The orally bioavailable met inhibitor PF‐2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model

Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Ninety percent of patients who present with metastatic and 30% to 40% of patients with nonmetastatic disease experience relapse, creating an urgent need for novel therapeutic strategies. The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are important for mitosis, motility, and cell survival. Upregulation of Met/HGF signaling via receptor overexpression, amplification, or mutation drives the proliferation, invasiveness, and metastasis of a variety of cancer cells, including OS, prompting the development of Met/HGF inhibitors. OS cells depend on Met overexpression because introduction of dominant‐negative Met inhibits in vivo tumorigenicity. Despite the importance of Met/HGF signaling in the development and maintenance of OS, the potential efficacy of pharmacologic Met inhibition in OS has been addressed only in in vitro studies. PF‐2341066 is an orally bioavailable, selective ATP‐competitive Met inhibitor that showed promising results recently in a phase I clinical trial in non–small cell lung cancer (NSCLC) patients. We tested the ability of PF‐2341066 to inhibit malignant properties of osteosarcoma cells in vitro and orthotopic xenograft growth in vivo. In vitro, PF‐2341066 inhibited osteosarcoma behavior associated with primary tumor growth (eg, proliferation and survival) as well as metastasis (eg, invasion and clonogenicity). In nude mice treated with PF‐2341066 via oral gavage, the growth and associated osteolysis and extracortical bone matrix formation of osteosarcoma xenografts were inhibited by PF‐2341066. PF‐2341066 may represent an effective new systemic therapy for localized and potentially disseminated osteosarcoma. © 2011 American Society for Bone and Mineral Research.     

Diabetes and cancer: Looking at the multiligand/RAGE axis

The association between diabetes and hyperglycemia and the associated increased risk of several solid and hematologic malignancies has been the subject of investigation for many years.Although the association is not fully understood,current knowledge clearly indicates that diabetes may influence malignant cell transformation by several mechanisms,including hyperinsulinemia,hyperglycemia and chronic inflammation.In this context,the receptor for advanced glycation end-products (RAGE) has emerged as a focal point in its contribution to malignant transformation and tumor growth.We high-light how RAGE,once activated,as it manifests itself in conditions such as diabetes or hyperglycemia,is able to continuously bring about an inflammatory milieu,thus supporting the contribution of chronic inflammation to the development of malignancies.     

Defecation disturbances after cystectomy for urinary bladder cancer

Study Type – Preference (prospective cohort) Level of Evidence 4 What’s known on the subject? and What does the study add? Functional gastrointestinal symptoms and problems are common after radical cystectomy with urinary diversion. This study adds new important epidemiological data on this group of symptoms.

OBJECTIVE

• ? To describe and compare long‐term defecation disturbances in patients who had undergone a cystectomy due to urinary bladder cancer with non‐continent urostomies, continent reservoirs and orthotopic neobladder urinary diversions.

PATIENTS AND METHODS

• ? During their follow‐up we attempted to contact all men and women aged 30–80 years who had undergone cystectomy and urinary diversion at seven Swedish hospitals.
• ? During a qualitative phase we identified defecation disturbances as a distressful symptom and included this item in a study‐specific questionnaire together with free‐hand comments. The patients completed the questionnaire at home.
• ? Outcome variables were dichotomized and the results are presented as relative risks with 95% confidence interval.

RESULTS

• ? The questionnaire was returned from 452 (92%) of 491 identified patients. Up to 30% reported problems with the physiological emptying process of stool (bowel movement, sensory rectal function, awareness of need for defecation, motoric rectal and anal function, straining ability).
• ? A sense of decreased straining capacity was reported by 20% of the men and women with non‐continent urostomy and 14% and 8% of those with continent reservoirs and orthotopic neobladders, respectively.

CONCLUSIONS

• ? Of the cystectomized individuals 30% reported problems with the physiological emptying process of stool (bowel movement, sensory rectal function, awareness of need for defecation, motoric rectal and anal function, straining ability).
• ? Those wanting to improve the situation for bladder cancer survivors may consider communicating before surgery the possibility of stool‐emptying problems, and asking about them after surgery.

