Temperature-controlled power modulation compensates for heterogeneous nanoparticle distributions: a computational optimization analysis for magnetic hyperthermia

Purpose: To study, with computational models, the utility of power modulation to reduce tissue temperature heterogeneity for variable nanoparticle distributions in magnetic nanoparticle hyperthermia.

Methods: Tumour and surrounding tissue were modeled by elliptical two- and three-dimensional computational phantoms having six different nanoparticle distributions. Nanoparticles were modeled as point heat sources having amplitude-dependent loss power. The total number of nanoparticles was fixed, and their spatial distribution and heat output were varied. Heat transfer was computed by solving the Pennes’ bioheat equation using finite element methods (FEM) with temperature-dependent blood perfusion. Local temperature was regulated using a proportional-integral-derivative (PID) controller. Tissue temperature, thermal dose and tissue damage were calculated. The required minimum thermal dose delivered to the tumor was kept constant, and heating power was adjusted for comparison of both the heating methods.

Results: Modulated power heating produced lower and more homogeneous temperature distributions than did constant power heating for all studied nanoparticle distributions. For a concentrated nanoparticle distribution, located off-center within the tumor, the maximum temperatures inside the tumor were 16% lower for modulated power heating when compared to constant power heating. This resulted in less damage to surrounding normal tissue. Modulated power heating reached target thermal doses up to nine-fold more rapidly when compared to constant power heating.

Conclusions: Controlling the temperature at the tumor-healthy tissue boundary by modulating the heating power of magnetic nanoparticles demonstrably compensates for a variable nanoparticle distribution to deliver effective treatment.     

A Multi-Institutional Phase II Trial of Preoperative Full-Dose Gemcitabine and Concurrent Radiation for Patients With Potentially Resectable Pancreatic Carcinoma

Background We report the results of a multi-institutional phase II trial that used preoperative full-dose gemcitabine and radiotherapy for patients with potentially resectable pancreatic carcinoma. Methods Patients were treated before surgery with three cycles of full-dose gemcitabine (1000 mg/m² intravenously), with radiation during the second cycle (36 Gy in daily 2.4-Gy fractions). Patients underwent surgery 4 to 6 weeks after the last gemcitabine infusion. Results There were 10 men and 10 women, with a median age of 58 years (range, 50–80 years). Nineteen patients (95%) completed therapy without interruption, and one experienced grade 3 gastrointestinal toxicity. The mean weight loss after therapy was 4.0%. Of 20 patients taken to surgery, 17 (85%) underwent resections (16 pancreaticoduodenectomies and 1 distal pancreatectomy). The complication rate was 24%, with an average length of stay of 13.5 days. There were no operative deaths. Pathologic analysis revealed clear margins in 16 (94%) of 17 and uninvolved lymph nodes in 11 (65%) of 17 specimens. One specimen contained no residual tumor, and three specimens revealed only microscopic foci of residual disease. With a median follow-up of 18 months, 7 (41%) of the 17 patients with resected disease are alive with no recurrence, 3 (18%) are alive with distant metastases, and 7 (41%) have died. Conclusions Preoperative gemcitabine/radiotherapy is well tolerated and safe when delivered in a multi-institutional setting. This protocol had a high rate of subsequent resection, with acceptable morbidity. The high rate of negative margins and uninvolved nodes suggests a significant tumor response. Preliminary survival data are encouraging. This regimen should be considered in future neoadjuvant trials for pancreatic cancer.     

Image-guided thermal therapy with a dual-contrast magnetic nanoparticle formulation: A feasibility study

Purpose/objective: The aim of this study was to develop and investigate the properties of a magnetic iron oxide nanoparticle–ethiodised oil formulation for image-guided thermal therapy of liver cancer.

