Citations

Abstract Background We conducted a phase 1 trial to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of cabozantinib in children with refractory or relapsed solid tumors. Methods Patients received cabozantinib tablets on a continuous dosing schedule in a rolling‐six escalating phase 1 trial design. PK and PD studies were performed. Results Forty‐one patients, median (range) age 13 (4–18) years, received cabozantinib to achieve a weekly cumulative dose equivalent to 30 (n = 6), 40 (n = 23). or 55 (n = 12) mg/m 2 /day. At 40 mg/m 2 /d, dose‐limiting toxicities (DLTs) were palmar‐plantar erythrodysesthesia syndrome, mucositis, and elevated alanine aminotransferase, lipase, and bilirubin. At 55 mg/m 2 /d, hypertension, reversible posterior leukoencephalopathy syndrome, headache, fatigue, and proteinuria were DLTs. Frequent non‐DLTs included diarrhea, hypothyroidism, fatigue, nausea, vomiting, elevated hepatic transaminases, and proteinuria. In subsequent cycles, DLTs occurred at all dose levels. Across all dose levels, the steady‐state exposure and peak cabozantinib concentrations were similar. Four patients experienced a confirmed partial response: medullary thyroid cancer (MTC; n = 2), Wilms tumor, and clear cell sarcoma. Stable disease (>6 cycles) was seen in seven patients (MTC [n = 2], Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, paraganglioma, and ependymoma). Conclusions A protocol‐defined MTD was not reached; DLTs and dose reductions for toxicity occurred in the first and subsequent cycles at all dose levels. Based on the toxicity profile, pharmacokinetics, and responses, the recommended dose of cabozantinib in pediatric patients with refractory solid tumors is 40 mg/m 2 /day. A phase 2 study of cabozantinib is being conducted.

BackgroundAppropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy and physician decision‐making.ObjectivesThe American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology.MethodsThe RAND/UCLA appropriateness methodology, which combines evidence‐based medicine, clinical experience and expert judgment, was used to develop AUC in dermatopathology.ResultsWith the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered “usually appropriate,” 52 (25%) “rarely appropriate” and 43 (20%) “uncertain appropriateness.”LimitationsThe methodology requires a focus on appropriateness without comparison between tests and irrespective of cost.ConclusionsThe ultimate decision of when to order specific test rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness—AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed “uncertain appropriateness” and where consensus was not reached may benefit from further research.

Objective: Acute kidney injury requiring renal replacement therapy in severe vasodilatory shock is associated with an unfavorable prognosis. Angiotensin II treatment may help these patients by potentially restoring renal function without decreasing intrarenal oxygenation. We analyzed the impact of angiotensin II on the outcomes of acute kidney injury requiring renal replacement therapy. Design: Post hoc analysis of the Angiotensin II for the Treatment of High-Output Shock 3 trial. Setting: ICUs. Patients: Patients with acute kidney injury treated with renal replacement therapy at initiation of angiotensin II or placebo ( n = 45 and n = 60, respectively). Interventions: IV angiotensin II or placebo. Measurements and Main Results: Primary end point: survival through day 28; secondary outcomes included renal recovery through day 7 and increase in mean arterial pressure from baseline of ≥ 10 mm Hg or increase to ≥ 75 mm Hg at hour 3. Survival rates through day 28 were 53% (95% CI, 38%–67%) and 30% (95% CI, 19%–41%) in patients treated with angiotensin II and placebo ( p = 0.012), respectively. By day 7, 38% (95% CI, 25%–54%) of angiotensin II patients discontinued RRT versus 15% (95% CI, 8%–27%) placebo ( p = 0.007). Mean arterial pressure response was achieved in 53% (95% CI, 38%–68%) and 22% (95% CI, 12%–34%) of patients treated with angiotensin II and placebo ( p = 0.001), respectively. Conclusions: In patients with acute kidney injury requiring renal replacement therapy at study drug initiation, 28-day survival and mean arterial pressure response were higher, and rate of renal replacement therapy liberation was greater in the angiotensin II group versus the placebo group. These findings suggest that patients with vasodilatory shock and acute kidney injury requiring renal replacement therapy may preferentially benefit from angiotensin II.

The PROSTALAC functional spacer is made of antibiotic-loaded acrylic cement but has a small metal-on-polythene articular surface. We have used it as an interim spacer in two-stage exchange arthroplasty for infected total knee replacement. PROSTALAC allows continuous rehabilitation between stages as it maintains good alignment and stability of the knee and a reasonable range of movement. It also helps to maintain the soft-tissue planes, which facilitates the second-stage procedure. We reviewed 45 consecutive patients, treated over a period of nine years. The mean follow-up was for 48 months (20 to 112). At final review, there was no evidence of infection in 41 patients (91%); only one had a recurrent infection with the same organism. There was improvement in the Hospital for Special Surgery knee score between stages and at final review. The range of movement was maintained between stages. Complications were primarily related to the extensor mechanism and stability of the knee between stages. Both of these problems decreased with refinement of the design of the implant. The rate of cure of the infection in our patients was similar to that using other methods. Movement of the knee does not appear to hinder control of infection.

