GC. The GAP regimen had higher rates of TRAEs without a statistically significant difference in discontinuation rates. Pts with locally advanced disease and GBC may benefit from the use of GAP. Further analyses are ongoing to understand potential benefit of GAP in subsets of BTC pts. Funding: NIH/National Cancer Institute grants CA180888, CA180819, CA180820, CA180821, and CA180868; and in part by Celgene Corporation, Summit, NJ (subsidiary of Bristol Myer Squibb)

Oxy-functionalization of olefins with neat and heterogenized binuclear V(IV)O and Fe(II) complexes: effect of steric hindrance on product selectivity and output in homogeneous and heterogeneous phase

Neat {[VO(sal2bz)]2; [Fe(sal2bz)(H2O)2]2·2H2O} and zeolite-Y immobilized {[VO(sal2bz)]2-Y; [Fe(sal2bz)(H2O)2]2-Y} binuclear complexes have been prepared and characterized by spectroscopic techniques (IR, UV–vis), elemental analyses (CHN, ICP-OES), thermal study (TGA), scanning electron micrograph (SEM), adsorption study (BET) and X-ray diffraction (XRD) patterns. Neat (homogeneous) and immobilized (heterogeneous) complexes were employed as catalysts in the oxidation of olefins, namely, cyclohexene, limonene and α-pinene in the presence of 30% hydrogen peroxide. 100% conversion of cyclohexene and α-pinene was obtained while limonene was oxidized up to 90%. Homogeneous catalysts showed highly selective result as neat [VO(sal2bz)]2 complex has provided 87% cyclohexane-1,2-diol and neat [Fe(sal2bz)(H2O)2]2·2H2O complex has provided 79% verbenone in oxidation of cyclohexene and α-pinene, respectively. We have observed that due to steric hindrance, formation of olefinic oxidation products increases on moving from α-pinene to limonene and limonene to cyclohexene. Additionally. recovered heterogeneous catalysts showed intact results up to two consecutive runs. Probable catalytic mechanism has been proposed for oxidation of cyclohexene

Drug targets and predictive biomarkers in the management of metastatic melanoma

Jaykumar Thumar, Eva Giesen, Harriet M KlugerYale Cancer Center, Yale School of Medicine, New Haven, CT, USAAbstract: Melanoma is the leading cause of fatal skin cancer, and in the past few decades, there has been an increase in the incidence of and mortality from metastatic melanoma. Until recently, the therapeutic options for treatment of metastatic melanoma were limited. The approval of ipilimumab (an anti-CTLA-4 antibody) and vemurafenib (mutant B-RAFV600E kinase inhibitor) by the Federal Drug Administration has led to a new era in melanoma treatment, and additional promising drugs and drug combinations are currently being investigated. As the choices of treatment for melanoma have expanded, the need to identify predictive biomarkers to tailor treatment strategies to individual tumor or immune system characteristics has become necessary. Such strategies have the potential of maximizing antitumor effect while minimizing toxicity and improving clinical benefit. In this article, we review the currently approved targeted therapies in melanoma and discuss the future of personalized therapy for this disease.Keywords: vemurafenib, mutations, inhibitors, tumor

<span style="font-size:15.0pt;mso-bidi-font-size: 14.0pt;font-family:"Times New Roman";mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-US;mso-fareast-language:EN-US;mso-bidi-language:AR-SA" lang="EN-US">Quality control parameters to detect adulteration of market samples of Indian <i style="mso-bidi-font-style:normal">Manjistha</i> by Irani <i style="mso-bidi-font-style:normal">Manjistha</i></span>

331-334The stems of Manjistha are official in Ayurvedic Pharmacopoeia of India and equated with Rubia cordifolia L. They are traditionally used for curing blood disorders, skin diseases, as anti-inflammatory, haemostatic, urolithotriptic, antipyretic, analgesic, anthelmintic and for improving complexion. They are found in several important traditional medicinal formulations and hold a great export potential as well. However, stems of <i style="mso-bidi-font-style: normal">Rubia tinctorum L. are also available in the Indian market, which are not official and have been found to contain lucidin, a genotoxic compound. The present investigation deals with comparative pharmacognostical study of stems of both species and establishment of various quality parameters. Morphologically, the stems of both the species vary a lot. Transverse section of both stems showed the presence of reddish dye in cortex and acicular crystals of calcium oxalate; however, the width of cork, cortex, stele and pith varied. Powder microscopy revealed the presence of annular and pitted xylem vessels, xylem fibers and acicular crystals in singular and bundles; however their sizes varied in both species. From the phytochemical screening, the detected phyto-constituents were estimated by their respective procedures, which also varied in both species. Thus, the present work can serve as a very useful botanical and phytochemical tool in the identification, authentication and standardization of the raw material and prepared formulations of R. cordifolia L. and distinguishing it from of R. tinctorum L., which will consequently benefit the herbal industries and traditional medicinal healers. </span

Pd(II)/β-ICD-Cocatalyzed Asymmetric Route to Oxindole Scaffold via Cascade Reaction of Diazoacetamides and MBH-Carbonates

We report an efficient method for asymmetric synthesis of chiral oxindoles. Allyl palladium­(II) chloride dimer (APC)-catalyzed, in combination with β-isocupreidine (β-ICD)-cocatalyzed, reaction of diazoacetamide with Morita–Baylis–Hillman (MBH) carbonates proves to be a facile protocol to access multifunctional oxindoles bearing a C-3 quaternary stereo center. This tandem reaction tolerates a wide variety of functional groups on the both aromatic rings. This method delivers a variety of chiral oxindoles in 50–75% yield and with up to 95:5 dr in most cases along with up to 93:7 er

Hypergammaglobulinemia and Impaired Transplacental Transfer of Respiratory Syncytial Virus Antibody in Papua New Guinea

BACKGROUND: Passively-acquired respiratory syncytial virus (RSV) neutralizing antibody (Ab) can protect against RSV-associated lower respiratory tract illness. Maternal RSV immunization is, therefore, an attractive strategy for protection of very young infants. Vaccines for this purpose are currently being evaluated in clinical trials, but conditions such as preterm birth, placental malaria, maternal hypergammaglobulinemia and HIV infection might threaten this strategy. Each has been shown to impair transplacental Ab transfer for a variety of pathogens, but RSV-specific data are limited. Work in The Gambia demonstrated that placental malaria impaired transplacental transfer of RSV Ab, but a subsequent study in malaria-endemic Papua New Guinea (PNG) indicated that such associations may have been confounded by hypergammaglobulinemia (IgG \u3e 1700 mg/dL). METHODS: Here we confirm and extend those findings by measuring RSV neutralizing Ab and maternal IgG in sera from a larger cohort of 325 mother/infant pairs in PNG, and demonstrate the applicability of a high-throughput assay for assessment of neutralizing Ab. RESULTS: One-third of mother-infant pairs demonstrated impaired RSV Ab transfer. Infants of hypergammaglobulinemic women were more likely to have both impaired transfer [cord-to-maternal titer ratio \u3c 1.0, adjusted odds ratio (OR): 3.36 (95% confidence interval: 1.81-6.30)] and the lowest RSV cord titers [adjusted OR: 5.09 (95% confidence interval: 1.95-13.32, P \u3c 0.001)], but neither outcome was associated with placental malaria. CONCLUSIONS: Once maternal RSV vaccines become available, successful implementation will require clear understanding and mitigation of factors that can impair passive protection, necessitating epidemiologic studies of such relationships ahead of vaccine availability. This study underscores the need to focus on hypergammaglobulinemia as a condition of importance