     

Improving cell engraftment with tissue engineering

Cardiac cell therapy has not yet resulted in long-term clinical benefits or major recovery of myocardial function in humans. To date, most of the cardiac effects of cell-based therapy are believed to be mediated by a local angiogenic response rather than by the formation of neosyncytial contractile units such as had initially been hoped for. Therefore, repopulation of the ischemic or infarcted heart with progenitor cells that have vasculogenic potential may be an important mechanism to improve contractile function, both in the presence of viable and nonviable myocardium. This constitutes a focus within scientific reach; however, the low engraftment and viability of progenitor cells after transplantation necessitate the exploration of novel delivery techniques. Because biomaterials have the capacity to improve cell retention, survival, and differentiation, tissue engineering is now being explored as an approach to support cell-based therapies and enhance their efficacy. In this article, we address current progress made in tissue engineering to support cell therapy for the heart, and summarize our work in the development of biomaterials toward improving cell delivery and vascularization of ischemic tissue.     

Alemtuzumab induction and triple maintenance immunotherapy in kidney transplantation from donors after cardiac death.

We have used alemtuzumab in combination with triple maintenance immunosuppression in renal transplantation from donors after cardiac death between 2002 and 2006. We compared outcomes of induction therapy with alemtuzumab with interleukin-2 (IL-2) receptor antagonists (RA) and anti-lymphocyte antibodies. We used a retrospective sequential study design to examine 170 recipients of kidneys from donor after cardiac death (DCD) for survival, graft survival, time to first rejection, glomerular filtration and complications. Patients were stratified into high-risk and low-risk groups based on the following criteria: panel of reactive antibodies >20%, retransplants, Afro-American race. Induction with alemtuzumab was compared with anti-thymocyte globulin (ATG) in the high-risk and with IL-2RA in the low-risk group. Patients received triple immunosuppression with steroids, mycophenolate mofetil and calcineurin inhibitors. Patient survival, graft survival, rejection rate and glomerular filtration rate did not significantly differ between patients treated with alemtuzumab versus IL-2RAs or ATG. There was a trend towards reduced graft- and patient survival in the alemtuzumab group. There was an increased incidence of cytomegalovirus (CMV) infections in the alemtuzumab-induced group and a trend towards increased BK virus and bacterial infections. Induction of DCD kidney transplants with alemtuzumab compared to IL-2RA and ATG has no significant impact on acute rejection. It appears however that CMV infections are increased in patients induced with alemtuzumab. We therefore conclude that induction with alemtuzumab does not confer any advantage over traditional induction agents.     

Selective approach to use of upper gastroesophageal imaging study after laparoscopic Roux-en-Y gastric bypass

BACKGROUND: Many institutions routinely perform upper gastroesophageal imaging (UGI) studies on their laparoscopic Roux-en-Y gastric bypass (LRYGB) patients after surgery. We had routinely studied our patients with UGI on postoperative day 1 to rule out an anastomotic leak or obstruction, until recently when we abandoned this practice. As previously reported, we found that routine UGI did not contribute significantly to patient care. The purpose of this study was to determine whether patient outcomes were affected by this change in protocol. METHODS: From March 2004 to September 2005, 508 LRYGB cases were performed at our institution. Linear cutting staplers were used to create both the gastrojejunostomy and the jejunojejunostomy. In each case, the Roux limb was brought up in an antecolic, antegastric configuration. Before changing our protocol, 194 LRYGB cases were performed, and each patient underwent a routine UGI study (group 1). After abandoning this practice, 314 LRYGB cases were performed (group 2), and an UGI study was obtained only if clinical indicators (e.g., tachypnea, tachycardia, nausea, vomiting, low urine output, and/or abdominal pain) were present. The patient demographics, including gender, age, body mass index, length of hospital stay, and complications were recorded in our bariatric database and reviewed retrospectively. RESULTS: A postoperative UGI study was obtained in 204 patients--in 194 patients routinely (group 1) and in 10 patients because of clinical indications (group 2). No obstructions or leaks were found in any of these 204 patients. In group 2, 304 patients were discharged without an UGI series and did well without any leak or obstruction, except for 1 patient who returned 3 months postoperatively with a stricture at his jejunojejunostomy. No statistically significant differences were found between the 2 groups. CONCLUSION: The results of our study have shown that routine UGI studies after LRYGB do not contribute significantly to postoperative patient care at our institution. We now perform them selectively according to clinical indications, without this change adversely affecting our clinical outcomes.     

