Wim J. Sluiter

Sentinel Node Dissection Is Safe in the Treatment of Early-Stage Vulvar Cancer

PURPOSE To investigate the safety and clinical utility of the sentinel node procedure in early-stage vulvar cancer patients. PATIENTS AND METHODS A multicenter observational study on sentinel node detection using radioactive tracer and blue dye was performed in patients with T1/2 (< 4 cm) squamous cell cancer of the vulva. When the sentinel node was found to be negative at pathologic ultrastaging, inguinofemoral lymphadenectomy was omitted, and the patient was observed with follow-up for 2 years at intervals of every 2 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS From March 2000 until June 2006, a sentinel node procedure was performed in 623 groins of 403 assessable patients. In 259 patients with unifocal vulvar disease and a negative sentinel node (median follow-up time, 35 months), six groin recurrences were diagnosed (2.3%; 95% CI, 0.6% to 5%), and 3-year survival rate was 97% (95% CI, 91% to 99%). Short-term morbidity was decreased in patients after sentinel node dissection only when compared with patients with a positive sentinel node who underwent inguinofemoral lymphadenectomy (wound breakdown in groin: 11.7% v 34.0%, respectively; P < .0001; and cellulitis: 4.5% v 21.3%, respectively; P < .0001). Long-term morbidity also was less frequently observed after removal of only the sentinel node compared with sentinel node removal and inguinofemoral lymphadenectomy (recurrent erysipelas: 0.4% v 16.2%, respectively; P < .0001; and lymphedema of the legs: 1.9% v 25.2%, respectively; P < .0001). CONCLUSION In early-stage vulvar cancer patients with a negative sentinel node, the groin recurrence rate is low, survival is excellent, and treatment-related morbidity is minimal. We suggest that sentinel node dissection, performed by a quality-controlled multidisciplinary team, should be part of the standard treatment in selected patients with early-stage vulvar cancer.

Improved Staging of Patients With Carcinoid and Islet Cell Tumors With 18F-Dihydroxy-Phenyl-Alanine and 11C-5-Hydroxy-Tryptophan Positron Emission Tomography

PURPOSE To evaluate and compare diagnostic sensitivity of positron emission tomography (PET) scanning in carcinoid and islet cell tumor patients with a serotonin and a catecholamine precursor as tracers. PATIENTS AND METHODS Carcinoid (n = 24) or pancreatic islet cell tumor (n = 23) patients with at least one lesion on conventional imaging including somatostatin receptor scintigraphy (SRS) and computed tomography (CT) scan underwent (11)C-5-hydroxytryptophan ((11)C-5-HTP) PET and 6-[F-18]fluoro-L-dihydroxy-phenylalanine ((18)F-DOPA) PET. PET findings were compared with a composite reference standard derived from all available imaging along with clinical and cytologic/histologic information. RESULTS In carcinoid tumor patients, per-patient analysis showed sensitivities for (11)C-5-HTP PET, (18)F-DOPA PET, SRS, and CT of 100%, 96%, 86%, 96%, respectively, and in islet cell tumors of 100%, 89%, 78%, 87%, respectively. In carcinoid patients, per-lesion analysis revealed sensitivities for (11)C-5-HTP PET, (11)C-5-HTP PET/CT, (18)F-DOPA PET, (18)F-DOPA PET/CT, SRS, SRS/CT, and CT alone of, respectively, 78%, 89%, 87%, 98%, 49%, 73%, and 63% and in islet cell tumors of 67%, 96%, 41%, 80%, 46%, 77%, and 68%, respectively. In all carcinoid patients (18)F-DOPA PET and (11)C-5-HTP PET detected more lesions than SRS (P < .001). (11)C-5-HTP PET was superior to (18)F-DOPA PET in islet cell tumors (P < .0001). In all cases, CT improved the sensitivity of the nuclear scans. CONCLUSION (18)F-DOPA PET/CT is the optimal imaging modality for staging in carcinoid patients and (11)C-5-HTP PET/CT in islet cell tumor patients.