Materials and methods: The formulation comprises bionised nano-ferrite (BNF) nanoparticles suspended in ethiodised oil, emulsified with polysorbate 20 (BNF-lip). Nanoparticle size was measured via photon correlation spectroscopy and transmission electron microscopy. In vivo thermal therapy capability was tested in two groups of male Foxn1^nu mice bearing subcutaneous HepG2 xenograft tumours. Group I (n?=?12) was used to screen conditions for group II (n?=?48). In group II, mice received one of BNF-lip (n?=?18), BNF alone (n?=?16), or PBS (n?=?14), followed by alternating magnetic field (AMF) hyperthermia, with either varied duration (15 or 20?min) or amplitude (0, 16, 20, or 24?kA/m). Image-guided fluoroscopic intra-arterial injection of BNF-lip was tested in New Zealand white rabbits (n?=?10), bearing liver VX2 tumours. The animals were subsequently imaged with CT and 3 T MRI, up to 7 days post-injection. The tumours were histopathologically evaluated for distribution of BNF-lip.

Results: The BNF showed larger aggregate diameters when suspended in BNF-lip, compared to clear solution. The BNF-lip formulation produced maximum tumour temperatures with AMF >20?kA/m and showed positive X-ray visibility and substantial shortening of T1 and T2 relaxation time, with sustained intratumoural retention up to 7 days post-injection. On pathology, intratumoural BNF-lip distribution correlated well with CT imaging of intratumoural BNF-lip distribution.

Conclusion: The BNF-lip formulation has favourable thermal and dual imaging capabilities for image-guided thermal therapy of liver cancer, suggesting further exploration for clinical applications.     

Barostat or dynamic balloon distention test: which technique is best suited for esophageal sensory testing?

Esophageal sensation is commonly assessed by barostat‐assisted balloon distension (BBD) or dynamic balloon distension (DBD) technique, but their relative merits are unknown. Our aim was to compare the usefulness and tolerability of both techniques. Sixteen healthy volunteers (male/female = 6/10) randomly underwent graded esophageal balloon distensions, using either BBD (n= 8) or DBD (n= 8). BBD was performed by placing a 5‐cm long highly compliant balloon attached to a barostat, and DBD by placing a 5‐cm long balloon attached to a leveling container. Intermittent phasic balloon distensions were performed in increments of 6 mm Hg. Sensory thresholds and biomechanical properties were assessed and compared. Sensory thresholds for first perception (mean ± standard deviation; 21 ± 6 vs. 21.2 ± 5, mm Hg, P= 0.9), discomfort (38 ± 8 vs. 35 ± 9, P= 0.5), and pain (44 ± 4 vs. 45 ± 3, P= 0.7) were similar with BBD and DBD techniques. However, more subjects tolerated DBD (7/8, 88%) when compared with BBD (4/8, 50%). Forceful expulsion of balloon into stomach (n= 4), pulling around the mouth (n= 4), chest discomfort (n= 2) and retching (n= 2) were overlapping reasons for intolerance with BBD. Esophageal wall distensibility was similar with both techniques. Both techniques provided comparable data on biomechanical properties. However, DBD was better tolerated than BBD for evaluation of esophageal sensation. Hence, we recommend DBD for performing esophageal balloon distension test.     

Bioactivation mechanisms of N-hydroxyaristolactams: Nitroreduction metabolites of aristolochic acids

