Stereotactic Radiosurgery for Patients with Single Brain Metastasis

The efficacy of stereotactic radiosurgery (SRS) was evaluated for patients with single brain metastasis from extracranial primary cancer and the outcome was compared with that of external whole brain irradiation (WBI) alone or with surgical resection. Between January 1976 and December 1996, 225 patients with single brain metastases were treated in the Department of Therapeutic Radiology—Radiation Oncology at the University of Minnesota Hospital. One hundred six patients (47%) were treated with WBI alone (Group 1), 71 patients (32%) underwent surgical resection prior to WBI (Group 2), and 48 patients (21%) underwent SRS ± WBI (Group 3). The most common site of primary cancer was the lung (40%), followed by breast (14%), unknown primary (11%), skin (malignant melanoma, 9%), gastrointestinal tract (8%), kidney (renal cell carcinoma, 8%), gynecological organs (3%), and other (6%). Median dose to the whole brain was 3750 cGy in 15 fractions (range, 2000–5000 cGy). Median radiosurgical dose of 1750 cGy (range, 1200–4000 cGy) was delivered to the 40 to 90% isodose line encompassing the target. Actuarial survival was calculated from the date of treatment using the Kaplan–Meier method and statistical significance was assessed with the log-rank test. Actuarial median survival was 3.8 months for Group 1 (range, 1–84 months), 10.5 months for Group 2 (range, 1–125 months), and 9.8 months for Group 3 (range, 1–51 months). Survival at 1 and 2 years was 20% and 8% for Group 1, 47% and 18% for Group 2, and 37% and 27% for Group 3, respectively. Group 2 (surgery + WBI) and Group 3 (SRS ± WBI) had a statistically significant survival advantage over Group 1 (WBI alone) (p < 0.0001, log-rank test). No survival advantage was found between Groups 2 and 3 (p = 0.69, log-rank test). Our retrospective data suggest that SRS (± WBI) improves survival when compared to WBI alone and is comparable to surgical resection and WBI. Given that SRS is minimally invasive, is able to treat lesions in surgically inaccessible locations, and is potentially more cost-effective than surgery, it is a reasonable and potentially more attractive alternative to surgery in the management of single brain metastasis.     

Permanent I Interstitial Radiation Therapy in the Treatment of Non-GBM High-Grade Gliomas

This study evaluates prognostic factors influencing survival outcomes for 50 patients with permanent¹²⁵ iodine-125 implants in the primary treatment of non-GBM high-grade gliomas. Stereotactic treatment planning aimed to encompass the contrast-enhancing rim of the tumor visualized by CT, with an initial dose rate of 0.05 Gy/hour with ¹²⁵I, delivering 100 Gy at 1 year and 103.68 Gy at infinity. Survival was evaluated using the Kaplan–Meier method for unvariate analysis and the Cox regressional method for multivariate analysis. In addition to the implant, 31 patients received external radiation therapy (5000 to 6000 cGy) before the implant; 10 patients were implanted without additional external beam radiation, and 9 patients underwent external radiation therapy before implant placement. With a mean follow-up of 40.76 months (range 3.47–87 months); 1–, 3–, and 5-year survival were 78.5% (± .05%), 58.7% (± .07%), and 56.2% (± .07%) respectively. Since 56.2% of the patients were alive at 5 years, median survival has not been reached yet. Second surgery was performed following the implant in 19 patients. Findings were tumor recurrence in 11 patients (22.5%), radiation necrosis in 7 patients (14.3%), and brain abcess in 1 patient (2%). Age, sex, tumor location, side of brain, tumor volume, Karnofsky, and neurological status were correlated with survival outcome. Favorable prognostic factors were age younger than 45 years, superficial tumor location, and preoperative Karnofsky greater than 70. Surgical treatment of patients with non-GBM high grade gliomas combined with external beam radiation and permanent ¹²⁵I implants represent a valuable alternative for the treatment of patients with malignant gliomas, allowing patients good quality of life and long survival.     

Simultaneous kidney-pancreas transplantation for end-stage renal disease patients with insulin-dependent diabetes and detectable C-peptide

Introduction

There is controversy regarding the place of simultaneous pancreas-kidney (SPK) transplantation in end-stage renal disease (ESRD) patients with insulin-dependent diabetes mellitus (IDDM) and detectable c-peptide. We sought to compare outcomes of recipients with and without pretransplantation c-peptide.

Methods

This retrospective single-center review included consecutive primary SPK transplantations performed between September 2007 and May 2010. Demographic characteristics and outcomes were compared between recipients with and without pretransplantation c-peptide.

