Exploring MR regression patterns in rectal cancer during neoadjuvant radiochemotherapy with daily T2- and diffusion-weighted MRI.

BACKGROUND: To date, only limited magnetic resonance imaging (MRI) data are available concerning tumor regression during neoadjuvant radiochemotherapy (RCT) of rectal cancer patients, which is a prerequisite for adaptive radiotherapy (RT) concepts. This exploratory study prospectively evaluated daily fractional MRI during neoadjuvant treatment to analyze the predictive value of MR biomarkers for treatment response. METHODS: Locally advanced rectal cancer patients were examined with daily MRI during neoadjuvant RCT. Contouring of the tumor volume was performed for each MRI scan by using T2- and diffusion-weighted-imaging (DWI)-sequences. The daily apparent-diffusion coefficient (ADC) was calculated. Volumetric and functional tumor changes during RCT were analyzed and correlated with the pathological response after surgical resection. RESULTS: In total, 171 MRI scans of eight patients were analyzed regarding anatomical and functional dynamics during RCT. Pathological complete response (pCR) could be achieved in four patients, and four patients had a pathological partial response (pPR) following neoadjuvant treatment. T2- and DWI-based volumetry proved to be statistically significant in terms of therapeutic response, and volumetric thresholds at week two and week four during RCT were defined for the prediction of pCR. In contrast, the average tumor ADC values widely overlapped between both response groups during RCT and appeared inadequate to predict treatment response in our patient cohort. CONCLUSION: This prospective exploratory study supports the hypothesis that MRI may be able to predict pCR of rectal cancers early during neoadjuvant RCT. Our data therefore provide a useful template to tailor future MR-guided adaptive treatment concepts.

68Ga-PSMA PET/CT in the evaluation of bone metastases in prostate cancer.

PURPOSE: The aims of this retrospective analysis were to compare 68Ga-PSMA PET findings and low-dose CT findings (120 kV, 30 mA), and to obtain semiquantitative and quantitative 68Ga-PSMA PET data in patients with prostate cancer (PC) bone metastases. METHODS: In total, 152 PET/CT scans from 140 patients were evaluated. Of these patients, 30 had previously untreated primary PC, and 110 had biochemical relapse after treatment of primary PC. All patients underwent dynamic PET/CT scanning of the pelvis and lower abdomen as well as whole-body PET/CT with 68Ga-PSMA-11. The PET/CT scans were analysed qualitatively (visually), semiquantitatively (SUV), and quantitatively based on a two-tissue compartment model and a noncompartmental approach leading to the extraction of the fractal dimension. Differences were considered significant for p values <0.05. RESULTS: In total, 168 68Ga-PSMA-positive and 113 CT-positive skeletal lesions were detected in 37 patients (8 with primary PC, 29 with biochemical recurrence). Of these 168 lesions, 103 were both 68Ga-PSMA PET-positive and CT-positive, 65 were only 68Ga-PSMA-positive, and 10 were only CT-positive. The Yang test showed that there were significantly more 68Ga-PSMA PET-positive lesions than CT-positive lesions. Association analysis showed that PSA plasma levels were significantly correlated with several 68Ga-PSMA-11-associated parameters in bone metastases, including the degree of tracer uptake (SUVaverage and SUVmax), its transport rate from plasma to the interstitial/intracellular compartment (K1), its rate of binding to the PSMA receptor and its internalization (k3), its influx rate (Ki), and its distribution heterogeneity. CONCLUSION: 68Ga-PSMA PET/CT is a useful diagnostic tool in the detection of bone metastases in PC. 68Ga-PSMA PET visualizes more bone metastases than low-dose CT. PSA plasma levels are significantly correlated with several 68Ga-PSMA PET parameters.

[Diagnostic criteria in MR neurography]. / Diagnostische Kriterien in der MR-Neurographie.