The Metabolic Syndrome and Disturbances in Hormone Levels in Long-Term Survivors of Disseminated Testicular Cancer

Purpose The metabolic syndrome may be an important risk factor for cardiovascular disease in long-term survivors of testicular cancer (TC). We investigated the associations between hormone levels and the metabolic syndrome in these men. Patients and Methods We included TC patients cured by orchidectomy and cisplatin-based chemotherapy, stage I TC patients after orchidectomy only, and healthy men of comparable age. Presence of the metabolic syndrome was determined using guidelines from the National Cholesterol Education Program Adult Treatment Panel III. Thyroid-stimulating hormone, follicle-stimulating hormone (FSH), inhibin B, luteinizing hormone (LH), total testosterone, sex-hormone–binding globulin, free testosterone, estradiol, dehydroepiandrosterone sulfate, and insulin-like growth factor 1 were determined in blood. Cortisol metabolite excretion was measured in urine. Results Eighty-six chemotherapy patients (median follow-up, 7 years) were compared with 44 stage I patients and 47 controls. LH and FS...

Association between angiotensin-converting-enzyme gene polymorphism and failure of renoprotective therapy

BACKGROUND Polymorphism in the gene for angiotensin-converting enzyme (ACE), especially the DD genotype, is associated with risk for cardiovascular disease. Glomerulosclerosis has similarities to atherosclerosis, and we looked at ACE gene polymorphism in patients with kidney disease who were in a trial of long-term therapy with an ACE inhibitor or a beta-blocker. METHODS 81 patients with non-diabetic renal disease had been entered into a randomised comparison of oral atenolol or enalapril to prevent progressive decline in renal function. The dose was titrated to a goal diastolic blood pressure of 10 mm Hg below baseline and/or below 95 mm Hg. The mean (SE) age was 50 (1) years, and the group included 49 men. Their renal function had been monitored over 3-4 years. We have looked at their ACE genotype, which we assessed with PCR. FINDINGS 27 patients had the II genotype, 37 were ID, and 17 were DD. 11 patients were lost to follow-up over 1-3 years. The decline of glomerular filtration rate over the years was significantly steeper in the DD group than in the ID and the II groups (p = 0.02; means -3.79, -1.37, and -1.12 mL/min per year, respectively). The DD patients treated with enalapril fared as equally a bad course as the DD patients treated with atenolol. Neither drug lowered the degree of proteinuria in the DD group. INTERPRETATION Our data show that patients with the DD genotype are resistant to commonly advocated renoprotective therapy.

Elevated plasma cholesteryl ester transfer in NIDDM: relationships with apolipoprotein B-containing lipoproteins and phospholipid transfer protein

Lecithin:cholesteryl acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP) are key factors in the esterification of cholesterol and the subsequent transfer of cholesteryl ester from high density lipoproteins (HDL) towards very low and low density lipoproteins (VLDL + LDL). Phospholipid transfer protein (PLTP), lipoprotein lipase (LPL) and hepatic lipase (HL) are involved in plasma phospholipid and triglyceride metabolism and also affect HDL. Equivocal changes in plasma cholesteryl ester transfer have been reported in non-insulin-dependent diabetes mellitus (NIDDM). In 16 NIDDM men with plasma triglycerides < or = 4.5 mmol/l and cholesterol < or = 8.0 mmol/l. plasma cholesteryl ester transfer (CET), cholesterol esterification rate, LCAT and PLTP activity levels were higher (P < 0.05 to P < 0.02) in conjunction with higher plasma triglycerides (P < 0.01) and lower HDL cholesterol and cholesteryl ester levels (P < 0.05) compared to 16 matched healthy men. Multiple stepwise regression analysis demonstrated that CET was positively related to VLDL + LDL cholesterol (P < 0.001), triglycerides (P = 0.001), PLTP activity (P = 0.007) and CETP activity (P = 0.008, multiple r = 0.94). NIDDM had no effect on CET, independently from these parameters. HDL cholesteryl ester was negatively related to CET (P= 0.017), HL activity (P = 0.033) and NIDDM (P = 0.047) and positively to LCAT activity levels (P = 0.034, multiple r = 0.68). It is concluded that the elevated CET in plasma from NIDDM patients is associated with higher plasma triglycerides and PLTP activity levels. Furthermore, our data suggest that in normo- and moderately dyslipidaemic subjects PLTP and CETP activity levels per se may influence the rate of cholesteryl ester transfer in plasma. Plasma cholesteryl ester transfer appears to be a determinant of HDL cholesteryl ester, but other factors are likely to contribute to lower HDL cholesteryl ester levels in NIDDM.

