Oral cancer treatment: developments in chemotherapy and beyond

Oncology is one of the few areas of medicine where most patients are treated intravenously rather than receiving oral drugs. Recently, several oral anti-cancer drugs have been approved and there are many more in development. Oral chemotherapy is attractive because of its convenience and ease of administration, particularly in the palliative setting. With an increasing number of oral agents emerging, we can expect to see a rapid rise in the use of oral chemotherapy in years to come. This article reviews recent developments in oral chemotherapy, both of traditional cytotoxics and novel, targeted agents, from the viewpoint of patients, physicians, drug developers and health-care providers

EORTC Early Clinical Studies Group early phase II trial of S-1 in patients with advanced or metastatic colorectal cancer

Cancer of the colon and rectum is one of the most frequent malignancies both in the US and Europe. Standard palliative therapy is based on 5-fluorouracil/folinic acid combinations, with or without oxaliplatin or irinotecan, given intravenously. Oral medication has the advantage of greater patient convenience and acceptance and potential cost savings. S-1 is a new oral fluorinated pyrimidine derivative. In a nonrandomized phase II study, patients with advanced/metastatic colorectal cancer were treated with S-1 at 40 mg m-2 b.i.d. for 28 consecutive days, repeated every 5 weeks, but by amendment the dose was reduced to 35 mg m-2 during the study because of a higher than expected number of severe adverse drug reactions. In total 47 patients with colorectal cancer were included. In the 37 evaluable patients there were nine partial responses (24%), 17 stable diseases (46%) and 11 patients had progressive disease (30%). Diarrhoea occurred frequently and was often severe: in the 40 and 35 mg m-2 group, respectively, 38 and 35% of the patients experienced grade 3-4 diarrhoea. The other toxicities were limited and manageable. S-1 is active in advanced colorectal cancer, but in order to establish a safer dose the drug should be subject to further investigations

Design, modeling, and optimization of 3D printed compliant mechanisms with applications to miniature walking robots

2018 Summer.Includes bibliographical references.Miniature robots have many applications ranging from military surveillance to search and rescue assistance in disaster areas. Traditionally, fabrication of these robots has been labor intensive, time-consuming, and expensive. This thesis proposes to leverage recent advances in 3D printing technology to fabricate centimeter-scale walking robots utilizing compliant elements printed directly into the walking mechanisms in replacement of traditional revolute joints or rigid links. The ability to design around the capabilities of 3D printers and novel material choices gives miniature robots the ability to have multiple functions in the same mechanism, reduces the overall number of parts that must be assembled to make a functional robot, and decrease the time and cost of prototyping. This thesis details three areas of study for compliant mechanisms with applications to walking robots. First, we utilize multi-material 3D printing to fabricate a miniature walking robot (49 x 38 x 25mm) that directly replaces the traditional revolute joints in the designed walking mechanism with a custom, soft joint. Some links are also printed with soft materials to enhance the robustness and durability of the robot. Along with design and testing of the robot, we develop two numerical models to simulate the effects of the soft elements on the mechanism trajectory. Second, we leverage the numerical models to optimize the design of the walking mechanism to produce a trajectory similar to that of the same mechanism using all revolute joints. Third, we redesign the original robot to utilize a conductive polylactic acid (PLA) material to 3D print linkages that allow for changing joints locations by softening the desired part through applied electricity. This variable joint mechanism can create multiple trajectories without changing the mechanical structure, therefore creating a multi-functional compliant mechianism. Such capabilities are demonstrated throughwalking on the ground and grasping objects using the same leg mechanism

Splicing inactivation generates hybrid mRNA-snoRNA transcripts targeted by cytoplasmic RNA decay