Results

Seven of 25 (28%) consecutive SPK transplant recipients with a diagnosis of IDDM and ESRD had detectable c-peptide prior to transplantation. The mean c-peptide level was 6.3 ± 6.1 ng/mL. For those recipients with and without c-peptide, mean age at diagnosis of IDDM (12.4 ± 7.8 vs 17.1 ± 6.6 years; P = not significant [NS]), duration of IDDM prior to transplantation (30 ± 10 vs 23 ± 9 years; P = NS), and body mass index (25.9 ± 4.5 vs 26.7 ± 4.5 kg/m²; P = NS) were equivalent between the groups. With a median follow-up of 17 months (range, 3–35 months) there was 1 graft loss (due to cardiovascular death) among the 25 patients. At the most recent follow-up, for recipients with and without c-peptide, both the mean serum creatinine (1.3 ± 0.6 vs 1.0 ± 0.2 ng/mL; P = NS) and the mean HbA1c level (5.3 ± 0.4 vs 5.3 ± 0.5; P = NS) were equivalent between the groups.

Conclusion

For nonobese ESRD patients diagnosed with IDDM at a young age, the presence of detectable c-peptide should not influence the decision to proceed with SPK transplantation.     

Growth of children following the initiation of dialysis: a comparison of three dialysis modalities

Maintenance dialysis usually serves as an interim treatment for children with end-stage renal disease (ESRD) until transplantation can take place. Some children, however, may require dialytic support for an extended period of time. Although dialysis improves some of the problems associated with growth failure in ESRD (acidosis, uremia, calcium, and phosphorus imbalance), many children continue to grow poorly. Therefore, three different dialysis modalities, continuous ambulatory peritoneal dialysis (CAPD), cycler/intermittent peritoneal dialysis (CPD), and hemodialysis (HD), were evaluated with regard to their effects on the growth of children initiating dialysis and remaining on that modality for 6–12 months. Growth was best for children undergoing CAPD when compared with the other two modalities with regard to the following growth parameters: incremental height standard deviation score for chronological age [–0.55±2.06 vs. –1.69±1.22 for CPD (P<0.05) and –1.80±1.13 for HD (P<0.05)]; incremental height standard deviation score for bone age [–1.68±1.71 vs. –2.45±1.43 for CPD (P=NS) and –2.03±1.28 for HD (P=NS)]; change in height standard deviation score during the dialysis period [0.00±0.67 vs. –0.15±.29 for CPD (P=NS) and –0.23±.23 for HD (P=NS)]. The reasons why growth appears to be best in children receiving CAPD may be related to its metabolic benefits: lower levels of uremia, as reflected by the blood urea nitrogen [50±12 vs. 69±16 mg/dl for CPD (P<0.5) and 89±17 for HD (P<0.05)], improved metabolic acidosis, as indicated by a higher serum bicarbonate concentration [24±2 mEq/l vs. 22±2 for CPD (P<0.05) and 21±2 for HD (P<0.05)]. In addition, children undergoing CAPD receive significant supplemental calories from the glucose absorbed during dialysis. CAPD, and possibly, other types of prolonged-dwell daily peritoneal dialysis appear to be most beneficial for growth, which may be of particular importance for the smaller child undergoing dialysis while awaiting transplantation.     

Apoptosis and antioxidant defense in the nephrotic syndrome

Nephrotic syndrome (NS) is accompanied, and probably caused by, abnormalities in T lymphocyte function. The aim of this study was to investigate the antioxidant status of children with NS and its influence on the apoptosis of T cells. Fifty-seven children with NS were studied, aged 4–16 years (mean 7.4 years), 34 with a first episode (group I) and 23 in remission (>6 months) of NS (group II). The control group comprised 26 healthy children matched for age. Annexin V-FITC was used as a sensitive probe for identifying cells undergoing apoptosis. We found that apoptotic T lymphocytes occurred more frequently in patients with a first episode of NS than in children in remission and in the controls. In group I, total antioxidant status (TAS, plasma) was significantly reduced compared with controls (0.77±0.14 vs. 1.18±0.42 mmol/l, P<0.001). In group I children, glutathione reductase (GR, red blood cells) and glutathione peroxidase (GPX, red blood cells) activity was lower than in controls (GR 8.10±2.40 vs.10.55±3.81 U/g Hb, P<0.001) (GPX 28.65±6.99 vs. 33.84±13.11 U/g Hb, P=0.010). TAS levels and GR activity in group II were also lower than in the controls. A negative correlation between GR activity and the apoptosis rate of T lymphocytes was found. We conclude that in patients with NS, reduced antioxidant defense may contribute to an increase in the apoptosis rate of circulating lymphocytes.     

