Hans-Helge Müller

Randomized, Multicenter Trial of Fluorouracil Plus Leucovorin Administered Either Via Hepatic Arterial or Intravenous Infusion Versus Fluorodeoxyuridine Administered Via Hepatic Arterial Infusion in Patients With Nonresectable Liver Metastases From Colorectal Carcinoma

PURPOSEnTo assess the efficacy and tolerability of three treatments for patients with documented adenocarcinoma of the colon and/or rectum who have undergone complete resection of primary tumor and have nonresectable liver metastases that do not exceed 75% of the liver volume.nnnPATIENTS AND METHODSnA total of 168 patients at 25 treatment centers were enrolled onto this prospective, multicenter, randomized study. The three treatment arms were as follows: (1) fluorouracil (5-FU)/leucovorin (LV) administered via hepatic arterial infusion (HAI), (2) 5-FU/LV administered via intravenous (IV) infusion, and (3) fluorodeoxyuridine (FUDR) administered via HAI.nnnRESULTSnMedian times to disease progression for the three treatment arms were as follows: 9.2 months for patients treated with HAI 5-FU/LV, 6.6 months for IV 5-FU/LV, and 5.9 months for HAI FUDR. Median survival times for patients treated with HAI 5-FU/LV, IV 5-FU/LV, and HAI FUDR were 18.7 months, 17.6 months, and 12.7 months, respectively. There was a nearly two-fold increase in time to progression in addition to a survival benefit among patients with an intrahepatic tumor burden of less than 25% who were treated with HAI 5-FU/LV. The most common adverse events were stomatitis, nausea and vomiting, skin irritation, diarrhea, and elevated serum levels of liver enzymes. Some patients exhibited severe reactions, including biliary sclerosis and chemical hepatitis.nnnCONCLUSIONnAlthough the use of HAI 5-FU/LV as a means of treating liver metastases after resection of colorectal carcinoma warrants further investigation, it cannot be recommended as a routine therapeutic measure at this time.

Sunitinib in Refractory Adrenocortical Carcinoma: A Phase II, Single-Arm, Open-Label Trial

CONTEXTnTreatment of refractory adrenocortical carcinoma (ACC) is not established. Animal experiments pointed toward adrenal toxicity of sunitinib.nnnOBJECTIVEnThe objective of the study was to determine the antitumor effects of sunitinib in refractory ACC.nnnDESIGNnThis was a phase II, open-label trial using a two-stage accrual design.nnnSETTINGnThe study was conducted at two tertiary referral centers.nnnPATIENTSnThirty-eight patients with refractory ACC progressing after mitotane and one to three cytotoxic chemotherapies participated in the study.nnnINTERVENTIONnThe intervention included sunitinib at a standard dose (50 mg/d, 4 wk on, 2 wk off).nnnMAIN OUTCOME MEASUREnResponse was defined as progression-free survival (PFS) of 12 wk or longer (first tumor evaluation).nnnRESULTSnThirty-five patients could be evaluated for response. Five patients experienced stable disease, 24 had progressive disease, and six patients died from ACC before the first evaluation (naïve estimate five of 35=14.3%, median unbiased response rate 15.4%, 95% confidence interval 5.0-33.4%). The median PFS was 2.8 months. In responders, PFS ranged between 5.6 and 11.2 months and overall survival between 14.0 and 35.5 months. Of 36 serious adverse events, only nine were possibly related to sunitinib. Concomitant mitotane appeared to negatively impact on outcome. Furthermore, a negative correlation between the serum concentrations of sunitinib plus its active metabolite N-desethylsunitinib (SU12662) and mitotane (r=-0.650; P=0.114) was observed in seven evaluable patients suggestive of a relevant drug interaction.nnnCONCLUSIONnSunitinib has modest activity in advanced refractory ACC, which compares favorably with other targeted treatments in these patients. Sunitinib serum levels might have been profoundly reduced by mitotane induced cytochrome P450-3A4 activity attenuating its antitumor activity and adverse effects. Together these findings suggest that sunitinib deserves further investigation in mitotane-naïve ACC patients.