Aristolochic acids (AAs) are human nephrotoxins and carcinogens found in concoctions of Aristolochia plants used in traditional medicinal practices worldwide. Genotoxicity of AAs is associated with the formation of active species catalyzed by metabolic enzymes, the full repertoire of which is unknown. Recently, we provided evidence that sulfonation is important for bioactivation of AAs. Here, we employ Salmonella typhimurium umu tester strains expressing human N-acetyltransferases (NATs) and sulfotransferases (SULTs), to study the role of conjugation reactions in the genotoxicities of N-hydroxyaristolactams (AL-I-NOH and AL-II-NOH), metabolites of AA-I and AA-II. Both N-hydroxyaristolactams show stronger genotoxic effects in umu strains expressing human NAT1 and NAT2, than in the parent strain. Additionally, AL-I-NOH displays increased genotoxicity in strains expressing human SULT1A1 and SULT1A2, whereas AL-II-NOH shows enhanced genotoxicity in SULT1A1/2 and SULT1A3 strains. 2,6-Dichloro-4-nitrophenol, SULTs inhibitor, reduced umuC gene expression induced by N-hydroxyaristolactams in SULT1A2 strain. N-hydroxyaristolactams are also mutagenic in parent strains, suggesting that an additional mechanism(s) may contribute to their genotoxicities. Accordingly, using putative SULT substrates and inhibitors, we found that cytosols obtained from human kidney HK-2 cells activate N-hydroxyaristolactams in aristolactam-DNA adducts with the limited involvement of SULTs. Removal of low-molecular-weight reactants in the 3.5–10 kDa range inhibits the formation of aristolactam-DNA by 500-fold, which could not be prevented by the addition of cofactors for SULTs and NATs. In conclusion, our results demonstrate that the genotoxicities of N-hydroxyaristolactams depend on the cell type and involve not only sulfonation but also N,O-acetyltransfer and an additional yet unknown mechanism(s). Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.     

Randomised clinical trial: dried plums (prunes) vs. psyllium for constipation

Aliment Pharmacol Ther 2011; 33: 822–828

Summary

Background Treatment of chronic constipation remains challenging with 50% of patients dissatisfied with current therapy. There is an unmet need for natural and safe alternatives. Dried plums (prunes) have been used traditionally for constipation but their efficacy is not known. Aim To assess and compare the effects of dried plums and psyllium in patients with chronic constipation. Methods Subjects were enrolled in an 8‐week, single‐blind, randomised cross‐over study. Subjects received either dried plums (50 g b.d., fibre = 6 gm/day) or psyllium (11 g b.d., fibre = 6 gm/day) for 3 weeks each, in a crossover trial with a 1‐week washout period. Subjects maintained a daily symptom and stool diary. Assessments included number of complete spontaneous bowel movements per week, global relief of constipation, stool consistency, straining, tolerability and taste. Results Forty constipated subjects (m/f = 3/37, mean age = 38 years) participated. The number of complete spontaneous bowel movements per week (primary outcome measure) and stool consistency scores improved significantly (P < 0.05) with dried plums when compared to psyllium. Straining and global constipation symptoms did not differ significantly between treatments (P = N.S.). Dried plums and psyllium were rated as equally palatable and both were safe and well tolerated. Conclusion Dried plums are safe, palatable and more effective than psyllium for the treatment of mild to moderate constipation, and should be considered as a first line therapy.     

Effects of tegaserod and erythromycin in upper gut dysmotility: a comparative study

Objectives  

Tegaserod may enhance upper gut transit, but, its prokinetic effects on antral/small bowel motility and how this compares with erythromycin is unknown. We prospectively assessed and compared the effects of tegaserod and erythromycin on upper gut motility.     

Email teleconsultations: well formulated clinical referrals reduce the need for clinic consultation

We examined how well primary-care physicians formulated their clinical referrals when asking for help with patient-related clinical problems using an email-based teleconsultation service. Over 100 family physicians made use of the service. The specialists were medical school faculty members. The service was initiated in May 1996 with 19 specialists and expanded to 34 specialties over the next five years. A total of 1618 patient-related clinical questions were analysed, the outcome for the analysis being whether specialists recommended a clinic consultation. Specialists recommended a clinic consultation in response to 10% of their clinical questions about patients. There was a strong association between how family physicians formulated their clinical questions and whether the specialist recommended a clinic consultation. When the family physicians specified a clinical task (P < 0.001), intervention (P = 0.004) and outcome (P < 0.001) in their questions, specialists were less likely to recommend a clinic consultation. This influence was independent of the amount of clinical information included with the question (P > 0.05). About 5% of the questions that included all three question components resulted in the recommendation for a clinic consultation, compared with nearly 30% of the questions containing none of these components. How family physicians formulate their clinical questions influences whether specialists request a clinic consultation.