<Superscript>68</Superscript>Ga- and <Superscript>111</Superscript>In-labelled DOTA-RGD peptides for imaging of αvβ3 integrin expression

PURPOSE: alphavbeta3 integrins are important cell adhesion receptors involved in angiogenic processes. Recently, we demonstrated using [(18)F]Galacto-RGD that monitoring of alphavbeta3 expression is feasible. Here, we introduce (68)Ga- and (111)In-labelled derivatives and compare them with [(18)F]Galacto-RGD. METHODS: For radiolabelling, cyclo(RGDfK(DOTA)) was synthesised using SPPS. For in vitro characterisation determination of partition coefficients, protein binding, metabolic stability, alphavbeta3 affinity and cell uptake and for in vivo characterization, biodistribution studies and micro positron emission tomography (PET) imaging were carried out. For in vivo and in vitro studies, human melanoma M21 (alphavbeta3 positive) and M21-L (alphavbeta3 negative) cells were used. RESULTS: Both tracers can be synthesised straightforward. The compounds showed hydrophilic properties and high metabolic stability. Up to 23% protein-bound activity for [(68)Ga]DOTA-RGD and only up to 1.4% for [(111)In]DOTA-RGD was found. Cell uptake studies indicate receptor-specific accumulation. This is confirmed by the biodistribution data. One hour p.i. accumulation in alphavbeta3-positive tumours was 2.9 +/- 0.3%ID/g and in alphavbeta3-negative tumours 0.8 +/- 0.1%ID/g for [(68)Ga]DOTA-RGD ([(111)In]DOTA-RGD: 1.9 +/- 0.3%ID/g and 0.5 +/- 0.2%ID/g; [(18)F]Galacto-RGD: 1.6 +/- 0.2%ID/g and 0.4 +/- 0.1%ID/g). Thus, tumour uptake ratios were comparable. Due to approx. 3-fold higher blood pool activities for [(68)Ga]DOTA-RGD, tumour/blood ratios were higher for [(111)In]DOTA-RGD and [(18)F]Galacto-RGD. However, microPET studies demonstrated that visualisation of alphavbeta3-positive tumours using [(68)Ga]DOTA-RGD is possible. CONCLUSIONS: Our data indicate that [(68)Ga]DOTA-RGD allows monitoring of alphavbeta3 expression. Especially, the much easier radiosynthesis compared to [(18)F]Galacto-RGD would make it an attractive alternative. However, due to higher blood pool activity, [(18)F]Galacto-RGD remains superior for imaging alphavbeta3 expression. Introduction of alternative chelator systems may overcome the disadvantages.     

Struma ovarii: management and follow-up of a rare ovarian tumour

INTRODUCTION

Struma ovarii represents about 1.0% of all ovarian tumours. While management involves surgery, there is a paucity of data regarding the extent and approach of surgery, and postoperative management. This study aimed to delineate the management of struma ovarii, its associated complications, and postoperative follow-up and investigations.

METHODS

We retrospectively reviewed cases of benign struma ovarii treated at KK Women’s and Children’s Hospital, Singapore, between January 2000 and May 2011.

RESULTS

A total of 68 patients underwent surgical removal of ovarian cyst or mass (24 cystectomy, 20 salpingo-oopherectomy and 24 total hysterectomy and bilateral salpingo-oopherectomy). Of the 68 surgeries, 39 (57.4%) included intraoperative frozen section sampling or procedures for staging of ovarian malignancy. The majority (73.5%) of surgeries were laparotomies. Histology revealed benign struma ovarii in all (98.5%) but one patient. Only 7 (10.3%) patients had postoperative complications – 3 wound-related, 2 thyroid-related, 1 incisional hernia and 1 nonspecific. The mean length of hospital stay was 4.2 days. During follow-up, 45 (66.2%) patients required no additional investigations. The most common investigation done was ultrasonography (n = 18, 26.5%). While no recurrences were diagnosed histologically, two patients were subsequently found to have complex/dermoid ovarian cysts on the ipsilateral side of the previous struma ovarii on ultrasonography.

CONCLUSION

Simple surgery is recommended for patients with struma ovarii, especially if they have fertility potential. Laparoscopic surgery is the recommended approach due to its shorter recovery time and lower morbidity. Most patients do not require extended periods of follow-up or postoperative investigations.     

Impact of innate and adaptive immunity on rejection and tolerance

Until recently, research on transplantation rejection and tolerance has been directed toward deciphering the mechanisms of the adaptive immune system. However, the emergence that the innate immune system, the body's first-line defense against pathogens, has a strong influence on adaptive immunity has galvanized interest in elucidating the interplay between these two arms of the immune system. The discovery of Toll-like receptors and the characterization of the cellular mediators involved in innate immunity have provided growing evidence that innate immunity affects the adaptive immune response. Emerging evidence has also shown that early "danger signals"' associated with ischemia-reperfusion injury or brain death contribute to innate immune activation, promoting rejection, and inhibiting tolerance induction. In addition, nonspecific stimuli such as increased donor age or patient disease may also serve to exert a synergistic influence on innate immune activation. Ultimately, controlling the events in innate immune activation may help drive tolerance induction and reduce the rate of rejection.     

