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Background: Subcutaneous (SC) trastuzumab is similar to intravenous trastuzumab in terms of pharmacokinetics, efficacy and tolerability. The use of dual anti-HER2 agents trastuzumab and pertuzumab has become the new standard for node-positive HER2-positive breast cancers at adjuvant setting, but the safety and tolerability of combining SC trastuzumab and intravenous pertuzumab is not well studied.Methods: This was a prospective single-arm pilot study with locally advanced HER2-positive breast cancer who received adjuvant SC trastuzumab and intravenous pertuzumab after standard anti-HER2 treatment with chemotherapy. Primary outcomes included adverse events (AEs), severe AEs and cardiac AEs. Secondary outcome was invasive disease-free survival (iDFS).Results: With a median follow-up of 21.7 months, 20 patients were enrolled. One patient (5%) developed asymptomatic drop in left ventricular ejection fraction from 69% to 53%. Two patients (10%) developed grade 1 injection site reaction related to SC trastuzumab. There were no grade 2 or above AEs. All AEs were transient. No new AEs were observed. The 1-year iDFS was 90% (95% CI 0.656 to 0.974) CONCLUSIONS: Combination of SC trastuzumab and intravenous pertuzumab for HER2-positive breast cancer is a safe and well-tolerated option in adjuvant setting. [ABSTRACT FROM AUTHOR]

Unlike metal-ion-catalyzed hydrolysis processes, metal-ion-catalyzed methanolysis processes have received scant attention in the literature particularly from the standpoint of mechanistic studies. [La.sup.3+], introduced into methanol solution as its triflate or perchlorate salt, is particularly effective in promoting methanolysis reactions of unactivated and activated esters, phosphate triesters, and activated amides such as acetyl imidazoles and lactams. Studies of the kinetics of methanolysis of these substrates as a function of solution pH and [[La.sup.3+]] indicate that the solution comprises lanthanum dimers with one to five associated methoxides ([[La.sub.2.sup.3+] ([sup.-]OC[H.sub.3]).sub.1-5]), the most catalytically active form being [La.sub.2.sup.3+]([[sup.-]OC[H.sub.3]).sub.2], which is produced at near neutral pH in methanol (8.4). Mechanisms for all the acyl and phosphoryl transfer reactions are proposed where the metal ion serves a dual role of acting as a Lewis acid to activate the C=O or P=O system to nucleophilic attack by a metal-coordinated methoxide nucleophile. In cases where direct comparisons can be made, the [La.sub.2.sup.3+] catalyst system is more active for the methanolysis of nonactivated substrates than for activated substrates. Another general characteristic of this system is that the catalytic rate constant for the metal complex exceeds the second-order rate constant for free methoxide, in some cases by as much as 4600-fold. Overall the catalytic effects exhibited by the [La.sub.2.sup.3+] system is spectacular for such substrates as paraoxon, where as little as 2 mmol [L.sup.-1] La[(OTf).sub.3] in the presence of equimolar NaOC[H.sub.3] accelerates the methanolysis by [10.sup.9]-fold relative to the background reaction at neutral pH and ambient temperature. Key words: kinetics of methanolysis, metal ion catalysis, lanthanides, methanolysis of carboxylate esters and phosphate esters.

It has been demonstrated that a methanol solution containing 2 x 10(super -3) M La(OTf)3, at (super s)(Sub s)PH values around neutrality can be used to promote the methanolysis of paraxon with a 10(super 9) -fold acceleration over the base reaction at the (super s)(Sub s)PH. The system seemed to provide the largest reported acceleration for many man-made catalyst capable of promoting the solvolysis of a phosphate triester.

The methanolysis of hydroxypropyl-p-nitrophenyl phosphate (HPNPP) promoted by La(OTf)(sub 3) under buffered conditions is studied in methanol as a function of (sub s)(super s)pH at 25 degrees Celsius. It is seen that throughout the (sub s)(super s)pH regime at high [La(super 3+], a saturation complex, (La(super 3+OCH3(super -1)(sub 2), is formed that spontaneously decomposes with a rate constant of (5-10) times 10(super -3)s(super -1), leading to an acceleration of 10(super 9)-fold at (sub s)(super s)pH 8.0.