The Role of Stereotactic Radiosurgery in the Management of Benign, Atypical, and Malignant Meningiomas

Stereotactic radiosurgery and fractionated Stereotactic radiotherapy (SR) offer precise localization of radiation dose (Gy) for the treatment of meningioma (M). For the multimodal treatment with preservation of function, SR is complementary to both microsurgery (S) and conventional external beam radiotherapy (XRT). The role of SR in the management of atypical and malignant meningiomas, however, remains unexplored. Fifty consecutive patients with meningioma: 18 males (60.1 +/– 2.3 years) and 32 females (56.9 +/– 2.2 years) (p = NS) received SR. Thirty-one patients had surgery 69.6 +/– 13.9 months (95% CI: 53.3–98.0) prior to SR. For patients having S, the incidence of atypical or malignant versus benign meningiomas (14 versus 17 patients) increased with age (p = 0.03). Twenty patients had XRT approximately 18 months prior to SR. For antecedent XRT, the range of doses was 3600–6400 cGy (median: 5040 cGy). Following failure of S and/or XRT, patients had SR. Compared to other series, the mean tumor volumes for SR were comparatively large: 9.8 +/– 1.3 cm³ (range 0.3–37.1 cm³). The median SR dose was 3500 cGy (range 540–5400 cGy) administered in seven fractions (range 1–30). Linear regression analysis showed a consistent method for fractionation: the number of administered fractions increased (p = 0.053) and the total dose increased (p = 0.054) with tumor size. During the interval for follow–up (17.9 +/– 2.9 months), one patient with malignant meningioma required surgery for progression 8 months after SR. In the remaining patients, post-SR MRIs showed control (unchanged or smaller tumor volume) regardless of histology. These results show that SR may provide control of M regardless of grade.     

111Indium (DTPA-octreotide) scintigraphy in patients with cerebral gliomas

Summary Somatostatin receptors (SR) have been identified in vitro in normal brain tissue, in neuro-endocrine tumours and in cerebral gliomas WHO grade 1 or 2 by autoradiography or using somatostatin-gold conjugates. In vivo, SR detection has become possible by scintigraphy applying the somatostatin analogue octreotide, radio-labelled with¹¹¹Indium. It was supposed that expression of SR in cerebral gliomas corresponds to low grade tumour malignancy and that, in vivo, somatostatin receptor scintigraphy (SRS) could refine and improve the WHO grading system for cerebral gliomas.Nineteen patients with cerebral gliomas (grade 2: n=8, grade 3: n=3, grade4: n=8) were examined with¹¹¹In (DTPA-octreotide) to evaluate, whether SRS could improve the pre-operative estimation of tumour biology and the postoperative management. The results of SRS were related with the histological findings and with the in vitro demonstration of somatostatin-binding sites on cultured tumour cells incubated with a somatostatin-gold conjugate.In vivo, none of the patients with glioma grade 2 showed enhanced tracer uptake in the SRS, whereas in vitro SR were detected in cultured tumour tissue in 5 out of 5 cases. Every patient with glioma grade 3 or 4 demonstrated a high focal uptake of¹¹¹In (DTPA-octreotide), as shown by SRS. Three patients with glioma grade 4, additionally examined with 99mTc-DTPA, showed an increased tracer uptake within the tumour area when compared with results of SRS. In vitro, SR were detected on tumour cell surface in 5 out of 6 tissue samples from patients with gliomas grade 3 or 4. One patient harbouring a cerebral abscess presented with a high focal tracer uptake in the SRS but with absence of somatostatinbinding sites in vitro.We concluded, that in glioma patients enhanced tracer uptake in receptor scintigraphy with¹¹¹In (DTPA-octreotide) does not depend on the presence of SR in tumour tissue but on the dysfunction of the blood-brain barrier. Thus, SRS does not improve the preoperative glioma grading or postoperative management in patients with cerebral tumours of glial origin.The article is dedicated to Prof. H. Leonhardt on the occasion of his 75th birthday.     

Gamma knife radiosurgery in skull base meningiomas: a possible relationship between somatostatin receptor decrease and early neurological improvement without tumour shrinkage at short-term imaging follow-up

Summary Background. This study investigates a possible relationship between the effects of gamma knife (GK) on meningioma somatostatin receptors (SRs) and the high rate of early neurological improvement without tumour reduction at short-term imaging follow-up.Methods. From December 1997 to December 2002, somatostatin receptor scintigraphy (SRS) using an ¹¹¹Indium-labelled somatostatin analogue, Octreotide, was performed both before and 7–12 months after radiosurgery in 20 patients with intracranial meningiomas. Semiquantitative data were calculated as an SRS index.Findings. The pre-GK SRS index was always >1, averaging 4.44±3.20. There were no statistically significant differences between the pre-GK average values of primary (4.80±3.65) and residual (3.75±1.93) meningiomas. At the first clinical/MRI follow-up, the neurological examination had improved in 15/20 (75%) and had not changed in 5/20 patients. A corresponding slight tumour shrinkage on high-resolution MRI was documented in 3/20 cases only. The post-GK average SRS index was lower than pre-GK values both in primary (3.87±3.19) and in adjuvant (2.52±1.14) treatments, but the differences were not significant. However, the subgroup of patients with early neurological improvement showed a higher pre-GK average SRS index (5.21±3.33) and a more substantial post-GK average SRS index decrease (3.86±3.00) than the patients whose clinical condition remained stable (2.10±0.59 and 1.99±0.55, respectively). The difference between the two subgroups of patients proved to be statistically significant (P<0.05).Conclusions. Our preliminary findings suggest a possible relationship between a decrease in the concentration of SRs on meningioma cells at short-term functional imaging follow-up after radiosurgery and early neurological improvement.     