Peripheral neuropathies are frequent and can mostly be correctly diagnosed by clinical examination and electrophysiology; however, diagnostically difficult cases are sometimes encountered especially with respect to precise localization of nerve lesions. Imaging of the peripheral nervous system has been shown to provide additional useful diagnostic information. In addition to the more widely available nerve sonography, magnetic resonance neurography (MRN) is the method of choice in diagnostically complex cases. The most important pulse sequence is a T2-weighted fat-saturated pulse sequence with high in-plane resolution and detects increased T2-weighted signals of nerve fascicles as a highly sensitive sign for nerve lesions. Further established diagnostic criteria are nerve caliber and, less commonly used, contrast agent uptake. The spatial pattern of nerve lesions aids in the diagnostic classification of neuropathies. Functional imaging techniques, such as diffusion tensor imaging (DTI) and nerve perfusion are currently under examination with respect to the clinical potential. If all other diagnostic methods, including clinical examination, electrophysiology and nerve sonography do not arrive at an unambiguous diagnosis of a peripheral neuropathy, MRN should be used. The special value of MRN is demonstrated particularly in complex nerve lesions, such as traumatic plexopathies and in partial fascicular neuropathies and many other indications.

Application of a Dedicated Surface Coil in Dental MRI Provides Superior Image Quality in Comparison with a Standard Coil.

PURPOSE: Purpose of our research was the evaluation of a dedicated dental surface coil in comparison with a standard head and neck coil for the improvement of dental magnetic resonance imaging (MRI). MATERIALS AND METHODS: Axial T1-weighted spin echo MRI was performed by using a newly developed dental coil for MRI and a standard head and neck coil on five volunteers. In addition, MRI was implemented with dental coil on five patients. Using the Wilcoxon test, we compared the volunteers' signal-to-noise ratio (SNR) of a variety of anatomical structures (e.g., hard tooth tissue, pulp tissue, bone, muscle tissue). Also subjective evaluation of image quality was performed on both volunteers and patients. RESULTS: Compared with the head and neck coil, the mean SNR was 3.5-fold higher on an average with the dental coil (range: from 2.7 [masseter muscle] to 4.6 [pulp tissue]). That difference was statistically significant for all evaluated structures. The higher SNR also resulted in a superior image quality as determined by subjective evaluation. CONCLUSION: Dental MRI benefits profoundly from using a dedicated dental coil.

Thoracic outlet syndrome in 3T MR neurography-fibrous bands causing discernible lesions of the lower brachial plexus.

OBJECTIVES: To investigate whether targeted magnetic resonance neurography (MRN) of the brachial plexus can visualise fibrous bands compressing the brachial plexus and directly detect injury in plexus nerve fascicles. METHODS: High-resolution MRN was employed in 30 patients with clinical suspicion of either true neurogenic thoracic outlet syndrome (TOS) or non-specific TOS. The protocol for the brachial plexus included a SPACE (3D turbo spin echo with variable flip angle) STIR (short tau inversion recovery), a sagittal-oblique T2-weighted (T2W) SPAIR (spectral adiabatic inversion recovery) and a 3D PDW (proton density weighted) SPACE. Images were evaluated for anatomical anomalies compressing the brachial plexus and for abnormal T2W signal within plexus elements. Patients with abnormal MR imaging findings underwent surgical exploration. RESULTS: Seven out of 30 patients were identified with unambiguous morphological correlates of TOS. These were verified by surgical exploration. Correlates included fibrous bands (n = 5) and pseudarthrosis or synostosis of ribs (n = 2). Increased T2W signal was detected within compressed plexus portion (C8 spinal nerve, inferior trunk, or medial cord) and confirmed the diagnosis. CONCLUSIONS: The clinical suspicion of TOS can be diagnostically confirmed by MRN. Entrapment of plexus structures by subtle anatomical anomalies such as fibrous bands can be visualised and relevant compression can be confirmed by increased T2W signal of compromised plexus elements. KEY POINTS: • MR neurography (MRN) can aid the diagnosis of thoracic outlet syndrome (TOS). • Identifiable causes of TOS in MRN include fibrous bands and bony anomalies. • Increased T2W signal within brachial plexus elements indicate relevant nerve compression. • High positive predictive value allows confident and targeted indication for surgery.