First-line treatments of cancer do not always work, and even when they do, they cure the disease at unequal rates mostly owing to biological and clinical heterogeneity across patients. Accurate prediction of clinical outcome and survival following the treatment can support and expedite the process of comparing alternative treatments. We describe the methodology to dynamically determine remission probabilities for individual patients, as well as their prospects of progressionfree survival (PFS). The proposed methodology utilizes the ex vivo drug sensitivity of cancer cells, their immunophenotyping results, and patient information, such as age and breed, in training machine learning (ML) models, as well as the Cox hazards model to predict the probability of clinical remission (CR) or relapse across time for a given patient. We applied the methodology using the three types of data obtained from 242 canine lymphoma patients treated by (L)-CHOP chemotherapy. The results demonstrate substantial enhancement in the predictive accuracy of the ML models by utilizing features from all the three types of data. They also highlight superior performance and utility in predicting survival compared to the conventional stratification method. We believe that the proposed methodology can contribute to improving and personalizing the care of cancer patients. [ABSTRACT FROM AUTHOR]

The systemic treatment of advanced, unresectable hepatocellular carcinoma (HCC) has undergone an evolution in recent years. In March 2020, a combination of nivolumab and ipilimumab was approved by the FDA for treatment of patients with advanced HCC who received prior sorafenib. This was based on the results of the phase I/II CheckMate-040 cohort 4 trials, which showed a promising overall response rate and encouraging overall survival with a manageable safety profile. This article reviews the pharmacology, efficacy and safety of nivolumab-ipilimumab in advanced HCC with prior sorafenib. Other existing systemic treatment options for advanced HCC will be described and compared to nivolumab-ipilimumab. Impact of different dose regimes, ongoing research and future developments of nivolumab-ipilimumab will be discussed. We focus on the analysis from the aforementioned CheckMate-040 cohort 4 registration trial. The approval of nivolumab-ipilimumab in the second-line treatment of advanced HCC by the FDA is an important development for treatment of advanced HCC. However, further investigations are needed to optimize dosing regimens and explore the use of nivolumab-ipilimumab in other combinations and settings. [ABSTRACT FROM AUTHOR]

We report a precision medicine platform that evaluates the probability of chemotherapy drug efficacy for canine lymphoma by combining ex vivo chemosensitivity and immunophenotyping assays with computational modelling. We isolated live cancer cells from fresh fine needle aspirates of affected lymph nodes and collected post‐treatment clinical responses in 261 canine lymphoma patients scheduled to receive at least 1 of 5 common chemotherapy agents (doxorubicin, vincristine, cyclophosphamide, lomustine and rabacfosadine). We used flow cytometry analysis for immunophenotyping and ex vivo chemosensitivity testing. For each drug, 70% of treated patients were randomly selected to train a random forest model to predict the probability of positive Veterinary Cooperative Oncology Group (VCOG) clinical response based on input variables including antigen expression profiles and treatment sensitivity readouts for each patient's cancer cells. The remaining 30% of patients were used to test model performance. Most models showed a test set ROC‐AUC > 0.65, and all models had overall ROC‐AUC > 0.95. Predicted response scores significantly distinguished (P <.001) positive responses from negative responses in B‐cell and T‐cell disease and newly diagnosed and relapsed patients. Patient groups with predicted response scores >50% showed a statistically significant reduction (log‐rank P <.05) in time to complete response when compared to the groups with scores <50%. The computational models developed in this study enabled the conversion of ex vivo cell‐based chemosensitivity assay results into a predicted probability of in vivo therapeutic efficacy, which may help improve treatment outcomes of individual canine lymphoma patients by providing predictive estimates of positive treatment response. [ABSTRACT FROM AUTHOR]