Permanent Iodine-125 Implants in the Treatment of Low-Grade Gliomas

We report a retrospective study on the use of the permanent iodine-125 (¹²⁵I) implants in the management of low-grade gliomas. From July 1988 to July 1997, 16 patients with low-grade gliomas underwent permanent ¹²⁵I implants in the management of their lesions. There were 7 males and 9 females ranging in age from 4 to 48 years (mean 19). The location was in the cerebral hemisphere in 7 patients, brainstem in 5 patients and thalamus/basal ganglia in 4 patients. Prior to brachytherapy, 9 patients underwent surgical resection and 7 patients underwent stereotactic biopsy procedures. Fourteen patients were treated as part of the initial management and 2 were recurrent. The histological diagnosis was: 9 WHO grade II astrocytomas, 3 oligodendrogliomas, 2 gemistocytic astrocytomas, 1 pilocytic astrocytoma, and 1 ependymoma. The tumor volume ranged from 0.7 to 33.4 cc (mean 8.4). Stereotactic treatment planning was used to encompass the contrast-enhancing rim of the tumor visualized by computerized tomography with an initial dose rate of 0.05 Gy/hour with ¹²⁵I. The total activity ranged from 0.8 to 20.5 mCi. With a median follow-up period of 35 months (range, 4–105 months), the 2- and 5-year survival rates were 93.7% and 87.5%, respectively. Three patients underwent reoperation after implants, two of three had recurrent disease, and one had radiation necrosis. Permanent ¹²⁵I implants appear to be safe and effective as a part of the multimodality management of low-grade gliomas.     

A contemporaneous comparison of hospital charges for laparoscopic and open Nissen fundoplication

Surgical treatment of gastroesophageal reflux disease is increasingly recognized as a costeffective alternative to long-term medical therapy. This fact, coupled with the advent of laparoscopic fundoplication as a safe and efficacious alternative to open surgery, underscores the importance of determining the costs associated with laparoscopic treatment.Hospital costs and charges of patients undergoing open (N=9) and laparoscopic (N=11) fundoplication were retrospectively analyzed. Both procedures were performed during the same time period (6/91–6/93), at the same hospital, and by the same surgical team. Operative time, and hospital stay, were recorded in addition to total, operating room, anesthesia, sterile supplies, and hospital room charges. Figures are reported as mean values ± standard error of the mean. The Wilcoxon signed rank test was used for comparison of groups.Operative time (221±18 vs 165±12 min, P=0.033) was longer in the laparoscopic group, while hospital stay (5.8±02 vs 8.8±04 days, P<0.001) was significantly shorter. Total hospital costs were similar for both groups of patients ($14,615±863 vs $15,891±921, P=0.247). Overall hospital charges were nearly identical ($26,634±1376 vs $27,189±1753, P=0.803). A detailed analysis demonstrated cost shifting, with laparoscopic fundoplication resulting in significantly higher charges associated with events in the operating room. Operating room ($6,064±252 vs $4,283±380, P=0.001), sterile supplies ($6,214±508 vs $5,403±390), and anesthesia charges ($1,593±76 vs $1,122±95, P<0.001) were all greater in the laparoscopic group. This was offset by significantly lower hospital-room charges following laparoscopy ($5,098±355 vs $6,983±511, P=0.006).Laparoscopic Nissen fundoplication is not more expensive than its open counterpart. At present, laparoscopy results in higher operating-room charges which offsets savings from a shorter hospital stay. Improvements in technique and attention to limiting the cost of sterile supplies may ultimately result in a cost savings in favor of laparoscopy.Presented at the annual meeting of the Society of American Gastrointestinal Endoscopic Surgeons (SAGES), Nashville, Tennessee, USA, 18–19 April 1994     