Internal to External Carotid Artery Transposition to Repair Recurrent Stenosis after Carotid Artery Stenting

Recently, carotid artery stenting (CAS) has emerged as a treatment option for carotid artery stenosis. Since the procedure is new, management of its complications is not standardized. This case report describes one method of arterial reconstruction after failed CAS. A 64-year-old male underwent CAS of his right internal carotid artery (ICA) for an asymptomatic 65% stenosis. Seven months later the stented area had narrowed to 95%. Arteriography revealed that the common and external carotid arteries (ECA) were free of disease so we elected to perform a transposition of the distal ICA onto the proximal ECA. The ECA and its branches were completely mobilized and the ascending pharyngeal and lingual arteries divided. The ICA was divided distal to the stent. Transection of the occipital artery provided an arteriotomy for an end ICA to side ECA anastamosis, thus preserving ECA flow. Postoperative surveillance after 8 months has revealed no recurrent stenosis. Operative repair of restenosis after CAS may be challenging if standard endarterectomy is not possible. Other options for reconstruction are feasible but if the common and external carotid arteries are disease-free, an ICA to ECA transposition provides a simple all-arterial repair that avoids bypass and prosthetic material.     

Incisional hernia in a 12-mm non-bladed trocar site following laparoscopic nephrectomy

Non-bladed trocars, radially-dilating systems, and conical blunt devices are considered less traumatic to the abdominal wall because they do not incise the fascia itself. Consequently, several authors have suggested that closure of the abdominal fascia may be unnecessary if such non-bladed laparoscopic trocars are used. We report of a case in whom a port-site hernia was diagnosed at the site of a 12-mm non-bladed trocar 11 days after laparoscopic nephrectomy.     

Management of a patient with shoulder pain and disability: a manual physical therapy approach addressing impairments of the cervical spine and upper limb neural tissue

STUDY DESIGN: Case report. BACKGROUND: Shoulder pain and disability is a common clinical problem that may be influenced by impairments from a variety of sources. The purpose of this case report is to illustrate a manual physical therapy management approach for a patient with shoulder pain and disability, specifically addressing impairments of the cervical spine and upper limb neural tissue believed to contribute to the patient's symptoms. CASE DESCRIPTION: The patient was a 45-year-old female research scientist with symptoms of anterior shoulder and posterior scapular region pain that limited her ability to use her right upper extremity for normal activities of daily living. An examination and evaluation revealed impairments of the cervical spine and upper limb neural tissue that were believed to contribute to the patient's symptoms. Intervention consisted of joint mobilization directed at the impaired cervical spine segment. The Shoulder Pain and Disability Index (SPADI) and goniometric measurement of shoulder range of motion (ROM) were used to measure outcomes following the intervention. OUTCOMES: The patient was seen once a week over the course of 5 weeks. The patient's SPADI score improved from 83% to 1.5% over the course of treatment. Active ROM of shoulder flexion improved from 50 degrees to 155 degrees over this period of time. A 6-month follow-up revealed a full return to usual activity and a SPADI score of 0%. DISCUSSION: A manual physical therapy approach addressing impairments of the cervical spine and upper limb neural tissue may lead to improved outcomes in the management of patients with shoulder pain and disability.