Accumulation of non-compressive fascicular lesions underlies NF2 polyneuropathy.

A distinct polyneuropathy (PNP) syndrome affects up to 66 % of patients with neurofibromatosis II (NF2). Whether this is primarily a diffuse PNP or due to single, surgically amenable mass lesions has not yet been conclusively demonstrated. We aimed to solve this question by investigating the pathomorphological MR imaging correlate of this rare disorder. Eight patients with NF2-PNP were characterized by clinical examination, electrophysiological studies, and genetic analysis. All patients additionally underwent extended peripheral nerve imaging by a novel protocol of large-coverage high-resolution MRI. Quantitative analyses were performed by separately evaluating cross-sectional images, and by categorizing lesions into non-compressive fascicular microlesions (<2 mm), intermediate lesions (2-5 mm), and compressive macrolesions (>5 mm). The predominant imaging findings were non-compressive fascicular microlesions and intermediate lesions. Proximal-to-distal cumulative lesion burden of these lesions correlated strongly with the severity of clinical symptoms of NF2-PNP. In contrast, compressive macrolesions were not found at all in several symptomatic extremities. We conclude that proximal-to-distal accumulation of non-compressive fascicular lesions instead of compressive mass lesions predominantly underlies the clinical manifestation and severity of NF2-associated PNP. Diagnostic management may now be assisted by large-coverage high-resolution imaging of plexus and peripheral nerves. Additionally, the results underscore the feasibility of this new method, which may open up new diagnostic and investigative possibilities for other disseminated disorders of the peripheral nervous system.

Neuroradiological response criteria for high-grade gliomas.

The recently introduced new response criteria of the response assessment in neuro-oncology (RANO) working group and its clinical implications are the topic of this article. Establishing this working group as a work-in-progress platform and its first report, the RANO criteria represent an important step forward in the accurate assessment of response to therapy in patients with malignant gliomas not only in clinical trials but also in daily practice. Anti-angiogenic therapy and other new treatment modalities have increased the incidence and awareness of novel imaging phenomena, such as pseudoprogression and pseudoresponse not only within clinical trials. The new RANO criteria also take clinical parameters, such as steroid medication and neurological symptoms into account. Neuroradiologists and neuro-oncologists need to be aware of and experienced in applying these new criteria to correctly assess the response to treatment in patients with malignant gliomas. Further research is needed to study new imaging techniques, such as perfusion and diffusion-weighted imaging and to investigate and incorporate these for routine tumor response criteria.

Magic angle effect: a relevant artifact in MR neurography at 3T?

BACKGROUND AND PURPOSE: MRN is an emerging diagnostic method for disorders of peripheral nerves. However, it is unclear whether the influence of the MA on intraneural T2 signal is severe enough to provoke false-positive findings. MATERIALS AND METHODS: Twenty-five healthy subjects underwent MRN of the sciatic nerve of the proximal thigh at 3T. The T2(app) was calculated from a DE-TSE sequence (TR = 3000 ms, TE1 = 12 ms, TE2 = 69 ms) at 7 angles of the sciatic nerve relative to B0 = 0°, 30°, 35°, 40°, 45°, 50°, and 55°. Precise angle adjustments were performed with a dedicated in-bore positioning aid. Qualitative evaluation of intraneural T2-weighted contrast between this group of healthy subjects and 14 patients with neuropathic lesions was performed by comparing CNRs of a TIRM sequence (TR = 5000 ms, TE = 76 ms, TI = 180 ms). RESULTS: In healthy subjects, the prolongation of T2(app) from 0° to 55° was from 74.5 ± 13.4 to 104.0 ± 16.9 ms (P < .001). The increase in T2(app) relative to baseline (0°) was 9.6% (30°), 18.4% (35°), 25% (40°), 27.6% (45°), and 37% (55°). Intraneural CNR increased by 1.98 ± 0.69 at 40° and 2.93 ± 0.46 at 55°. Nevertheless, the mean CNR of healthy subjects was substantially lower than that in patients at 40° (P < .0001) and even at the position of maximum MA (55°: 20.6 ± 5.11 versus 52.6 ± 7.12, P < .0001). CONCLUSIONS: Neuropathic lesions are clearly distinguishable from an artificial increase of intraneural T2 by the MA. Even at a maximum MA (55°), the false-positive determination of a neuropathic lesion is unlikely.