Reoperations for primary hyperparathyroidism—improvement of outcome over two decades

PurposeReoperations (R-PTX) for primary hyperparathyroidism (pHPT) are challenging, since they are associated with increased failure and morbidity rates. The aim was to evaluate the results of reoperations over two decades, the latter considering the implementation of Tc99msestamibi-SPECT (Mibi/SPECT), intraoperative parathormone (IOPTH) measurement, and intraoperative neuromonitoring (IONM).Patients and methodsData of 1,363 patients who underwent surgery for pHPT were retrospectively analyzed regarding reoperations. Causes of persistent (p) pHPT or recurrent (r) pHPT, preoperative imaging studies, surgical findings, and outcome were analyzed. Data of patients who underwent surgery between 1987 and 1997 (group 1; G1) and between 1998 and 2008 (group 2; G2) with the use of Mibi/SPECT, IOPTH, and IONM were evaluated.ResultsOne hundred twenty-five patients with benign ppHPT (nu2009=u2009108) or rpHPT (nu2009=u200917) underwent reoperations (R-PTX). Group 1 included 54, group 2 71 patients. Main cause of ppHPT (G1u2009=u200965xa0% vs. G2u2009=u200953xa0%) and rpHPT (G1u2009=u200980xa0% vs. G2u2009=u200960xa0%) was the failed detection of a solitary adenoma (pu2009=u20090.2). Group 1 patients had significantly less unilateral/focused neck re-explorations (G1u2009=u200923xa0% vs. G2u2009=u200957xa0%, pu2009=u20090.0001), and more sternotomies (G1u2009=u200935 vs. G2u2009=u200914xa0%, pu2009=u20090.01). After a median follow-up of 4 (range 0.9–23.4) years, reversal of hypercalcemia was achieved in 91xa0% (G1) and in 98.6xa0% in group 2 (pu2009=u20090.08, OR 7.14 [0.809–63.1]). The rates of permanent recurrent laryngeal nerve palsy (G1u2009=u2009G2u2009=u20099xa0%, pu2009=u20091) and of postoperative permanent hypoparathyroidism (G1u2009=u20099xa0% vs. G2u2009=u20096xa0%, pu2009=u20090.5) were not significantly different. Other complications such as wound infection, postoperative bleeding, and pneumonia were significantly lower in group 2 (pu2009<u20090.001).ConclusionNowadays, cure rates of R-PTX are nearly the same as in primary operations for pHPT. These results can be achieved in high-volume centers by routine use of well-established preoperative Mibi/SPECT and US in combination with IOPTH. However, morbidity is still considerably high.

Relevance of neoadjuvant and adjuvant treatment for patients with resectable liver metastases of colorectal carcinoma

Abstractu2002Background: Excellent results after resection of colorectal liver metastases are associated with a high rate of recurrence. Influenced by positive results of palliative and adjuvant treatment in advanced cancer, various chemotherapy regimens were evaluated to improve long-term results. Methods: The databases Medline and Cancerlit (1982–1998) gave information about 675 patients who were treated either by means of systemic, intra-arterial, intraportal or intraperitoneal administration before or after liver resection. Results: In general, the feasibility of an adjuvant treatment was tested. Proof has been furnished for the practicability of systemic and arterial therapy and for immunotherapy after liver resection whereas, for peritoneal and portal treatment, further studies are necessary. In a few non-randomised trials, it has been possible to discern a trend towards an improvement due to adjuvant postoperative therapy using historical or matched-pair control groups. Until now, only one of five randomised studies has been published. Six months of postoperative adjuvant intra-arterial treatment using 5-fluorouracil (1000 mg/m2 for 5 days every 28 days) and folinic acid (200 mg/m2 for 5 days every 28 days) was compared with observation only. Neither in the intention-to-treat nor in the as-treated analysis was median survival time (34.5 months versus 40.8 months and 39.7 months versus 44.8 months, respectively) significantly increased. As neoadjuvant treatment was successful in primary non-resectable patients, this approach is now being tested in resectable patients. Conclusion: Despite several theoretical reasons for post- or preoperative treatment in resectable patients, every approach should be tested using of controlled studies.

Does Footprint Preparation Influence Tendon-to-Bone Healing After Rotator Cuff Repair in an Animal Model?

PURPOSEnThe aim of this study was to investigate the influence of footprint spongialization and radiofrequency ablation on rotator cuff repair outcomes compared with an untreated group in a rat model.nnnMETHODSnWe randomly assigned 189 Sprague-Dawley rats to either a spongialization, radiofrequency ablation, or untreated group. After separation of the supraspinatus tendon from the greater tubercle, the footprint was prepared by removing the cortical bone with a burr (spongialization), was prepared by ablating soft tissue with a radiofrequency ablation device, or was left unaltered (untreated). Biomechanical testing (after 7 weeks, n = 165) and histologic analysis after 1 and 7 weeks (n = 24) followed reinsertion.nnnRESULTSnThe mean load to failure was 17.51 ± 4.46 N/mm(2) in the spongialization group, 15.56 ± 4.85 N/mm(2) in the radiofrequency ablation group, and 19.21 ± 5.19 N/mm(2) in the untreated group. A significant difference was found between the spongialization and radiofrequency ablation groups (P = .0409), as well as between the untreated and radiofrequency ablation groups (P = .0014). There was no significant difference between the spongialization and untreated groups (P = .2456). The mean area of fibrocartilage transition, characterized by the presence of type II collagen, was larger after 1 and 7 weeks in the spongialization group (0.57 ± 0.1 mm(2) and 0.58 ± 0.1 mm(2), respectively) and untreated group (0.51 ± 0.1 mm(2) and 0.51 ± 0.2 mm(2), respectively) than in the radiofrequency ablation group (0.11 ± 0.1 mm(2) and 0.4 ± 0.1 mm(2), respectively) with P < .05 and P < .01.nnnCONCLUSIONSnThe results of this study show that radiofrequency ablation of the footprint results in a poor biomechanical and histologic outcome in an animal model. No preparation of the footprint has the same effect as spongialization.nnnCLINICAL RELEVANCEnDifferent techniques of footprint preparation in rotator cuff repair may influence tendon-to-bone healing.