The purpose of this review is to compare conventional endovascular procedures and the robotic endovascular approach in aortic aneurysm repair. Despite advantages over open surgery, conventional endovascular surgery has limitations. To develop an alternative, efforts have been focused on robotic endovascular systems. Two of the 3 studies comparing procedure times demonstrated reduced procedure time in the robotic group, by 6 times (p < 0.05). One study demonstrated that robotic procedures reduced fluoroscopic exposure time by 12 minute (p < 0.001). Three in-vitro studies showed that the number of movements required in robotic surgery was reduced up to 10 times (p < 0.05). One of 2 studies measuring robotic performance score showed a better performance score in the robotic endovascular group (p = 0.007). These results demonstrate that the robotic technique has multiple advantages over the conventional procedure, including improved catheter stability, a shorter learning curve, reduced procedure time, and better performance in cannulating tortuous vessels. However, robotic endovascular technology may be limited by the cost of the system, the size of the catheter, and the setup time required preoperatively. Further comparative studies between conventional and robotic approaches regarding cost-effectiveness, safety, and performance in cases involving complex anatomy and fenestrated stent grafts are essential. Nevertheless, this revolutionary technology is increasingly popular and may be the next milestone in endovascular surgery. [ABSTRACT FROM PUBLISHER]

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The methanolysis of the insecticide paraoxon (2) was investigated in methanol solution containing varying [La(OTf)[sub 3]] (OTf = [sup -]OS(O)[sub 2]CF[sub 3]) as a function of [sup s, sub s]pH at 25 °C. Plots of the pseudo-first-order rate constants (k[sub obs]) for methanolysis as a function of [La(OTf)[sub 3]][sub total] were obtained under buffered conditions from [sup s, sub s]pH 5.15 to 10.97, and the slopes of the linear parts of these were used to determine the secondorder rate constants (k[sub 2, sup obs]) for the La[sup 3+]-catalyzed methanolysis of 2. Detailed analysis of the potentiometric titration data of La(OTf)[sub 3] in methanol through fits to a multicomponent equilibrium mixture of dimers of general stoichiometry La[sup 3+, sub 2](-OCH[sub 3])[sub n], where n assumes values of 1-5, gives the equilibrium distribution of each as a function of [sup s, sub s]pH. These data, when fit to a second expression describing k[sub 2, sup obs] in terms of a linear combination of individual rate constants k[sub 2, sup 2:1], k[sub 2, sup 2:2].....k[sub 2, sup 2:n] for the dimers, allow one to describe the overall catalytic profile in terms of the individual contributions. The most catalytically important species are the three dimers La[sup 3+, sub 2]([sup -]OCH[sub 3])[sub 1], La[sup 3+, sub 2]([sup -]OCH[sub 3])[sub 2], and La[sup 3+, sub 2]([sup -]OCH[sub 3])[sub 3]. The catalysis of the methanolysis of 2 is spectacular: a 2 × 10[sup -3] M solution of [La[sup 3+]][sub total], at neutral [sup s, sub s]pH, affords a 10[sup 9]-fold acceleration relative to the base reaction (t[sub ½] ≈ 20 s at [sup s, sub s]pH 8.2) with excellent turnover. A mechanism of the catalyzed reaction involving the La[sup 3+, sub 2]([sup -]OCH[sub 3])[sub 2] species is proposed. [ABSTRACT FROM AUTHOR]

The highly functionalized [5.9.5] tricyclic framework resident in jatrophatrione (1) and citlalitrione (2) has been synthesized. The route begins with the tandem anionic oxy-Cope rearrangement/methylation/ transannular ene cyclization of 21 and subsequent introduction of a conjugated enone double bond. Hydroxyldirected 1,4-reduction of this functionality in 25 with LiAIH[sub 4]/Cul/hexamethylphosphoramide/tetrahydrofuran sets the stage for the implementation of a Grob fragmentation and expedited generation of 27. Stereocontrolled intramolecular hydrosilylation allows for the subsequent introduction of a cyctic carbonate as in 53. This intermediate undergoes remarkably efficient, fully regiocontrolled Treibs reaction to generate 54, with this maneuver serving as a pivotal step for making 1 available five steps later. Treatment of 1 with m-chloroperbenzoic acid leads to 2, with attack occurring preferentially on a α-face of the double bond more remote to the carbonyl. [ABSTRACT FROM AUTHOR]