Many small nucleolar RNAs (snoRNA)s are processed from introns of host genes, but the importance of splicing for proper biogenesis and the fate of the snoRNAs is not well understood. Here, we show that inactivation of splicing factors or mutation of splicing signals leads to the accumulation of partially processed hybrid messenger RNA-snoRNA (hmsnoRNA) transcripts. hmsnoRNAs are processed to the mature 3' ends of the snoRNAs by the nuclear exosome and bound by small nucleolar ribonucleoproteins. hmsnoRNAs are unaffected by translation-coupled RNA quality-control pathways, but they are degraded by the major cytoplasmic exonuclease Xrn1p, due to their messenger RNA (mRNA)-like 5' extensions. These results show that completion of splicing is required to promote complete and accurate processing of intron-encoded snoRNAs and that splicing defects lead to degradation of hybrid mRNA-snoRNA species by cytoplasmic decay, underscoring the importance of splicing for the biogenesis of intron-encoded snoRNAs

The potential impact of plastic surgery expertise on body contouring procedure outcomes

Background: With the increasing demand for body contouring procedures in the United States over the past 2 decades, more surgeons with diverse specialty training are performing these procedures. However, little is known regarding the comparative outcomes of these patients. Objectives: The purpose of this study was to compare outcomes of body contouring procedures based on the specialty training of the surgeon. Methods: Data from the American College of Surgeons National Surgical Quality Improvement Program (2005-2015) were reviewed for all body contouring procedures. Patients were stratified by surgeon training (plastic surgery [PS] vs general surgery [GS]). Descriptive statistics and regression analyses were used to evaluate differences in outcomes. Results: A total of 11,658 patients were included; 9502 PS cases and 2156 GS cases. Most were women (90.4%), aged 40 to 59 (52.7%) and white (79.5%). Compared with PS patients, GS patients were more likely to be obese (61.4% vs 40.6%), smokers (13.6% vs 9.8%), and with ASA classification ≥3 (35.3% vs 18.6%) (all P \u3c 0.001). Abdominal contouring procedures were the most common (76%) cases. Multivariate regression revealed that compared with PS cases, those performed by GS practitioners were associated with increased wound and infectious complications (adjusted odds ratio [aOR], 1.81; 95% confidence interval [CI], 1.44-2.27), reoperation (aOR, 1.85; 95% CI, 1.31-2.62), and predicted mean length of stay (1.12 days; 95% CI, 0.64-1.60 days). Conclusions: The variable outcomes in body contouring procedures performed by PS compared with GS practitioners may imply procedural-algorithmic differences between the subspecialties, leading to the noted outcome differential. Level of Evidence: 2

A phase I clinical and pharmacokinetic study of Ro 31-7453 given as a 7- or 14-day oral twice daily schedule every 4 weeks in patients with solid tumors

Purpose: This is a dose-finding Phase I study of oral Ro 31-7453, a new class of antimitotic drug with promising preclinical activity in several chemoresistant models. Experimental Design: Two schedules of oral Ro 31-7453 (every 12 h) given for either 7 or 14 consecutive days repeated every 4 weeks were explored consecutively. Results: Thirty-seven patients with refractory cancer entered the study (14 on the 7-day schedule and 23 on the 14-day schedule). Median age was 63 years (range, 40-77 years), and median Karnofsky performance status was 80 (range, 60-100); the most frequent diagnosis was colorectal carcinoma (16 patients). Dose levels of 100, 200, 240, and 280 mg/m(2) twice daily (bid) for 7 days and 70, 100, 125, and 150 mg/m(2) bid for 14 days were explored. A total of 110 cycles were administered, the median number of cycles received was 3 (range, 1-7); six patients completed 6 or more cycles. Myelosuppression and mucositis were dose-limiting with both schedules. Fatigue and gastrointestinal toxicities other than mucositis were frequent but generally mild. The maximum tolerated doses were 200 mg/m(2) bid and 125 mg/m(2) bid for the 7- and 14-day schedules, respectively. Pharmacokinetic analysis showed rapid absorption and metabolism. The area under the concentration-time curve and trough concentrations of Ro 31-7453 and two active metabolites appeared dose proportional with a t(1/2) of similar to9 h and a t(max) of similar to4 h. One patient with pretreated lung cancer had a partial response. Conclusions: Both Ro 31-7453 regimens were feasible, but the 14-day schedule at the recommended dose of 125 mg/m(2) bid was selected for further monotherapy Phase II evaluation because of its higher preclinical activity. This regimen is convenient, well tolerated, and has a favorable pharmacokinetic profile