Racecadotril demonstrates intestinal antisecretory activity in vivo.

BACKGROUND: Racecadotril (acetorphan), a potent enkephalinase inhibitor, protects endogenous enkephalins from degradation. Racecadotril exhibits experimental and clinical antidiarrhoeal activity without any effect on intestinal motility, suggesting selective antisecretory activity. The antisecretory effect of racecadotril was directly assessed in the present study. METHODS: A 1 m, jejunal, Thiry-Vella loop was created in six mongrel dogs, and water and ionic fluxes were evaluated during infusion (2 mL/min) of Tyrode solution labelled with 14C-polyethylene glycol. Fluxes were determined both in the basal state and 5-6 h after commencement of a 2-h infusion of cholera toxin (0.4 microgram/mL). Racecadotril (10 mg/kg) or vehicle was given orally with and without prior intravenous administration of naloxone (0.1 mg/kg) or phentolamine (0.2 mg/kg). RESULTS: Basal absorption remained unchanged following racecadotril administration; however, racecadotril significantly decreased (P = 0.01) cholera toxin-induced water, sodium, and potassium hypersecretion, from 0.73 +/- 0.15 to 0.37 +/- 0.13 mL/min; from 125.0 +/- 16.1 to 14.7 +/- 9.5 microMol/min; and from 3.41 +/- 0.66 to 1.66 +/- 0.61 microMol/min, respectively. This antisecretory activity of racecadotril was suppressed by naloxone but not by phentolamine. CONCLUSIONS: This study directly demonstrates the antisecretory activity of racecadotril in relation to the protection of endogenous enkephalins.

Effects of racecadotril and loperamide on bacterial proliferation and on the central nervous system of the newborn gnotobiotic piglet.

METHODS: The effects of 4 days of oral administration of different doses of two drugs, an enkephalinase inhibitor (the antisecretory agent, racecadotril) and a mu-receptor agonist (loperamide), on intestinal growth of a bacterial nonpathogenic strain (Escherichia coli E 404) and on the central nervous system (CNS) were compared in newborn gnotobiotic piglets. RESULTS: The E. coli content of the proximal jejunum (segment S1) and the E. coli ratio of stomach:segment S1 were similar in the racecadotril (20 mg/kg b.d., n = 5) and control groups. In contrast, in the loperamide group (1 mg/kg b.d., n = 4), the E. coli content of segment S1 and the E. coli ratio stomach:S1 were both significantly higher than with racecadotril or control (P = 0.04 and 0.005, respectively, for E. coli content; P = 0.05 and 0.03, respectively, for stomach:S1). There were no clinical signs of neurotoxicity and no deaths with racecadotril given orally at a high dose of 130 mg/kg b.d. (n = 5)--nearly 60 times the paediatric dosage. In contrast, an equivalent high dose of loperamide (5 mg/kg b.d.) resulted in death in three out of four piglets. CONCLUSIONS: In contrast to loperamide, racecadotril did not induce bacterial overgrowth and did not produce central neurotoxicity.

Racecadotril versus placebo in the treatment of acute diarrhoea in adults.

