Frozen Elephant Trunk Completion: Endovascular Extension in The Distal Thoracic Aorta.

INTRODUCTION: Complex pathologies involving the aortic arch can be treated using the frozen elephant trunk (FET) technique, which is versatile and continues to be improved with different innovations to further reduce, for example, circulatory arrest time and the need for hypothermia. FET may or may not be a definitive repair, however. Distal extension or completion-especially endovascular-is common but not well described in the literature. This review describes the considerations that are necessary during FET planning and preparation, how pathology specifics and sizing decisions will affect the subsequent need for treatment, and how outcomes might be better reported to improve understanding of the advantages and limitations of the technique. MATERIALS AND METHODS: This literature review was performed to identify reports of second-stage endovascular completion after FET repair, and included any literature that described such interventions after index FET, for any aortic arch pathology. RESULTS: Secondary intervention after FET is an important parameter to establish the success or failure of the index procedure. However, unplanned extensions are often reported with insufficient detail and follow up, and studies rarely differentiate between unplanned or adjunctive procedures. In addition, prediction of the need for extension is complicated by the response of the pathology to the index procedure. CONCLUSION: FET is a versatile, established surgical technique that allows for several applications in different pathologies and innovative adaptations. How, when, and why FET is extended needs to be reported in greater detail, with specific consideration given to the interaction of FET and endovascular devices in sizing, integrity, and possible complications.

Research methodology and practical issues relating to the conduct of a medical device registry.

BACKGROUND: The postmarket research goal is to assess "generalizability" or "external validity" to see if the early results of clinical trials with investigational devices are reproducible in everyday practice in the real world and the longer term. Registries have an important but ambivalent role in achieving this goal. METHODS: Although registries are common, in practice they follow the regulatory processes that appear designed primarily for pharmaceutical clinical trials and confirmatory studies. We review the literature to assess different definitions and the role of registries in the hierarchy of scientific evidence. We analyze common characteristics affecting registry design, implementation, and governance as well as safety reporting and off-label use while describing the experience of setting up an international, prospective registry for an endovascular device used to treat abdominal aortic aneurysms. RESULTS: Key areas in which to distinguish registries from trials are as follows: eligibility, setting (patients and institutions), device configurations and iterations, the use of design and quality "spaces," a focus on systematic quality checks (rather than source data monitoring), open-ended follow-up, flexibility in the definition of end points and sample sizes, data sharing, and publishing commitments. CONCLUSION: Both clinical trials and registries are essential and complementary research methods and the strengths and weaknesses of each need to be recognized. The specific characteristics of registry research deserve to be acknowledged and safeguarded in the regulations governing clinical investigations with medical devices.

Well-Defined Chiral Gold(III) Complex Catalyzed Direct Enantioconvergent Kinetic Resolution of 1,5-Enynes.

The development of a gold(III) catalyzed direct enantioconvergent 1,5-enyne cycloisomerization and kinetic resolution reaction is described. The transformation results in highly enantioenriched bicyclo[3.1.0]hexenes at all levels of conversion, with no racemization or symmetrization taking place during the course of the reaction, and simultaneously affords optically enriched 1,5-enynes. This report marks the first highly enantioselective transformation catalyzed by a well-defined cationic gold(III) catalyst and demonstrates the unique potential of gold(III) complexes in enantioselective catalysis.

Phase I clinical and pharmacokinetic study of PM01183 (a tetrahydroisoquinoline, Lurbinectedin) in combination with gemcitabine in patients with advanced solid tumors.

Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dose (FD)/gemcitabine 1000 mg/m2 was the highest dose level tested. Dose-limiting toxicities (DLTs) were mostly hematological and resulted in the expansion of a lower dose level (PM01183 3.5 mg FD/gemcitabine 800 mg/m2); 19 patients at this dose level were evaluable but >30% had DLT and >20% had febrile neutropenia. No DLT was observed in 11 patients treated at PM01183 3.0 mg FD/gemcitabine 800 mg/m2, which was defined as the RD. This regimen was feasible and tolerable with manageable toxicity; mainly grade 3/4 myelosuppression. Non-hematological toxicity comprised fatigue, nausea, vomiting, and transaminases increases. Fifteen (33%) patients received ≥6 cycles with no cumulative hematological toxicity. Pharmacokinetic analysis showed no evidence of drug-drug interaction. Nine of 38 patients had response as per RECIST (complete [3%] and partial [21%]), for an overall response rate (ORR) of 24% (95% Confidence Interval [CI] 12-40%). Eleven patients (29%) had disease stabilization ≥4 months. Responses were durable (median of 8.5 months): overall median progression-free survival (PFS) was 4.2 months (95% CI, 2.7-6.5 months). Conclusions The RD for this combination is PM01183 3.0 mg FD (or 1.6 mg/m2)/gemcitabine 800 mg/m2 d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types.

Palladium-catalyzed, ring-forming aromatic C-H alkylations with unactivated alkyl halides.