Second-Look Operation for Unresectable Pancreatic Ductal Adenocarcinoma at a High-Volume Center

Background The value of re-exploration for pancreatic ductal adenocarcinoma after the initial diagnosis of unresectability is unclear. Methods In this study, we analyzed 33 patients who were re-explored after an initial diagnosis of unresectability. Results At the time of reoperation, a resectable tumor was found in 18 patients: therefore, 15 pancreaticoduodenectomies, two total pancreatectomies and one left resection were performed with three vascular resections. Morbidity and mortality rates for the cohort were 6/33 and 1/33, without significant differences between resectable and nonresectable patients. Length of stay, duration of operation, and blood loss were significantly increased in the resection group. Kaplan–Meier survival analysis demonstrated increased median survival for resected patients (1078 days after the initial operation versus 547 days in the group of unresectable patients; p = 0.018). Analysis of the reasons against initial resection showed that, if the patients had been sent to a tertiary referral center for pancreatic surgery, a different decision in favor of resection would probably have been made in 14 out of 33 patients. A review of 10 published reports on reoperation for pancreatic cancer revealed results comparable to our study in terms of low morbidity and mortality as well as a survival benefit. Conclusions Reoperation for pancreatic ductal adenocarcinoma that is initially deemed unresectable can be safely performed in a selected group of patients by experienced surgeons, supporting the concept of patient centralization in pancreatic surgery. Resection at the second operation may confer a survival benefit even when the initial findings preclude a potentially curative approach.     

Methodological considerations for end-of-life research in patients with chronic kidney disease

Good quality information is lacking about how patients die. This is particularly true for chronic kidney disease (CKD) patients who have extensive and unique end-of-life care considerations and needs. Research specific to CKD is required to develop systematic and comprehensive information on the end-of-life care needs and the quality of end-of-life care for patients with CKD, to describe the effectiveness of existing end-of-life care strategies in CKD (including cost-effectiveness), to identify areas that should be priorities for improvement and ultimately to develop innovative strategies for improving the end-of-life care for patients dying with CKD. This paper will highlight the challenges and limitations of the current approaches to end-of-life care research and will outline what is required, both in content and methodology, to move the field of renal palliative care forward.     

Screening for brain aneurysm in the Familial Intracranial Aneurysm study: frequency and predictors of lesion detection

OBJECT: Approximately 20% of patients with an intracranial saccular aneurysm report a family history of intracranial aneurysm (IA) or subarachnoid hemorrhage. A better understanding of predictors of aneurysm detection in familial IA may allow more targeted aneurysm screening strategies. METHODS: The Familial Intracranial Aneurysm (FIA) study is a multicenter study, in which the primary objective is to define the susceptibility genes related to the formation of IA. First-degree relatives (FDRs) of those affected with IA are offered screening with magnetic resonance (MR) angiography if they were previously unaffected, are > or = 30 years of age, and have a history of smoking and/or hypertension. Independent predictors of aneurysm detection on MR angiography were determined using the generalized estimating equation version of logistic regression. RESULTS: Among the first 303 patients screened with MR angiography, 58 (19.1%) had at least 1 IA, including 24% of women and 11.7% of men. Ten (17.2%) of 58 affected patients had multiple aneurysms. Independent predictors of aneurysm detection included female sex (odds ratio [OR] 2.46, p = 0.001), pack-years of cigarette smoking (OR 3.24 for 20 pack-years of cigarette smoking compared with never having smoked, p < 0.001), and duration of hypertension (OR 1.26 comparing those with 10 years of hypertension to those with no hypertension, p = 0.006). CONCLUSIONS: In the FIA study, among the affected patients' FDRs who are > 30 years of age, those who are women or who have a history of smoking or hypertension are at increased risk of suffering an IA and should be strongly considered for screening.     

Intraoperative Iatrogenic Rupture of Hepatocellular Carcinoma

Intraoperative iatrogenic rupture of hepatocellular carcinoma (HCC), which can occur during hepatic resection when large tumors are being mobilized, may adversely affect the operative outcome. Little information is available in the literature on this serious intraoperative complication. The aim of the present study is to document iatrogenic rupture of HCC as a serious complication during hepatic resection and its effects on the operative and long-term outcomes of patients with this complication. A retrospective study was performed on all patients with intraoperative iatrogenic rupture of HCC during hepatic resection from 1989 to 1997, and the operative and long-term survival outcomes were compared with those of patients without the complication. Among 194 patients who underwent hepatic resection for a large HCC (> or =5 cm) during the study period, 8 (4.1%) had intraoperative iatrogenic rupture of the tumor. When compared with 186 patients with similar clinical parameters but without intraoperative rupture, patients with intraoperative rupture had significantly more intraoperative blood loss (median 5.7 vs. 2.0 L;p = 0.01) and blood transfusion requirement (median 3.1 vs 0.9 L; p = 0.02). On follow-up, patients in the intraoperative rupture group had a significantly higher intraperitoneal extrahepatic recurrence rate (33.3% vs. 2.9%; p =0.02) and significantly shorter survival (median 11.5 vs. 37.9 months,p = 0.04) when compared with patients without the complication. Intraoperative iatrogenic rupture is a serious complication of hepatic resection for HCC because it is associated with increased intraoperative blood loss, increased incidence of intraperitoneal extrahepatic recurrence, and short survival. Extreme care should be taken during mobilization of the tumor, and an alternative operative approach in the presence of a difficult hepatic resection of a large HCC may be required to avoid the complication.     

