A Comparative Assessment Study of Known Small-molecule GPVI Modulators.

The GPVI platelet receptor was recently validated as a safe antiplatelet target for the treatment of thrombosis using several peptidic modulators. In contrast, few weakly potent small-molecule GPVI antagonists have been reported. Those that have been published often lack evidence for target engagement, and their biological efficacy cannot be compared because of the natural donor variability associated with the assays implemented. Herein, we present the first side-by-side assessment of the reported GPVI small-molecule modulators. We have characterized their functional activities on platelet activation and aggregation using flow cytometry as well as light transmission and electrical impedance aggregometry. We also utilized microscale thermophoresis (MST) and saturation transfer difference (STD) NMR to validate GPVI binding and have used this along with molecular modeling to suggest potential binding interactions. We conclude that of the compounds examined, losartan and compound 5 are currently the most viable GPVI modulators.

Adverse Surgical Outcomes Associated with Robotic Retroperitoneal Lymph Node Dissection Among Patients with Testicular Cancer.

Surgery for metastatic testicular disease has been an essential factor in the long-term cure rates for men with testicular germ cell tumors. Robotic approaches to retroperitoneal lymph node dissection (R-RPLND) have been proposed as an alternative to open surgery with few if any adverse events reported. We report the clinical course for five recent patients referred to our center for recurrences after R-RPLND, focusing on recurrence patterns, treatment burden, and treatment-related morbidity and mortality. The median time to recurrence after R-RPLND was 259d. The recurrence patterns after R-RPLND were aberrant from our past experience in managing recurrences after open RPLND. One man experienced an in-field recurrence located in close proximitry to an undivided lumbar vessel. Four patients had out-of-field recurrence in abnormal locations: pericolic space invading the sigmoid colon, peritoneal carcinomatosis with a perinephric mass, large-volume liver lesions with suprahilar disease extending into the retrocrural space, and lymph nodes in the celiac axis. The treatment burden was high: the five men were subjected to 12 different chemotherapy regimens and three underwent additional surgeries. Three patients developed significant cisplatin-induced toxicity. One patient died due to progression of testicular cancer after failing all chemotherapy and surgical options. PATIENT SUMMARY: We report our initial experience in managing patients with testicular cancer referred to our institution after robotic retroperitoneal lymph node dissection (RPLND). We found that the recurrences were highly variable and in unusual locations and were associated with a high treatment burden. We conclude that further investigation into the safety and long-term oncologic efficacy of robotic RPLND is necessary before widespread implementation.

Incidence, histology and management of intraluminal thrombus at post-chemotherapy retroperitoneal lymph node dissection.

PURPOSE: We determined the incidence, histology and management of intraluminal thrombus in a large group of patients treated with post-chemotherapy retroperitoneal lymph node dissection. MATERIALS AND METHODS: We queried the testicular cancer database at our institution from January 1990 to June 2010. Tumor resection en bloc with major vascular structures and/or thrombectomy at post-chemotherapy retroperitoneal lymph node dissection was done in 240 patients, of whom 89 had a total of 98 intraluminal thrombi involving major vasculature. RESULTS: The site of the 98 thrombi was the inferior vena cava (72), aorta (1) and renal vein (20). Management of the 72 vena caval thrombi included cavectomy (36), partial cavectomy (9) and thrombectomy (27). For the 20 renal vein thrombi management included nephrectomy (18) and thrombectomy (2). The single aortic thrombus was managed by aortic resection and replacement. Pathological evaluation revealed bland thrombi in 31 cases, necrosis in 23, teratoma in 28, active germ cell cancer in 12 and sarcoma in 4. In 40 patients a total of 71 additional procedures were required, including nephrectomy in 32, liver resection in 6, bowel resection in 7, thoracotomy in 6, vertebral resection in 3, orchiectomy in 11, and duodenal repair, ureteroureterotomy, stent removal, cholecystectomy, appendectomy and paraspinal tumor removal in 1 each. There were 17 Clavien III or worse complications in a total of 11 patients, including 2 deaths. Average estimated blood loss was 1,165 ml (range 200 to 7,000) and average hospital stay was 9.3 days (range 2 to 70). CONCLUSIONS: The incidence of intraluminal thrombus at post-chemotherapy retroperitoneal lymph node dissection is 5.8%. Cancer pathology was observed in 44.9% of cases. Surgeons who perform post-chemotherapy retroperitoneal lymph node dissection should be well versed in vascular techniques with respect to the major vasculature.