The catalytic ability of a dinuclear Zn2+ complex of 1,3-bis-N1-(1 ,5,9-triazacyclododecyl)propane (3) in promoting the cleavage of an RNA model, 2-hydroxypropyl-p-nitrophenyl phosphate (HPNPP, 1), and a DNA model, methyl p-nitrophenyl phosphate (MNPP, 4), was studied in methanol solution in the presence of added CH3O at 25 °C. The di-Zn2+ complex (Zn2:3), in the presence of 1 equiv of added methoxide, exhibits a second-order rate constant of (2.75 ± 0.10) × 105 M-1 s-1 for the reaction with 1 at sspH 9.5, this being 108-fold larger than the k2 value for the CH3O- promoted reaction (kOCH3 = (2.56 ± 0.16) × 10-3 M-1 s-1). The complex is also active toward the DNA model 4, exhibiting Michaelis—Menten kinetics with a KM and kmax of 0.37 ± 0.07 mM and (4.1 ± 0.3) × 10-2 s-1, respectively. Relative to the background reactions at sspH 9.5, Zn2:3 accelerates cleavage of each phosphate diester by a remarkable factor of 1012-fold. A kinetic scheme common to both substrates is discussed. The study shows that a simple model system comprising a dinuclear Zn2+ complex and a medium effect of the alcohol solvent achieves a catalytic reactivity that approaches enzymatic rates and is well beyond anything seen to date in water for the cleavage of these phosphate diesters. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to determine the feasibility of fetal surgical repair of myelomeningocele (MMC) in a rodent model using human placental mesenchymal stromal cells (PMSCs) seeded onto extracellular matrix (ECM) and to characterize the resulting changes in spinal cord tissue., Methods: Fetal rodents with retinoic acid (RA) induced MMC underwent surgical repair of the MMC defect using an ECM patch on embryonic age (EA) 19 and were collected via caesarean section on EA 21. Various seeding densities of PMSC-ECM and ECM only controls were evaluated. Cross-sectional compression (width/height) and apoptotic cell density of the lumbosacral spinal cord were analyzed., Results: 67 dams treated with 40mg/kg of RA resulted in 352 pups with MMC defects. 121 pups underwent MMC repair, and 105 (86.8%) survived to term. Unrepaired MMC pups had significantly greater cord compression and apoptotic cell density compared to normal non-MMC pups. Pups treated with PMSC-ECM had significantly less cord compression and demonstrated a trend towards decreased apoptotic cell density compared to pups treated with ECM only., Conclusion: Surgical repair of MMC with a PMSC-seeded ECM disc is feasible with a postoperative survival rate of 86.8%. Fetal rodents repaired with PMSC-ECM have significantly less cord deformity and decreased histological evidence of apoptosis compared to ECM only controls., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The catalytic ability of a dinuclear Zn2+ complex of 1,3-bis-N1-(1,5,9-triazacyclododecyl)propane (3) in promoting the cleavage of an RNA model, 2-hydroxypropyl-p-nitrophenyl phosphate (HPNPP, 1), and a DNA model, methyl p-nitrophenyl phosphate (MNPP, 4), was studied in methanol solution in the presence of added CH3O- at 25 degrees C. The di-Zn2+ complex (Zn2 :3), in the presence of 1 equiv of added methoxide, exhibits a second-order rate constant of (2.75 +/- 0.10) x 10(5) M(-1) s(-1) for the reaction with 1 at s(s)pH 9.5, this being 10(8)-fold larger than the k2 value for the CH3O- promoted reaction (kOCH3 = (2.56 +/- 0.16) x 10(-3) M(-1) s(-1)). The complex is also active toward the DNA model 4, exhibiting Michaelis-Menten kinetics with a KM and kmax of 0.37 +/- 0.07 mM and (4.1 +/- 0.3) x 10(-2) s(-1), respectively. Relative to the background reactions at s(s)pH 9.5, Zn2 :3 accelerates cleavage of each phosphate diester by a remarkable factor of 1012-fold. A kinetic scheme common to both substrates is discussed. The study shows that a simple model system comprising a dinuclear Zn2+ complex and a medium effect of the alcohol solvent achieves a catalytic reactivity that approaches enzymatic rates and is well beyond anything seen to date in water for the cleavage of these phosphate diesters.