CI-1033 is an orally available 4-anilinoquinazolone irreversible tyrosine kinase inhibitor of erbB-1, erbB-2, and erbB-4. We conducted a dose escalation study of CI-1033 with docetaxel to assess the ...safety profile and pharmacokinetics of the combination and to establish the maximum tolerated dose.
Twenty-six patients with advanced solid tumors were treated on four dosing cohorts starting at CI-1033 (50 mg/d) + docetaxel (75 mg/m2). An intermittent dosing schedule avoided concurrent drug dosing.
CI-1033 alone was escalated from 50 to 75 mg/d (dose level 2), where diarrhea was dose limiting; a 38% incidence of cycle 1 febrile neutropenia prompted dose de-escalation of both CI-1033 and docetaxel for dose level 3, where dose-limiting toxicities prompted further de-escalation of CI-1033 to 45 mg/d. Given equivalent safety profiles for dose level 1 CI-1033 (50 mg/d) + docetaxel (75 mg/m2) and dose level 4 CI-1033 (45 mg/d) + docetaxel (60 mg/m2), the former was determined to be the recommended phase II dose, given greater dose intensity of both drugs. Antitumor activity was noted in three patients, including a complete response in a patient with cervix uteri cancer. Pharmacokinetic analysis showed a possible effect of docetaxel on CI-1033 pharmacokinetics.
It is feasible to combine the irreversible pan-erbB tyrosine kinase inhibitor CI-1033 with docetaxel on an intermittent dosing schedule in advanced cancer patients. We established the maximum tolerated dose and recommended phase II dose for the combination. Further investigation of this combination should include a rigorous analysis of the effect of docetaxel on CI-1033 pharmacokinetics.
Inefficient transfer of personal health records among providers negatively impacts quality of health care and increases cost. This multicenter study evaluates the implementation of the first ...Internet-based image-sharing system that gives patients ownership and control of their imaging exams, including assessment of patient satisfaction.
Patients receiving any medical imaging exams in four academic centers were eligible to have images uploaded into an online, Internet-based personal health record. Satisfaction surveys were provided during recruitment with questions on ease of use, privacy and security, and timeliness of access to images. Responses were rated on a five-point scale and compared using logistic regression and McNemar's test.
A total of 2562 patients enrolled from July 2012 to August 2013. The median number of imaging exams uploaded per patient was 5. Most commonly, exams were plain X-rays (34.7%), computed tomography (25.7%), and magnetic resonance imaging (16.1%). Of 502 (19.6%) patient surveys returned, 448 indicated the method of image sharing (Internet, compact discs CDs, both, other). Nearly all patients (96.5%) responded favorably to having direct access to images, and 78% reported viewing their medical images independently. There was no difference between Internet and CD users in satisfaction with privacy and security and timeliness of access to medical images. A greater percentage of Internet users compared to CD users reported access without difficulty (88.3% vs. 77.5%, P < 0.0001).
A patient-directed, interoperable, Internet-based image-sharing system is feasible and surpasses the use of CDs with respect to accessibility of imaging exams while generating similar satisfaction with respect to privacy.
Thromboembolism is a significant cause of morbidity and mortality in inflammatory bowel disease. Several prothrombotic conditions have been investigated in inflammatory bowel disease. The aim of this ...study was to evaluate the incidence of symptomatic postoperative superior mesenteric vein thrombosis in inflammatory bowel disease patients undergoing colonic resections and to identify and characterize their clinical presentation.
Between January 1999 and December 2001, 83 consecutive patients undergoing total colectomy for inflammatory bowel disease were studied retrospectively. Patients who developed new-onset postoperative acute abdominal pain were evaluated by CT scan of the abdomen. A complete coagulation profile, including thrombin time, platelet count, protein C, protein S, antithrombin III, homocysteine level, factor V Leiden mutation, plasminogen, and prothrombin G20210A mutation, was obtained in patients diagnosed with superior mesenteric vein thrombosis.
Four patients (4.8 percent; 3 females; 3 patients with ulcerative colitis and 1 with Crohn's colitis) developed symptomatic postoperative superior mesenteric vein thrombosis. Two of these patients had extension of the clot into the portal vein. Their presenting symptom was abdominal pain, with a median interval of ten days from the index surgery. The hematologic workup was negative in three patients, with one heterozygous for prothrombin G20210A mutation. All patients were treated with systemic anticoagulation for at least six months. One ulcerative colitis patient was diagnosed after abdominal colectomy and underwent an uneventful ileal pouch-anal anastomosis after systemic anticoagulation.