METHODS: A two-centre, double-blind, parallel-group, randomized study was carried out to compare the efficacy and tolerability of racecadotril (100 mg three times daily) and placebo in 70 adult patients with acute diarrhoea. An objective criterion of antisecretory activity, stool weight, was used. RESULTS: Racecadotril produced a significant (P = 0.025) decrease in stool weight during the first day of treatment compared with placebo, and was also associated with significantly fewer diarrhoeic stools than placebo after 1 day of treatment (p = 0.027). Racecadotril and placebo were equally well tolerated, and the frequency of symptoms and signs was similar in both groups after 4 days of treatment. Fewer patients on racecadotril suffered from abdominal distension following treatment (5.6% vs. 18.2% on placebo). CONCLUSIONS: Racecadotril acts rapidly to resolve acute diarrhoea and has an incidence of adverse events similar to that of placebo.

Treatment of refractory diarrhoea in AIDS with acetorphan and octreotide: a randomized crossover study.

OBJECTIVE: To compare the efficacy and tolerance of acetorphan, an orally active enkephalinase inhibitor whose antidiarrhoeal properties derive from a purely antisecretory activity, to that of octreotide, a subcutaneously administered somatostatin analogue, in the treatment of refractory diarrhoea in AIDS patients. DESIGN: An open randomized crossover trial. SETTING: The inpatient medical units of three hospitals. PATIENTS: Thirteen adult inpatients with AIDS and refractory diarrhoea that lasted for 35 +/- 8 weeks despite use of traditional antidiarrhoeal agents and was characterized by 7.0 +/- 1.2 stools/day, weighing 1033 +/- 174 g/day with a lipid output of 18.8 +/- 3.5 g/day. INTERVENTIONS: Acetorphan (100-300 mg thrice daily) and octreotide (50-150 micrograms thrice daily) were given in random order during two 1-week periods. MAIN OUTCOME MEASURES: Response was defined as a reduction by at least one-third of both daily stool number and weight. RESULTS: The mean daily stool number was reduced to 4.6 +/- 1.1 with acetorphan (P < or = 0.05) but was 5.6 +/- 1.2 with octreotide (NS). Whereas two patients responded to both treatments, two responded to acetorphan alone and one to octreotide alone. Daily lipid output in faeces was reduced non-significantly with acetorphan (11.5 +/- 2.3 g) but was nearly doubled with octreotide (33.7 +/- 12.0 g). Acetorphan was very well tolerated. CONCLUSION: Enkephalinase inhibitors may be a useful alternative to somatostatin analogues in the management of refractory diarrhoea in AIDS.

The enkephalinase inhibitor, acetorphan, in acute diarrhoea. A double-blind, controlled clinical trial versus loperamide.

The antidiarrhoeal properties of acetorphan, an inhibitor of enkephalinase (EC 3.4.24.11) that prevents endogenous enkephalin degradation, and loperamide, a mu opiate receptor agonist, were compared. The double-blind study included 69 patients with acute diarrhoea of presumed infectious origin, allocated at random to two parallel groups. Acetorphan and loperamide were both rapidly and similarly effective, diarrhoea resolving in both cases in nearly 2 days. With acetorphan, however, abdominal distension vanished significantly more rapidly, and reactive constipation was less frequent (8% versus 31% with loperamide). These differences can be accounted for by the distinct mechanisms of antidiarrhoeal activity of the two drugs--that is, primary antitransit effect for loperamide and antisecretory activity for acetorphan.

Effects of acetorphan, an antidiarrhoeal enkephalinase inhibitor, on oro-caecal and colonic transit times in healthy volunteers.