Medicare financial status, budget impact, and sustainability--which concept is which?

Medicare is continually undergoing change, as it must in order to reflect advances in medical technology, new health care delivery systems, financial pressures, and other developments. Modifications to the program are debated by policymakers in Congress and the administration, together with academic experts and others. These debates would be improved if policymakers and the public had a clearer understanding of Medicare and certain commonly cited views of the program's overall status. Three such concepts--the financial status of the Medicare trust funds, the impact of Medicare on the Federal budget, and the long-run sustainability of Medicare-are often confused with each other and are sometimes used interchangeably. Each concept is important but needs to be used for its own purpose. This article clarifies the differences among these three views of Medicare and provides examples of each.

Delayed orchiectomy at postchemotherapy retroperitoneal lymph node dissection due to laterality of retroperitoneal metastatic pattern consistent with testicular primary: assessment of pathologic findings.

OBJECTIVES: It has been estimated that extragonadal germ cell tumors (EGCTs) constitute 3% to 5% of germ cell neoplasms. An interesting clinical scenario occurs when a patient with a presumed EGCT and normal testicular examination and ultrasound findings has a retroperitoneal metastatic pattern consistent with either a right or left-sided testicular primary. We reviewed the pathologic data of patients presenting with these clinical findings after delayed orchiectomy at postchemotherapy retroperitoneal lymph node dissection (PC-RPLND). METHODS: We identified 14 patients with apparent EGCT who had undergone simultaneous orchiectomy at PC-RPLND at our institution from July 1979 to July 2002 because of a lateralizing pattern of retroperitoneal metastases concerning for a testicular primary. Of the 14 patients, 3 had completely normal testicular ultrasound findings after chemotherapy and 11 had minimal ultrasound findings not consistent with a testicular tumor. RESULTS: Two (14%) of the PC orchiectomy specimens contained mature teratoma and eight (57%) contained necrosis and/or focal fibrosis. Thus, 10 (71%) of 14 patients undergoing PC orchiectomy at PC-RPLND because of metastatic disease laterality had evidence of a testicular primary. CONCLUSIONS: Most (71%) patients with a presumed EGCT who underwent PC orchiectomy because of lateralizing retroperitoneal metastases had histologic evidence of a testicular primary (20% teratoma, 80% focal necrosis or fibrosis). If the retroperitoneal pattern of metastatic tumor spread is consistent with a primary testicular tumor, we offer PC orchiectomy to patients with apparent EGCT at PC-RPLND, even if the PC testicular examination and ultrasound findings are normal.

Medicare financial status, budget impact, and sustainability--which concept is which?

Medicare is continually undergoing change, as it must in order to reflect advances in medical technology, new health care delivery systems, financial pressures, and other developments. Modifications to the program are debated by policymakers in Congress and the administration, together with academic experts and others. These debates would be improved if policymakers and the public had a clearer understanding of Medicare and certain commonly cited views of the program's overall status. Three such concepts--the financial status of the Medicare trust funds, the impact of Medicare on the Federal budget, and the long-run sustainability of Medicare--are often confused with each other and are sometimes used interchangeably. Each concept is important but needs to be used for its own purpose. This article clarifies the differences among these three views of Medicare and provides examples of each.

Trends in Medicare Expenditures and Financial Status, 1966-2000.

In this article, the author reviews expenditure growth trends over Medicare's 35-year history and comments on how the program's long-range financial outlook has changed over time. The author focuses on the various legislative, economic, and demographic factors that have affected expenditure growth and financial status. In addition, Medicare's share of total U.S. health costs is briefly reviewed. In an appended comment, the author considers whether the impact of the Balanced Budget Act of 1997 (BBA) was greater than intended by Congress and the Administration. The author concludes with a plea for greater attention to correcting the projected long-range deficits for the Hospital Insurance (HI) Trust Fund.