The HLA class II allele DQB1 0309 is associated with dilated cardiomyopathy.

Previous studies have shown weak associations between human dilated cardiomyopathy (DCM) and certain human leucocyte antigen (HLA) class II polymorphisms. Using a sequence-specific primer-PCR (SSP-PCR) technology, we compared the allelic distribution in the HLA-DQ and -DR locus in a cohort of German DCM patients (n=165) and DCM-free controls (n=79). With the exception of HLA-DQB1 0309, we found no significant differences between the two groups, even without adjustment for multiple testing. The HLA-DQB1 0309 allele, however, was detected more frequently in DCM patients as compared to controls (28.5% versus 10.1%, p=0.0010), leading to an odds ratio of 3.5 (95% confidence interval=1.5-9.1). The frequency of this allele was significantly higher in DCM patients without lymphocytic infiltrates in endomyocardial biopsies as compared to patients classified histologically as inflammatory DCM (33.1% versus 14.6%, p=0.028). There was no significant difference in the allelic HLA-DQB1 0309 distribution between DCM patients with and without viral genomes detected in the heart (24.2% versus 29.5%, p=0.668). In summary, the frequency of the HLA-DQB1 0309 allele is overrepresented in DCM patients, suggesting that carriers of this HLA class II variant are associated with an increased risk for developing DCM. Although Bonferroni adjustment was applied, controlled studies in larger samples of DCM patients and in different ethnic populations are warranted to confirm this observation and reveal the pathophysiological mechanisms behind this association.

Safety and efficacy of immunotherapy with the recombinant B-cell epitope–based grass pollen vaccine BM32

Background: BM32 is a grass pollen allergy vaccine based on recombinant fusion proteins consisting of nonallergenic peptides from the IgE‐binding sites of the 4 major grass pollen allergens and the hepatitis B preS protein. Objective: We sought to study the safety and clinical efficacy of immunotherapy (allergen immunotherapy) with BM32 in patients with grass pollen–induced rhinitis and controlled asthma. Methods: A double‐blind, placebo‐controlled, multicenter allergen immunotherapy field study was conducted for 2 grass pollen seasons. After a baseline season, subjects (n = 181) were randomized and received 3 preseasonal injections of either placebo (n = 58) or a low dose (80 &mgr;g, n = 60) or high dose (160 &mgr;g, n = 63) of BM32 in year 1, respectively, followed by a booster injection in autumn. In the second year, all actively treated subjects received 3 preseasonal injections of the BM32 low dose, and placebo‐treated subjects continued with placebo. Clinical efficacy was assessed by using combined symptom medication scores, visual analog scales, Rhinoconjunctivitis Quality of Life Questionnaires, and asthma symptom scores. Adverse events were graded according to the European Academy of Allergy and Clinical Immunology. Allergen‐specific antibodies were determined by using ELISA, ImmunoCAP, and ImmunoCAP ISAC. Results: Although statistical significance regarding the primary end point was not reached, BM32‐treated subjects, when compared with placebo‐treated subjects, showed an improvement regarding symptom medication, visual analog scale, Rhinoconjunctivitis Quality of Life Questionnaire, and asthma symptom scores in both treatment years. This was accompanied by an induction of allergen‐specific IgG without induction of allergen‐specific IgE and a reduction in the seasonally induced increase in allergen‐specific IgE levels in year 2. In the first year, more grade 2 reactions were observed in the active (n = 6) versus placebo (n = 1) groups, whereas there was almost no difference in the second year. Conclusions: Injections of BM32 induced allergen‐specific IgG, improved clinical symptoms of seasonal grass pollen allergy, and were well tolerated.

Development of a formula to predict parathyroid carcinoma in patients with primary hyperparathyroidism.