Bone histology in steroid-treated children with non-azotemic nephrotic syndrome

Patients with nephrotic syndrome (NS) and normal glomerular filtration rate (GFR) frequently exhibit abnormalities of calcium and vitamin D homeostasis, mainly hypocalcemia and reduced circulating vitamin D metabolites. These abnormalities have been linked to alterations of bone histology in adults with non-azotemic NS, particularly osteomalacia and excessive bone resorption. Whether similar abnormalities of bone histology occur in children and adolescents with NS, particularly in those requiring prolonged treatment with corticosteroids, remains largely unknown. Thus, bone histomorphometry and selected bone-modulating hormones were studied in eight children (aged 2–16 years) with normal GFR (range 85–169 ml/min per 1.73 m²) and NS. All patients received corticosteroids for at least 12 months prior to bone biopsy. At the time of bone biopsy, the urine protein/creatinine ratio was elevated (2.1±3.6), while the average concentrations of parathyroid hormone (36±13 pg/ml), 25-hydroxyvitamin D [25(OH) D] (22±14 ng/ml), and 1,25(OH)₂D (59±22 pg/ml) were normal. Bone histomorphometry displayed focal osteomalacia (OM) and mild increased bone resorption in most patients. The mineralization lag time, an indicator of the degree of osteomalacia, correlated with the time elapsed since the original diagnosis of NS (r=0.93, P<0.0005). Overt hyperparathyroidism was not evident, but increased eroded perimeter and elevated bone formation rate (BFR) were evident in two patients, suggesting high-turnover bone disease. The BFR was inversely correlated with the administered dose of prednisone at the time of biopsy (r=–0.78, P<0.05) and one patient exhibited low bone turnover changes. The growth velocity standard deviation score (SDS) at time of biopsy ranged from –1.6 to 3.2, resulting in a height SDS range of –1.9 to 0.6. The height SDS at time of bone biopsy correlated inversely with the dose of administered glucocorticoid (r=–0.71, P<0.05) and with the duration of the disease (r=–0.7, P=0.05). These data, albeit preliminary, demonstrate that children with NS treated with prolonged corticosteroid therapy exhibit bone histopathological changes without a concomitant impairment in GFR. While the OM appears to be related to the disease process, the alterations of bone formation and the adynamic changes are likely the result of the corticosteroid therapy. The potential consequences of these findings on adult bone mass and ultimate height deserve further studies.     

Homocysteine and C-reactive protein levels in Haemodialysis patients

Background: Mild to moderatehyperhomocysteinemia is very common amongpatients undergoing haemodialysis. There issufficient evidence that hyperhomocysteinemiais an independent risk factor forcardiovascular and or atheromatous disease inend stage renal failure patients. Vitaminsupplementation such as vitamin B6, B12 orfolate has been proposed to correct thismetabolic disturbance and it is to be proved ifthis intervention benefit these patients, butthere is no agreement whether oral folatesupplementation is capable to normalizehomocysteine levels in end stage renal failurepatients.Methods: In 53 patients, undergoinghaemodialysis, homocysteine levels (Hcy),folate, vitamin B12, ferritin and C-reactiveprotein (CRP) were estimated before and afterdialysis, without folate supplementation.Thirty voluntary blood donors were used ascontrols to compare homocysteine levels. Afterfour weeks of oral folate supplementation(10 mg/24 hours) the levels of homocysteine,serum folate and intra-erythrocyte folate wereestimated again. Eighteen months later thesurvival rate of our patients was recorded andanalyzed in relation to Hcy and CRP levels.Results: The results showed thathaemodialysis patients exhibited, almost,fourfold higher homocysteine levels thancontrols (27.39 ± 11.54 vs 7.38 ± 3.5, t = –8.2, p = 0.000000). Folate levels, vitamin B12 and CRP increase significantly afterhaemodialysis where as homocysteine levelsdecrease (Hcy1 vs. Hcy2: z = 2.08, p = 0.03).Fourteen (14) patients suffered from coronaryheart disease (CHD) and they exhibited thehigher levels of homocysteine (Hcy1 vs. CHD: z =–3.4, p = 0.0006). All estimations performedrevealed a negative correlation betweenhomocysteine levels and plasma orintra-erythrocyte folate. No other variableexhibited any significant influence uponhomocysteine levels. After folatesupplementation homocysteine levels in thewhole number of patients were unchanged(Hcy(before) vs. Hcy(after): 27.39 ± 11.54vs. 26.95 ± 8.22, z = 0.3, p = 0.7, NS). Whenpatients with homocysteine levels higher than24 µmol/L were selected, a significantdecrease was observed (34.77 ± 9.32 vs.30.0 ± 8.05, z = 2.09, p = 0.02). Forty-twopatients were treated with erythropoietin fortheir anemia and we found a positivecorrelation between C-reactive protein levelsand rhu-Epo dose (CRP vs. Epo: r = 0.45,p = 0.002). Homocysteine levels did not exhibitany significant influence upon short-termsurvival (U = –0.37, p = 0.3, NS) where as CRPlevels exhibit a significant influence uponshort-term survival (U = 2.15, p = 0.005).Conclusions: Homocysteine levels inhaemodialysis patients are fourfold higher thanhealthy controls. Folate, vitamin B12 and CRPincrease significantly after dialysis. Patientswith coronary heart disease exhibit the highestlevels of homocysteine. The homocysteine levelsare inversely related with the folate levels.The exogenous folate supplementation increasethe serum folate levels but decreaseshomocysteine only in patients with higher thanmild hyperhomocysteinemia. Hcy doesn't exertany significant effect upon the short-termsurvival of the haemodialysis patients but CRPlevel is a god predictor of the short-termsurvival of these patients.     