Size of sentinel-node metastasis and chances of non-sentinel-node involvement and survival in early stage vulvar cancer: results from GROINSS-V, a multicentre observational study

BACKGROUND Currently, all patients with vulvar cancer with a positive sentinel node undergo inguinofemoral lymphadenectomy, irrespective of the size of sentinel-node metastases. Our study aimed to assess the association between size of sentinel-node metastasis and risk of metastases in non-sentinel nodes, and risk of disease-specific survival in early stage vulvar cancer. METHODS In the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V), sentinel-node detection was done in patients with T1-T2 (<4 cm) squamous-cell vulvar cancer, followed by inguinofemoral lymphadenectomy if metastatic disease was identified in the sentinel node, either by routine examination or pathological ultrastaging. For the present study, sentinel nodes were independently reviewed by two pathologists. FINDINGS Metastatic disease was identified in one or more sentinel nodes in 135 (33%) of 403 patients, and 115 (85%) of these patients had inguinofemoral lymphadenectomy. The risk of non-sentinel-node metastases was higher when the sentinel node was found to be positive with routine pathology than with ultrastaging (23 of 85 groins vs three of 56 groins, p=0.001). For this study, 723 sentinel nodes in 260 patients (2.8 sentinel nodes per patient) were reviewed. The proportion of patients with non-sentinel-node metastases increased with size of sentinel-node metastasis: one of 24 patients with individual tumour cells had a non-sentinel-node metastasis; two of 19 with metastases 2 mm or smaller; two of 15 with metastases larger than 2 mm to 5 mm; and ten of 21 with metastases larger than 5 mm. Disease-specific survival for patients with sentinel-node metastases larger than 2 mm was lower than for those with sentinel-node metastases 2 mm or smaller (69.5%vs 94.4%, p=0.001). INTERPRETATION Our data show that the risk of non-sentinel-node metastases increases with size of sentinel-node metastasis. No size cutoff seems to exist below which chances of non-sentinel-node metastases are close to zero. Therefore, all patients with sentinel-node metastases should have additional groin treatment. The prognosis for patients with sentinel-node metastasis larger than 2 mm is poor, and novel treatment regimens should be explored for these patients.

Effects of active and passive smoking on disease course of Crohn's disease and ulcerative colitis

Background: Smoking is a remarkable risk factor for inflammatory bowel disease (IBD), aggravating Crohns disease (CD) while having beneficial effects on ulcerative colitis (UC). We studied the effects of active and passive smoking in Dutch IBD patients. Methods: A questionnaire focusing on cigarette smoke exposure was sent to 820 IBD patients. Returned questionnaires were incorporated into a retrospective chart review, containing details about disease behavior and received therapy. Results: In all, 675 IBD patients (380 [56%] CD and 295 [44%] UC) responded. At diagnosis there were 52% smokers in CD, 41% in the general population, and 28% in UC. The number of present smokers in CD is lower than in the general population (26% versus 35%). No detrimental effects of active smoking on CD were observed, but passive smokers needed immunosuppressants and infliximab more frequently than nonpassive smokers. Active smoking had beneficial effects on UC, indicated by reduced rates of colectomy, primary sclerosing cholangitis, and backwash‐ileitis in active smokers compared to never smokers, and higher daily cigarette dose correlated with less extensive colitis and a lower need for therapy. Furthermore, smoking cessation after diagnosis was detrimental for UC patients, indicated by increased needs for steroids and hospitalizations for patients that stopped smoking after compared to before the diagnosis. Conclusions: Active smoking is a risk factor for CD, but does not affect the outcome; passive smoking is detrimental for the outcome of CD patients. In UC, active smoking shows dose‐dependent beneficial effects. Our data suggest that passive smoking is a novel risk factor for CD. (Inflamm Bowel Dis 2009)

6-[F-18]Fluoro-l-Dihydroxyphenylalanine Positron Emission Tomography Is Superior to Conventional Imaging with 123I-Metaiodobenzylguanidine Scintigraphy, Computer Tomography, and Magnetic Resonance Imaging in Localizing Tumors Causing Catecholamine Excess