Postoperative superior mesenteric vein thrombosis is a more frequent occurrence than previously reported in patients with inflammatory bowel disease. Direct surgical trauma to the middle colic veins, with resulting thrombosis, is likely to be the precipitating factor in a borderline intrinsically hypercoagulable environment. All patients became asymptomatic after systemic anticoagulation and recovered uneventfully.
The sharing of radiologic images has become a fundamental part of radiology services and is essential for delivering high-quality care. Film is quickly becoming obsolete as a means of transporting ...and sharing large volumes of imaging data. Image sharing has evolved from film to transportable media (eg, compact disks) to direct electronic exchange over the Internet. The latter two means of image sharing have associated work flow-related and technical challenges for which solutions are being developed. Integrating the Healthcare Enterprise (IHE) provides a standards-based approach to the development of robust, universally accepted solutions. Several IHE profiles have been developed to provide a framework for current image sharing efforts. The Philadelphia and New Jersey Health Information Exchanges and the Canada Health Infoway represent efforts to apply IHE technical profiles to facilitate the secure and confidential exchange of electronic images over the Internet. The research community is concomitantly developing solutions that solve image exchange issues that are specific to research (eg, the sharing of deidentified data) but that might also be encountered in the general population. The personal health record is a more recent development that may provide consumers with direct control over the process of sharing images electronically with their healthcare providers.
Summary
Background
This trial evaluated the safety, tolerability and maximum tolerated dose (MTD) of afatinib, a novel ErbB Family Blocker.
Methods
In this open-label, dose-escalation Phase I study, ...afatinib was administered continuously, orally, once-daily for 28 days to patients with advanced or metastatic solid tumors. Dose escalation was performed in a 3 + 3 design, with a starting dose of 10 mg/day (d); doses were doubled for each successive cohort until the MTD was defined. The MTD cohort was expanded to a total of 19 patients. Incidence and severity of adverse events (AEs), antitumor activity and pharmacokinetics were assessed.
Results
Thirty patients received at least one dose of afatinib. Twenty-nine patients were evaluable for response. Dose-limiting toxicities (DLTs) consisting of Grade 3 diarrhea were observed in two out of three patients treated at 60 mg/d. The MTD was determined at 40 mg/d. The most frequent treatment-related AEs were diarrhea and mucosal inflammation reported in 76.7 % and 43.3 % of patients respectively. Five patients had stable disease with a median progression-free survival of 111 days. No objective responses occurred. Pharmacokinetic data showed no deviation from dose-proportionality and steady-state was reached on Day 8 at the latest.
Conclusions
Afatinib was well tolerated with manageable side effects when administered once-daily, continuously at a dose of 40 mg.
Background—Bone must have sufficient strength to withstand both instantaneous forces and lower repetitive forces. Repetitive loading, especially when bone strain and/or strain rates are high, can ...create microdamage and result in stress fracture Aim—To measure in vivo strains and strain rates in human tibia during high impact and moderate impact exercises. Methods—Three strain gauged bone staples were mounted percutaneously in a rosette pattern in the mid diaphysis of the medial tibia in six normal subjects, and in vivo tibial strains were measured during running at 17 km/h and drop jumping from heights of 26, 39, and 52 cm. Results—Complete data for all three drop jumps were obtained for four of the six subjects. No statistically significant differences were found in compression, tension, or shear strains with increasing drop jump height, but, at the 52 cm height, shear strain rate was reduced by one third (p = 0.03). No relation was found between peak compression strain and calculated drop jump energy, indicating that subjects were able to dissipate part of the potential energy of successively higher drop jumps by increasing the range of motion of their knee and ankle joints and not transmitting the energy to their tibia. No statistically significant differences were found between the principal strains during running and drop jumping from 52 cm, but compression (p = 0.01) and tension (p = 0.004) strain rates were significantly higher during running. Conclusions—High impact exercises, as represented by drop jumping in this experiment, do not cause higher tibial strains and strain rates than running and therefore are unlikely to place an athlete who is accustomed to fast running at higher risk for bone fatigue.
Aims
The aim of the study was to determine the effect of renal impairment and prior platinum‐based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended ...doses for patients with renal impairment or prior platinum‐based (PB) chemotherapy.
Methods
A multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. Patients were grouped by normal renal function with limited or prior PB chemotherapy or impaired renal function (mild creatinine clearance (CLcr) = 50–79 ml min−1, moderate CLcr = 30–49 ml min−1, severe CLcr <30 ml min−1).
Results
Fifty‐nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration–time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non‐Asian patients with the same degree of renal impairment. Thirteen dose‐limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m−2 day−1, given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m−2 day−1 for patients with moderate renal impairment (suggested dose 1.9 mg m−2 day−1 for non‐Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m−2 day−1 in this cohort.
Conclusions
Oral topotecan dose adjustments are not required in patients with prior PB chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment.
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