An analysis of the cement mantle obtained with the Exeter impaction allografting system at one centre showed that it was either deficient or absent in almost 47% of Gruen zones. We therefore examined the mantle obtained using this system at another hospital and compared the results with those from the CPT and Harris Precoat Systems at other centres. The surgical indications for the procedure and the patient details were broadly similar in all four hospitals. There was some variation in the frequency of use of cortical strut allografts, cerclage wires and wire mesh to supplement the impaction allograft. Analysis of the cement mantles showed that when uncertain Gruen zones were excluded, the incidence of zones with areas of absence or deficiency of the cement was 47% and 50%, respectively, for the two centres using the Exeter system, 21% for the CPT system and 18% for the Harris Precoat system. We measured the difference in size between the proximal allograft impactors and the definitive prosthesis for each system. The Exeter system impactors are shorter than the definitive prosthesis and taper sharply so that the cavity created is inadequate, especially distally. The CPT proximal impactors are considerably longer than the definitive prosthesis and are designed to give a mantle of approximately 2 mm medially and laterally and 1.5 mm anteriorly and posteriorly. The Harris Precoat proximal impactors allow for a mantle with a circumference of 0.75 mm in the smaller sizes and 1 mm in the larger. Many reports link the longevity of a cemented implant to the adequacy of the cement mantle. For this reason, femoral impaction systems require careful design to achieve a cement mantle which is uninterrupted in its length and adequate in its thickness. Our results suggest that some current systems require modification.

We describe a U-shaped approach to the distal femur which, having divided the extensor mechanism and elevated the entire quadriceps muscle, gives excellent exposure and allows a number of reconstructive options. It was used in 14 patients, 13 of whom were followed up for a mean of 3.5 years (1 to 11). There was no case of flap necrosis, and complications related to the reconstruction were acceptable.

Background: Most hand surgeons use a dorsal approach for proximal interphalangeal (PIP) joint implant arthroplasty. However, a volar approach offers the advantage of no disturbance to the extensor mechanism, thus allowing early initiation of active range of motion. We examined our results in patients who underwent PIP joint arthroplasty via a volar approach.Methods: Using a retrospective chart review, we evaluated the outcomes of patients undergoing PIP joint arthroplasty through a volar approach between 2001 and 2005 by 3 fellowship-trained hand surgeons at our institution. The indication for surgery was PIP joint pain with radiographic evidence of joint destruction. Variables included implant type, diagnosis, affected digit(s), preoperative and postoperative range of motion, and complications. Hand therapy was initiated on postoperative day 3 or 4.Results: Over the 5 years, 25 PIP joints were replaced in 18 women and 2 men with the volar approach. Replacements consisted of 14 surface replacement prostheses, 9 pyrocarbon prostheses, and 2 silicone prostheses. The average age of patients at prosthesis implantation was 64 years (range, 39–75 years). Prostheses were placed in 1 index, 12 long, 7 ring, and 5 small digits. Average follow-up period was 33 months (range, 24–69 months). Preoperative diagnoses were osteoarthritis (14), rheumatoid arthritis (4), and posttraumatic arthritis (2). Preoperative total arc of motion averaged 42° (range, 0° extension to 80° flexion); postoperative total arc of motion averaged 56° (range, –10° extension to 90° flexion). Complications comprised 1 swan neck deformity, 1 deep infection, 1 dislocation (early), and 2 loose implants with flexion contractures. Seventeen patients had minimal or no pain at their last follow-up visit.Conclusions: PIP joint arthroplasty can be successfully implemented through a volar approach with various implant types and has outcomes similiar to the published results of the dorsal approach.

This pilot study examined the functional impact of computerized versus compensatory calendar training in cognitive rehabilitation participants with mild cognitive impairment (MCI). Fifty-seven participants with amnestic MCI completed randomly assigned calendar or computer training. A standard care control group was used for comparison. Measures of adherence, memory-based activities of daily living (mADLs), and self-efficacy were completed. The calendar training group demonstrated significant improvement in mADLs compared to controls, while the computer training group did not. Calendar training may be more effective in improving mADLs than computerized intervention. However, this study highlights how behavioral trials with fewer than 30–50 participants per arm are likely underpowered, resulting in seemingly null findings.

Shape memory polymers can be programmed into a secondary geometry and recovered to their primary geometry with the application of a controlled stimulus. Porous shape memory polymer foam scaffolds that respond to body temperature show particular promise for embolic medical applications. A limitation for the minimally invasive delivery of these materials is an inherent lack of X-ray contrast. In this work, a triiodobenzene containing a monomer was incorporated into a shape memory polymer foam material system to chemically impart X-ray visibility and increase material toughness. Composition and process changes enabled further control over material density and thermomechanical properties. The proposed material system demonstrates a wide range of tailorable functional properties for the design of embolic medical devices, including X-ray visibility, expansion rate, and porosity. Enhanced visualization of these materials can improve the acute performance of medical devices used to treat vascular malformations, and the material porosity provides a healing scaffold for durable occlusion.