A catalytic C-H alkylation using unactivated alkyl halides and a variety of arenes and heteroarenes is described. This ring-forming process is successful with a variety of unactivated primary and secondary alkyl halides, including those with ß-hydrogens. In contrast to standard polar or radical cyclizations of aromatic systems, electronic activation of the substrate is not required. The mild, catalytic reaction conditions are highly functional group tolerant and facilitate access to a diverse range of synthetically and medicinally important carbocyclic and heterocyclic systems.

A systematic review and meta-analysis of retrograde type A aortic dissection after thoracic endovascular aortic repair in patients with type B aortic dissection.

BACKGROUND: Retrograde type A dissection (RTAD) is a devastating complication of thoracic endovascular repair (TEVAR) with low incidence but high mortality. The objective of this study is to report the incidence, mortality, potential risk factors, clinical manifestation and diagnostic modalities, and medical and surgical treatments. METHODS: A systematic review and single-arm and two-arm meta-analyses evaluated all published reports of RTAD post-TEVAR through January 2021. All study types were included, except study protocols and animal studies, without time restrictions. Outcomes of interest were procedural data (implanted stent-grafts type, and proximal stent-graft oversizing), the incidence of RTAD, associated mortality rate, clinical manifestations, diagnostic workouts and therapeutic management. RESULTS: RTAD occurred in 285 out of 10,600 patients: an estimated RTAD incidence of 2.3% (95% CI: 1.9-2.8); incidence of early RTAD was approximately 1.8 times higher than late. Wilcoxon signed-rank testing showed that the proportion of RTAD patients with acute type B aortic dissection (TBAD) was significantly higher than those with chronic TBAD (P = .008). Pooled meta-analysis showed that the incidence of RTAD with proximal bare stent TEVAR was 2.1-fold higher than with non-bare stents: risk ratio was 1.55 (95% CI: 0.87-2.75; P = .13). Single arm meta-analysis estimated a mortality rate of 42.2% (95% CI: 32.5-51.8), with an I2 heterogeneity of 70.11% (P < .001). CONCLUSION: RTAD is rare after TEVAR but with high mortality, especially in the first month post-TEVAR with acute TBAD patients at greater risk as well as those treated with proximal bare stent endografts.

Phase Ib/II study of elisidepsin in metastatic or advanced gastroesophageal cancer (IMAGE trial).

PURPOSE: To determine the recommended dose and antitumor activity of single-agent elisidepsin as a 24-h intravenous (i.v.) infusion fortnightly [biweekly, d1 and 15 every 4 weeks (q4wk); Arm A, dose-intensity strategy] or as a 3-h i.v. infusion weekly (d1, 8, 15 and 22 q4wk; Arm B, dose-density strategy) in adult patients with unresectable, locally advanced or metastatic pretreated esophageal, gastroesophageal junction and gastric cancer. METHODS: Patients were randomized to one of two elisidepsin dosing schedules. Phase Ib starting doses were 8.0 mg flat dose (FD) in Arm A and 3.0 mg FD in Arm B. Phase II subsequently explored antitumor activity of both dosing schedules at the respective recommended doses. RESULTS: Forty-four patients received elisidepsin: 12 in stage Ib and 32 in stage II. The recommended doses were defined as 10 mg FD (Arm A) and 3.75 mg FD (Arm B). Both schedules were well tolerated. Most adverse events were mild or moderate, reversible and predictable with no meaningful differences between schedules. The pharmacokinetic profiles of both schedules were similar to those reported previously in patients with solid tumors treated with a comparable dose. An interim analysis found tumor control in one patient receiving elisidepsin fortnightly, and in none given elisidepsin weekly; patient accrual was therefore discontinued due to lack of efficacy. CONCLUSIONS: Both schedules at the recommended doses presented an acceptable safety profile, but lack of response means that we do not recommend further evaluation of single-agent elisidepsin as chemotherapy for unresectable, locally advanced or metastatic gastroesophageal cancer.

Use of a systems-based approach to an environmental health assessment for a waterborne disease outbreak investigation at a snowmobile lodge in Wyoming.

Investigations into disease outbreaks generally incorporate an epidemiologic investigation, laboratory analysis, and an environmental health assessment. This last component is designed to discover connections between factors in the environment and the outbreak, but is often limited, either by time and resources, or the expertise of the personnel included in outbreak investigation teams. A waterborne Norovirus outbreak investigation in Sheridan County, Wyoming, in 2001 provides an excellent example of the importance of including an in-depth, systems-based environmental health assessment in outbreak investigations. The epidemiologic component of this investigation identified the water supply of a snowmobile lodge in the Bighorn Mountains as the source of the outbreak, a result that was confirmed by laboratory analysis. Including a systems-based environmental health assessment in this investigation also helped to uncover the underlying environmental factors that led to contamination of the water supply. Those factors included an onsite wastewater disposal system that was overloaded by increased use and not well suited to local soil and geologic conditions and a drinking water system with no treatment or disinfection. In addition, heavy precipitation and increased pumping of wells to satisfy higher demands probably facilitated the contamination of the drinking water wells by causing greater movement of wastewater through the soil and underlying bedrock. By focusing on these links between factors in the environment and adverse health outcomes, the systems-based environmental health assessment also helped to highlight prevention strategies for avoiding recurrences.