Subarachnoid lumbar drains: A case series of fractured catheters and a near miss

PURPOSE: Lumbar subarachnoid catheters for cerebrospinal fluid (CSF) drainage (lumbar drains) are indicated for several medical and surgical conditions. A number of complications can occur from the placement of this type of catheter, including catheter breakage from excessive traction or shearing over the Tuohy needle. CLINICAL FEATURES: Five cases of lumbar subarachnoid catheter breakage/shearing and catheter fragment retention, as well as one near miss, were identified over a one-year period at a single institution. All (n = 6) patients were undergoing neurosurgical procedures. Four patients required surgical retrieval of the catheter fragments. No patient experienced log-term neurological sequelae. DISCUSSION: From these experiences, the following risks factors for catheter rupture are identified: 1) intentional or accidental retraction of the catheter through the needle during placement; 2) faulty use of the guidewire; or 3) use of excessive force during removal of the catheter. Methods to prevent such complications are suggested, including minimal use, or complete avoidance of a guidewire.     

Inadequate dietary calcium and vitamin D intakes in renal-transplant recipients in Ireland.

OBJECTIVE: To quantify the dietary calcium and vitamin D intake in adult renal-transplant recipients attending at a large teaching hospital in Ireland for follow-up. SETTING: Outpatient renal-transplant follow-up clinic. SUBJECTS: Fifty-nine adult renal transplant recipients (58% male) with a mean age of 46 years, a median transplant duration of 6 years, and a mean estimated glomerular filtration rate (eGFR) of 50 mL/min per 1.73 m2. Fifty-three percent were at National Kidney Foundation stage 3 chronic kidney disease, and 14% had stage 4 chronic kidney disease. INTERVENTION: This cross-sectional, observational study used a tailored food frequency questionnaire specific for calcium and vitamin D intake in Irish adults, which was completed during a face-to-face interview with each subject. MAIN OUTCOME MEASURE: The main outcome measure was the average daily dietary and supplemented calcium and vitamin D intake. RESULTS: The median interquartile range (IQR) dietary calcium intake was 820 mg/day (range, 576-1,177 mg/day), and was similar in men and women (recommended intake > or = 1,000 mg/day in adult men and nonmenopausal adult women, > or = 1,500 mg/day in menopausal women). Five participants received calcium supplementation. Overall, 59% of men and 64% of women had total calcium intakes below the recommended amounts. The median IQR estimated dietary vitamin D intake was 5.2 microg/day (range, 2.4-6.4 microg/day) in women, and 4.6 microg/day (range, 2.2-6.6 microg/day) in men (recommended intake, > or = 10 microg/day). Six subjects received vitamin D supplementation. Total vitamin D intakes were suboptimal in 91% of men and 87% of women. Dietary calcium and vitamin D intakes significantly correlated with each other, but neither was significantly related to eGFR category, and was similarly low in both presumed menopausal women and in the initial year posttransplantation. CONCLUSION: These findings suggest that dietary and total calcium and vitamin D intakes in adult renal-transplant patients are in many cases inadequate.     

Validity of prostate-specific antigen as a tumour marker in men with prostate cancer managed by watchful-waiting: correlation with findings at serial endorectal magnetic resonance imaging and spectroscopic imaging

OBJECTIVE: To investigate the validity of prostate-specific antigen (PSA) as a tumour marker in men with clinically localized prostate cancer who have selected watchful waiting, by determining if serial PSA level measurements are correlated with findings of malignancy or benign prostatic hyperplasia (BPH) at serial endorectal magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI). PATIENTS AND METHODS: We retrospectively identified 69 men with biopsy-proven prostate cancer being managed by watchful waiting, who underwent serial endorectal MRI/MRSI and who had contemporaneous serial PSA measurements. The mean (range) follow-up was 392 (294-571) days. A panel of three experienced readers reviewed the initial and follow-up MRI/MRSI studies, and classified findings of prostate cancer as stable or progressive. Another reader assessed BPH by calculating total gland and central gland volumes on all studies. RESULTS: At the follow-up MRI/MRSI, 51, 17 and one patient had stable, progressive, or unevaluable prostate cancer, respectively. The mean PSA velocity was significantly greater in patients with radiologically progressive disease (1.42 vs 0.42 ng/mL/year, P = 0.04). A PSA velocity of >0.75 ng/mL/year identified those with radiologically progressive disease with a true-positive fraction of 0.71 and a false-positive fraction of 0.39. PSA levels were not correlated with changes in total or central gland volumes (P > 0.05). CONCLUSIONS: In men with clinically localized prostate cancer who select watchful waiting, serial PSA levels are correlated with findings of malignancy but not BPH at serial endorectal MRI/MRSI, suggesting that PSA is a useful longitudinal tumour marker in this population.