CONTEXT Catecholamine excess is rare, but symptoms may be life threatening. OBJECTIVE The objective of the study was to investigate the sensitivity of 6-[F-18]fluoro-l-dihydroxyphenylalanine positron emission tomography ((18)F-DOPA PET), compared with (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy and computer tomography (CT)/magnetic resonance imaging (MRI) for tumor localization in patients with catecholamine excess. DESIGN AND SETTING All consecutive patients with catecholamine excess visiting the University Medical Center Groningen, Groningen, The Netherlands, between March 2003 and January 2008 were eligible. PATIENTS Forty-eight patients were included. The final diagnosis was pheochromocytoma in 40, adrenal hyperplasia in two, paraganglioma in two, ganglioneuroma in one, and unknown in three. MAIN OUTCOME MEASURES Sensitivities and discordancy between (18)F-DOPA PET, (123)I-MIBG, and CT or MRI were analyzed for individual patients and lesions. Metanephrines and 3-methoxytyramine in plasma and urine and uptake of (18)F-DOPA with PET were measured to determine the whole-body metabolic burden and correlated with biochemical tumor activity. The gold standard was a composite reference standard. RESULTS (18)F-DOPA PET showed lesions in 43 patients, (123)I-MIBG in 31, and CT/MRI in 32. Patient-based sensitivity for (18)F-DOPA PET, (123)I-MIBG, and CT/MRI was 90, 65, and 67% (P < 0.01 for (18)F-DOPA PET vs. both (123)I-MIBG and CT/MRI, P = 1.0 (123)I-MIBG vs. CT/MRI). Lesion-based sensitivities were 73, 48, and 44% (P < 0.001 for (18)F-DOPA PET vs. both (123)I-MIBG and CT/MRI, P = 0.51 (123)I-MIBG vs. CT/MRI). The combination of (18)F-DOPA PET with CT/MRI was superior to (123)I-MIBG with CT/MRI (93 vs. 76%, P < 0.001). Whole-body metabolic burden measured with (18)F-DOPA PET correlated with plasma normetanephrine (r = 0.82), urinary normetanephrine (r = 0.84), and metanephrine (r = 0.57). CONCLUSION To localize tumors causing catecholamine excess, (18)F-DOPA PET is superior to (123)I-MIBG scintigraphy and CT/MRI.

18F-dihydroxyphenylalanine PET in patients with biochemical evidence of medullary thyroid cancer: relation to tumor differentiation.

Curative treatment for recurrent medullary thyroid cancer (MTC), diagnosed by rising serum calcitonin, is surgery, but tumor localization is difficult. Therefore, the value of 18F-dihydroxyphenylanaline PET (18F-DOPA PET), 18F-FDG PET, 99mTc-V-di-mercaptosulfuricacid (DMSA-V) scintigraphy, and MRI or CT was studied. Methods: Twenty-one patients with biochemical recurrent or residual MTC underwent 18F-DOPA PET, 18F-FDG PET, DMSA-V scintigraphy, and MRI or CT. Patient- and lesion-based sensitivities were calculated using a composite reference consisting of all imaging modalities. Results: In 76% of all patients with MTC, one or more imaging modalities was positive for MTC lesions. In 6 of 8 patients with a calcitonin level of <500 ng/L, imaging results were negative. In 15 patients with positive imaging results, 18F-DOPA PET detected 13 (sensitivity, 62%; with 4.6 lesions per patient [lpp]). Morphologic imaging (n = 19) was positive in 7 (sensitivity, 37%; 4.7 lpp), DMSA-V (n = 18) in 5 (sensitivity, 28%; 1.1 lpp), and 18F-FDG PET (n = 17) in 4 (sensitivity, 24%; 1.6 lpp). In a lesion-based analysis, 18F-DOPA PET detected 95 of 134 lesions (sensitivity, 71%), morphologic imaging detected 80 of 126 (sensitivity, 64%), DMSA-V detected 20 of 108 (sensitivity, 19%), and 18F-FDG PET detected 48 of 102 (sensitivity, 30%). In 2 of 3 patients with a calcitonin/carcinoembryonic antigen (CEA) doubling time of ≤12 mo, 18F-FDG PET performed better than 18FDOPA PET; in the third patient, 18F-FDG PET was not performed. Conclusion: MTC lesions are best detectable when serum calcitonin was >500 ng/L. 18F-DOPA PET is superior to 18F-FDG PET, DMSA-V, and morphologic imaging. With short calcitonin doubling times (≤12 mo), 18F-FDG PET may be superior.

Effect of intravenous infusion of low-dose dopamine on renal function in normal individuals and in patients with renal disease.

A low dose of dopamine was infused in 28 normal volunteers and in 137 patients with varying degrees of renal insufficiency during a routine measurement of the glomerular filtration (GFR) and the effective renal plasma flow (ERPF). Dopamine infusion led to an increase in ERPF and GFR and to fall in the filtration fraction. The effect of dopamine on renal function was most pronounced if the baseline GFR was normal. However, healthy individuals showed greater increases in both ERPF and GFR than renal patients with a comparable baseline GFR. In renal patients no effect was observed if the baseline GFR was below 50 ml/min/1.73 m2. Firstly, it is concluded that already early in renal disease there exists a diminished reserve filtration capacity. Secondly, if the GFR is less than 50 ml/min/1.73 m2, the renal reserve filtration capacity seems to be exhausted.