Elevation of glutathione and related enzyme activities in high-grade and metastatic extremity soft tissue sarcoma

Background: Glutathione is a free radical scavenger implicated in the chemoresistance of certain tumors. As treatment with chemotherapy has added little to improved survival in adult soft tissue sarcoma and little is known concerning the mechanisms of chemoresistance in sarcoma, we studied concentrations of glutathione (nmol/mg protein) and activities of-glutamylcysteine synthetase (GCS; nmol/mg protein/h) and-glutamyl transpeptidase (GGTP; U/mg protein) in extremity soft tissue sarcoma. Methods and Results: Tumor specimens (n=65) were frozen in liquid nitrogen at the time of resection. Fourteen low-grade tumors, 40 high-grade tumors, and 11 pulmonary metastases were analyzed. Glutathione concentrations and GGTP activity were significantly lower in low-grade (3.97±0.7 nmol/mg protein and 1.07±0.2 U/mg protein) than in high-grade (8.98±1.2 nmol/mg protein, p<0.001; 2.10±0.4 U/mg protein, p<0.002) tumors and pulmonary metastases (10.05±1.8 nmol/mg protein, p<0.008; 3.14±2.8 U/mg protein, p<0.04). While GCS activity was lower in low-grade (0.81±0.3 nmol/mg protein/h) than high-grade (1.49±0.5 nmol/mg protein/h) tumors and pulmonary metastases (1.03±0.2 nmol/mg protein/h), these differences were not significant. In those patients with a high-grade tumor presenting with a local recurrence, glutathione levels were higher in those patients who had received preoperative doxorubicin-based chemotherapy (9.25±1.7 nmol/mg protein; n=7) than in those who had no preoperative chemotherapy (4.71±3.1 nmol/mg protein; n=4, p=0.08). Conclusions: In extremity soft tissue sarcoma, glutathione concentration and GGTP activity are significantly elevated in patients with high-grade and metastatic sarcomas. In addition, there is a trend for increased glutathione levels in tumors previously exposed to doxorubicin-based chemotherapy. Glutathione may play a role in soft tissue sarcoma chemoresistance.This work was presented at the 49th Annual Cancer Symposium of the Society of Surgical Oncology, Atlanta, GA, U.S.A., March 21–24, 1996.     

Pamidronate treatment of pediatric fracture patients on chronic steroid therapy

Pediatric nephrology and rheumatology patients with steroid-induced osteopenia are at risk of skeletal fracture. Bisphosphonate therapy has not been routinely advocated as a primary or secondary intervention for steroid-associated fractures in this population. This case control study evaluates the role of pamidronate therapy as a secondary fracture intervention. Children with symptomatic pathological fractures of the axial spine or ribs were treated with pamidronate 1 mg/kg/dose (n=17) IV at 60-day intervals for 1 yr (n=15) or 2 yr (n=2). Bone mineral density of L1–L4 (BMD) was assessed prior to treatment and at six-month intervals, and compared to 17 disease-age-gender-steroid dose-matched control patients. Alkaline phosphatase, calcium, phosphate, PTH, renal biochemistry, and 24-hr urine collections for CrCl, N-telopeptide/creatinine ratio, phosphate excretion, and calcium excretion were obtained every two months in the pamidronate population. Pamidronate caused a first exposure transient flu-like illness lasting <24 h in three patients and one patient had a new pathological fracture. No adverse events of hypocalcemia, allergic reaction or thrombophlebitis were noted. All patients reported improvement of skeletal pain. Despite ongoing steroid treatment, pamidronate significantly increased L1–L4 BMD Z-scores (mean±SE) relative to baseline (pamidronate vs control: 0–6 months: 0.27±0.14 vs –0.82±0.31; 0–12 months: 0.63±0.17 vs –0.46±0.27; 0–18 months: 0.55±0.32 vs 0.17±0.27; 0–24 months: 0.15±0.21 vs –0.23±0.22; 0–30 or 36 months: 0.77±0.71 vs –0.68±0.25) with repeated measures ANOVA assessment (F=11.27, p=0.0057). This study supports the safety and efficacy of pamidronate in steroid-induced fractures in pediatric nephrology and rheumatology patients.This study was presented in part at the IPNA Seventh Symposium of Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany     

Postoperative Changes in Duplex Ultrasound Velocity Characteristics in the Nonmobilized Right Internal Mammary Artery in Patients with Left Internal Mammary Artery Bypass Grafting