BackgroundCure of parathyroid carcinoma (PC) requires initial en bloc resection, including resection of all tumor-bearing tissue, with hemithyroidectomy and dissection of the central lymph node compartment. Unfortunately, no reliable preoperative criteria have yet been assessed to indicate a high likelihood of PC. Thus, the aim of the present study was to develop a formula to indicate preoperatively the presence of PC.MethodsA prospective database of 1,363 patients with primary hyperparathyroidism (pHPT) was screened for patients with PC. Age, gender, surgical procedures, laboratory data, and follow-up results were evaluated and compared to a group of patients with benign pHPT. Based on preoperative serum calcium (Ca) and parathyroid hormone (PTH) levels, as well as patients’ age at the time of diagnosis, a formula was developed by a multivariate logistic model that estimates the individual risk for PC.ResultsBetween 1987 and 2008, 19 patients with PC were identified. Ca (3.8xa0±xa00.3 vs 2.9xa0±xa00.3 mmo/l; pxa0=xa00.0002) and PTH levels (1,250xa0±xa0769 vs 194xa0±xa0204xa0pg/ml; pxa0=xa00.0030) were significantly higher in patients with PC than in those with benign pHPT. Patients with PC were also significantly younger than patients with benign pHPT (48.9xa0±xa012.1 vs 59.1xa0±xa013.8xa0years; pxa0<xa00.05). With a ≥5xa0% probability that a given patient suffered from PC, the sensitivity and specificity to identify the disease were 100 and 30xa0%, respectively, with the new Ca, PTH, and age based logarithmic formula.ConclusionsThe new logarithmic formula can be used to calculate the individual risk for PC. If the calculated individual risk exceeds 5xa0%, en bloc resection seems to be justified to provide long-term cure in case of PC.

Genotype-specific effects on left ventricular function in parvovirus B19-positive patients with dilated cardiomyopathy

Genotype‐specific effects of parvovirus B19 (B19V) infections on left ventricular function in patients with dilated cardiomyopathy (DCM) have not been investigated so far. In this prospective clinical study, the prevalences of B19V genotypes in endomyocardial biopsies from patients presenting with inflammatory heart disease and DCM were determined. A total of 139 consecutive patients were included in the study; among them 53 patients were diagnosed as DCM. Among the total study cohort, B19V DNA was detected in 65 study participants (46.8%). Genotyping of the B19V genomes in the total cohort identified genotype 1 in 38 samples (27.3%), genotype 2 in 25 samples (18.0%), and genotype 3 in only two patients (1.4%). During an average follow‐up period of 8 months left ventricular ejection fraction (LVEF) improved significantly both in B19V‐positive (7.1u2009±u200913.8%, nu2009=u200917, Pu2009=u20090.038) as well as B19V‐negative patients with DCM (9.5u2009±u200913.9%, nu2009=u200920, Pu2009=u20090.017). However, mean LVEF improved only in patients with genotype 1 (11.0u2009±u200914.4%, nu2009=u20097), whereas it even decreased in patients with genotype 2 (−6.2u2009±u20096.3%, nu2009=u20095, Pu2009=u20090.033). These data from a small sample of patients diagnosed as DCM suggested that myocardial function during short‐time follow‐up differed between genetic variants of B19V. Patients with genotype 1 were on average younger than genotype 2 and appeared to be more prone to a beneficial course of left ventricular function than patients with genotype 2. Future studies with larger sample sizes and longer follow‐up periods will be required to confirm this observation. J. Med. Virol. 83:1818–1825, 2011.

Effects of increasing sevoflurane MAC levels on mid-latency auditory evoked potentials in infants, schoolchildren, and the elderly

BACKGROUNDnDetection of mid-latency auditory evoked potentials (MLAEPs) is a technology to monitor central nervous structures. As seen in adults and children, general anaesthesia influences the MLAEP latencies. MLAEP detection seems to be a promising tool to assess different levels of anaesthesia depth in adults and children.nnnMETHODSnMLAEPs were recorded in 10 infants (2 months-3 yr), 12 schoolchildren (6-14 yr), and 10 elderly (75-89 yr) under general anaesthesia with increasing concentrations of sevoflurane at steady state. In addition, MLAEPs were detected before and after the application of sufentanil.nnnRESULTSnAt all different ages, MLAEP latencies increased significantly with higher volume percentages of sevoflurane. These results were also detectable when MAC values of sevoflurane were compared with MLAEP peaks. An age-dependent effect could be displayed as elderly people need lower absolute sevoflurane concentrations to achieve the same MLAEP peak increase. Overall, the application of sufentanil under steady-state sevoflurane application at 1 MAC did not importantly affect the MLAEP latencies.nnnCONCLUSIONSnMLAEP latencies increase at the influence of sevoflurane in a dose-dependent manner and in relation to age. These results imply that MLAEP detection is a reasonable tool for monitoring hypnotic effects at all ages. Further studies are required to standardize MLAEP alterations related to effects of medication used for general anaesthesia at all different ages.