Acetorphan is a potent enkephalinase inhibitor displaying antidiarrhoeal activity attributable to its intestinal antisecretory action mediated by endogenous enkephalins. The effect of acetorphan on digestive motility was studied in 12 healthy volunteers. Oro-caecal transit time was evaluated using the sulphasalazine/sulphapyridine method and colonic transit times using radiopaque markers. These measurements were successively performed after one week treatment with an antidiarrhoeal dose of acetorphan (100 mg t.d.s.) or placebo. There was no significant modification in transit time linked to acetorphan treatment: total oro-caecal times were 303 +/- 32 min vs. 287 +/- 27 min and colonic transit times 25.8 +/- 5.8 h vs. 31.3 +/- 5.5 h after acetorphan and placebo, respectively (means +/- S.E.M.). There was no significant modification either in right colonic, left colonic or rectosigmoid segmental transit times, or in the mean number of stools. These results, consistent with those from animal studies, confirm that, unlike classical antidiarrhoeal mu opiate receptor agonists, which act by delaying intestinal transit, acetorphan does not affect the transit. Antidiarrhoeal activity not accompanied by a delayed intestinal transit could have beneficial therapeutic consequences in the management of infectious diarrhoea. In addition, we show that the sulphasalazine and radiopaque markers methods can be simultaneously applied in the same study.

Effects of acetorphan, an enkephalinase inhibitor, on experimental and acute diarrhoea.

Acetorphan is an orally active inhibitor of enkephalinase (EC 3.4.24.11) with antidiarrhoeal activity in rodents apparently through protection of endogenous enkephalins and a purely antisecretory mechanism. Its antidiarrhoeal activity in man was assessed in an experimental model of cathartic induced secretory diarrhoea as well as in acute diarrhoea of presumed infectious origin. In six healthy volunteers receiving castor oil and pretreated with acetorphan or placebo in a crossover controlled trial, the drug significantly decreased the number and weight of stools passed during 24 hours. About 200 outpatients with severe acute diarrhoea (more than five stools per day) were included in a randomised double blind study of acetorphan against placebo. The significant antidiarrhoeal activity of acetorphan was established using a variety of criteria: (i) the duration of both diarrhoea and treatment were diminished; (ii) no acetorphan treated patient withdrew from the study whereas five dropped out because of worsening in the placebo group; (iii) the frequency of symptoms associated with diarrhoea--for example, abdominal pain or distension, nausea and anorexia--remaining after two weeks was nearly halved; (iv) using visual analogue scales acetorphan treatment was found more effective than placebo by both investigators and patients. There was statistically no significant difference between acetorphan and placebo in respect of side effects, particularly constipation, which often accompanies the antidiarrhoeal activity of mu opioid receptor agonists this difference is attributable to the lack of antipropulsive activity of acetorphan in man. The efficacy and tolerance of acetorphan suggest that enkephalinase inhibition may represent a novel therapeutic approach for the symptomatic management of acute secretory diarrhoea without impairing intestinal transit.

Stereoselective protection of exogenous and endogenous atrial natriuretic factor by enkephalinase inhibitors in mice and humans.

We compared the relative potencies of sinorphan and retorphan, the S- and R-enantiomers of acetorphan a potent inhibitor of enkephalinase (EC 3.4.34.11), to inhibit membrane metalloendopeptidase in vivo and to protect exogenous and endogenous ANF after oral administration. In mice, sinorphan was 2-3 fold as potent as retorphan in inhibiting the specific in vivo binding of [3H]acetorphan to kidney enkephalinase. The same potency ratio was found for the enhancement of trichloroacetic acid-precipitated radioactivity in kidneys of mice that had received 125I-ANF, which is used as a test for the protection of the hormone against inactivation in vivo. In nine healthy human volunteers who had received a low oral dosage of sinorphan or retorphan in a double-blind, placebo-controlled, randomized trial, sinorphan was also 2-3 fold more potent than retorphan in inhibiting plasma enkephalinase activity. These effects were accompanied by a related rise in plasma ANF immunoreactivity, which also reflected the difference in the effectiveness of the two compounds. Sinorphan was also more potent than retorphan in enhancing urinary cyclic GMP excretion and sodium excretion in five of these subjects. These data indicate that, in humans as in rodents, enkephalinase plays a crucial role in the inactivation of ANF, its partial inhibition in vivo being accompanied by a significant protection of the exogenous or endogenous hormone as well as by typical ANF-like responses. Thus orally administered sinorphan appears to be a promising compound for therapeutic use in cardiovascular and renal diseases in which ANF has been postulated to exert beneficial effects.