The internal mammary artery (IMA) is the conduit of choice in coronary revascularization because of its long-term patency. We analyzed the effect of left internal mammary artery (LIMA) harvesting on sternal perfusion. Diameters and velocity parameters of the nonmobilized right internal mammary artery (RIMA) were noninvasively analyzed with duplex ultrasound in 41 patients with LIMA myocardial revascularization pre- (2.6 ± 5 days) and postoperatively (4.9 ± 3.9 months). Data of 41 patients were analyzed; 38 patients underwent all examinations with adequate supraclavicular signals. The proximal RIMA diameter and all velocity parameters increased significantly at follow-up (3.1 ± 0.6 vs. 3.2 ± 0.5 mm, p = 0.03; diastolic peak velocity [DPV] 15 ± 7 vs. 27 ± 9 cm/sec, p < 0.0001; systolic peak velocity [SPV] 90 ± 24 vs. 105 ± 29 cm/sec, p < 0.02). This was more pronounced for the diastolic parameters and for all parameters in the proximal part of the RIMA than in the distal part (DPV 11.9 ± 10.1 vs. 9.5 ± 10.2 cm/sec, p = NS; SPV 14.9 ± 33.9 vs. 7.4 ± 26.0 cm/sec, p = NS). With longer time intervals of follow-up the increase in all diastolic velocity parameters became less pronounced. As demonstrated in the RIMA velocity parameters, patients with skeletonized LIMA grafts (n = 4) had significantly more flow, suggesting hyperemic flow, than patients with pedicled LIMA grafts (n = 34). Only in diastolic velocity integral (DVI) and systolic/diastolic velocity ratio (SDVRA) were there significant differences between diabetics (n = 9) and nondiabetics (n = 29) and only in DVI between female, (n = 8) and male (n = 30) patients. This study indicates that duplex ultrasound is a useful tool for noninvasive RIMA follow-up in LIMA myocardial revascularization.Presented at the Twenty-fifth World Congress of the International Society for Cardiovascular Surgery, Cancun, Mexico, September 9-13, 2001.     

Hypofractionated Stereotactic Radiotherapy for Recurrent Malignant Gliomas

Objective: The results of hypofractionated stereotactic radiotherapy (SRT) for the treatment of unselected patients with malignant glioma recurrent after conventional therapy were analyzed. Materials and Methods: Between January 1997 and March 1999, 21 patients with recurrent malignant glioma received SRT at UCLA. All patients received prior conventional radiotherapy (median 6000 cGy). The interval from initial diagnosis to SRT varied from 3 to 99 months (median 11). Tumor volume ranged from 4.5 to 33.7 cc (median 12). Fifteen patients had glioblastoma multiforme and 3 had anaplastic astrocytoma with an oligodendroglial component. Two patients with prior low-grade astrocytoma and one with an unbiopsied brainstem tumor did not have pathological confirmation of tumor grade at time of relapse. Five patients had multifocal recurrences and 11 had imaging evidence of indistinct tumor. Twelve patients had progressive disease after receiving salvage chemotherapy. Patients received 4–6 daily fractions of 400 to 600 cGy. Median total SRT dose was 2500 cGy. Follow-up ranged from 1 to 20 months and no patients were lost. Results: The actuarial median and one-year survival were 6.7 months and 15%, respectively. Fifteen patients died of progressive glioma and one of a pulmonary embolus. Sixteen patients relapsed after SRT: 11 local, 4 local plus distant, one marginal. All patients with distant relapse also had local failure at some time. The median time to local relapse for the 14 patients with an initial component of local failure was 5 months. There were trends to superior survival for those with an initial diagnosis of nonglioblastoma and those with frontal/occipital lobe recurrences. No patient developed documented radionecrosis. Two patients underwent operation following SRT. Histopathological analysis of the operative specimen revealed malignant glioma. Conclusions: The authors conclude that hypofractionated SRT is a feasible, safe alternative for patients with recurrent malignant glioma. Local failure represents the overwhelming pattern of relapse after SRT, regardless of the clinical or imaging characteristics of patients with recurrent tumor. Improving the outcome for this group of patients may require a multimodality approach of SRT plus concurrent chemotherapy.     

Prognostic Factors for Survival in Patients With Locally Recurrent Extremity Soft Tissue Sarcomas

Background Factors prognostic for survival in patients with locally recurrent extremity soft tissue sarcomas (STS) are poorly defined, thus making it difficult to identify high-risk patients who may benefit from adjuvant therapy.Methods A total of 1421 patients underwent surgical treatment for primary extremity STS at a single institution between 1982 and 2002. Of these, 179 (13%) patients underwent complete surgical resection of an isolated local recurrence and were the subjects of this study. Clinicopathologic factors from both the primary tumor and the local recurrence were analyzed.Results The median interval to initial local recurrence was 16 months: 65% developed a local recurrence by 2 years and 90% by 4 years. Only four patients who presented with a low-grade primary tumor progressed to a high-grade local recurrence. Independent prognostic factors for disease-specific survival after local recurrence were a high histological grade (hazard ratio, 5.1; P = .0004), a large local recurrence tumor size (hazard ratio, 1.5; P = .0001), and a short local recurrence–free interval (hazard ratio, 1.6; P = .0001). Patients who developed a local recurrence >5 cm in 16 months (n = 44; 0 low grade) had a 4-year disease-specific survival of 18%, compared with 81% for patients who developed a local recurrence 5 cm in >16 months (n = 46; 11 low grade).Conclusions Histological grade, local recurrence size, and local recurrence–free interval are independently predictive of survival in patients with locally recurrent extremity STS. A large local recurrence that develops in a short interval indicates a biologically aggressive tumor with a high tumor-specific mortality. Patients who develop such recurrences are ideal subjects for systemic neoadjuvant therapy trials.     

Post-transplant diabetes mellitus: risk factors, frequency of transplant rejections, and long-term prognosis

Background Estimates of the incidence of new-onset diabetes after renal transplantation vary between 2% and 54%. It was the aim of the present trial to study the prevalence of post-transplant diabetes mellitus (DM), the risk factors, the frequency of transplant rejections, and the long-term prognosis.Methods We studied all consecutive patients with endstage renal disease, but without DM who received kidney transplantation at our center since 1992 (n = 253; age, 52.2 ± 12.6 years; body mass index, 22.0 ± 7.9 kg/m²). Follow up was 3.3 ± 1.6 years (range, 0.1–17.7) years.Results In total, 43/253 patients (17%) developed new-onset DM after transplantation. Patients with new-onset diabetes were significantly older (58.3 ± 11.4 vs 50.9 ± 12.5 years; P < 0.01) and had a tendency to a higher body mass index (24.0 ± 8.5 vs 21.6 ± 7.8 kg/m²; P = 0.077). There were no differences between the groups in respect of blood pressure control (137.7 ± 19.0/81.8 ± 14.2 vs 137.1 ± 21.9/83.9 ± 13.1 mmHg; P = 0.89/0.39), glomerular filtration rate (58.0 ± 28.1 vs 64.1 ± 22.1 ml/min per 1.73 m²; P = 0.13), steroid dosage (4.5 ± 1.2 [n = 21] vs 4.6 ± 2.2 [n = 135] mg/day; P = 0.13), or the frequency and dosage of immunosuppressive drugs such as cyclosporine, tacrolimus, and sirolimus during the follow up. However, more patients with post-transplant diabetes received steroids (83.7% vs 64.3%; P = 0.021) and azathioprine (41.9% vs 24.3%; P = 0.030). Patients with new-onset diabetes had higher serum creatinine values (163.4 ± 67.9 vs 138.7 ± 59.5 µmol/l; P = 0.017). The mean hemoglobin (Hb)A1c in patients with DM was 6.28 ± 1.29% (Tosho HPLC; mean normal, 5.15%). In 18 patients (7.1%) transplant rejections occurred (16 patients without DM [7.6%] vs 2 patients with new-onset DM [4.7%]; P = 0.39). On performing multivariate analysis, the only parameter found to be associated with new-onset DM was the body mass index (R² = 0.05; β = 0.23; P = 0.02), and the only factor associated with transplant rejection was fasting blood glucose (R² = 0.07; β = 0.28; P = 0.02). None of the other parameters included in the models (age, duration after transplantation, diabetes duration, immunosuppressive therapy, HbA1c, HLA mismatches) showed any associations.Conclusions The prevalence of new-onset DM after renal transplantation was 17%. The most important parameter associated with new-onset diabetes was a higher body mass index, and the most important parameter associated with transplant rejection was an elevated fasting blood glucose level. To prevent transplant rejections and to improve patients’ outcome, in addition to providing optimal immunosuppressive therapy and HLA matching, good blood pressure control and HbA1c, but also near normal fasting blood glucose levels, should be achieved.     

Urinary Excretion of Pyridinium Cross-Links and Serum Osteocalcin Levels in Patients with Primary High-Grade Osteosarcoma

Osteosarcoma is the most frequent primary high grade bone tumor, usually occurring in adolescents and children. The aim of the present study was to investigate parameters of bone turnover as urinary excretion of pyridinoline (Pyr), and deoxypyridinoline (D-Pyr), serum osteocalcin (OC), and total alkaline phosphatase (AP) in patients with osteosarcoma. Thirty-five patients aged 7–22 (median age 14) with primary high-grade osteosarcoma of the extremity entered the study. A control population of age- and sex-matched healthy individuals was studied. Urinary excretion of Pyr, D-Pyr was measured on fasting urine specimens, corrected for creatine excretion (Ucr), and expressed as pM/µM UCr. At the same time as urine collection, blood samples were taken for measurement of AP and OC. In patients with osteosarcoma the urinary excretion of D-Pyr (74.5 ± 41) was significantly higher (P = 0.005) than in controls (38.2 ± 22.5). The serum level of OC was significantly lower (P < 0.001) in patients with osteosarcoma than in controls. Moreover, significantly (P = 0.03) higher excretion of D-Pyr (85.3 ± 43) was found in patients who relapsed after surgical removal of the tumor and chemotherapeutic treatment compared with those (58.1 ± 22) who remained continuously free of disease. The present study showed significant abnormalities of urinary excretion of pyridinium crosslinks and serum OC level in patients with osteosarcoma. The relation between urinary excretion of D-Pyr and biological tumor aggressiveness observed in the present study requires further investigation.