Endovascular transplantation of stem cells to the injured rat CNS

Introduction

Transplantation procedures using intraparenchymal injection of stem cells result in tissue injury in addition to associated surgical risks. Intravenous injection of mesenchymal stem cells gives engraftment to lesions, but the method has low efficiency and specificity. In traumatic brain injuries (TBI), there is a transient breakdown of the blood–brain barrier and an inflammatory response, which increase migration of cells from blood to parenchyma. The aim of this investigation was to analyze the effect of intra-arterial administration on cellular engraftment.

Methods

Experimental TBI was produced in a rat model. Endovascular technique was used to administer human mesenchymal stem cells in the ipsilateral internal carotid artery. Evaluation of engraftment and side effects were performed by immunohistochemical analysis of the brain and several other organs. The results were compared to intravenous administration of stem cells.

Results

Intra-arterial transplantion of mesenchymal stem cells resulted in central nervous system (CNS) engraftment without thromboembolic ischemia. We observed a significantly higher number of transplanted cells in the injured hemisphere after intra-arterial compared to intravenous administration both 1 day (p?<?0.01) and 5 days (p?<?0.05) after the transplantation. Some cells were also detected in the spleen but not in the other organs analyzed.

Conclusion

Selective intra-arterial administration of mesenchymal stem cells to the injured CNS is a minimally invasive method for transplantation. The method is significantly more efficient than the intravenous route and causes no side effects in the current model. The technique can potentially be used for repeated transplantation to the CNS after TBI and in other diseases.     

Modulation of radiation-induced oral mucositis by pentoxifylline: Preclinical studies

Background and purpose

Oral mucositis is a frequent early side effect of radio(chemo)therapy of head-and-neck malignancies. The epithelial radiation response is accompanied by inflammatory reactions; their interaction with epithelial processes remains unclear. The aim of the present study was to investigate the effect of pentoxifylline (PTX) on the oral mucosal radiation response in the mouse tongue model.

Materials and methods

Irradiation comprised fractionation (5 fractions of 3 Gy/week) over 1 (days 0–4) or 2 weeks (days 0–4, 7–11), followed by graded local top-up doses (day 7/14), in order to generate complete dose–effect curves. PTX (15 mg/kg subcutaneously) was applied once daily over varying time intervals. Ulceration of mouse tongue epithelium, corresponding to confluent mucositis, was analyzed as the clinically relevant endpoint.

Results

With fractionated irradiation over 1 week, PTX administration significantly reduced the incidence of mucosal reactions when initiated before (day???5) the onset of fractionation; a trend was observed for start of PTX treatment on day 0. Similarly, PTX treatment combined with 2 weeks of fractionation had a significant effect on ulcer incidence in all but one experiment. This clearly illustrates the potential of PTX to ameliorate oral mucositis during daily fractionated irradiation.

Conclusion

PTX resulted in a significant reduction of oral mucositis during fractionated irradiation, which may be attributed to stimulation of mucosal repopulation processes. The biological basis of this effect, however, needs to be clarified in further, detailed mechanistic studies.

     

Systemic administration of heparin ameliorates radiation-induced oral mucositis—preclinical studies in mice

Purpose

The present study investigates the impact of systemic application of heparins on the manifestation of radiation-induced oral mucositis in a well-established mouse model.

Materials and methods

Male C3H/Neu mice were irradiated with either single-dose or fractionated irradiation protocols with 5?×?3 Gy/week, given over one (days 0–4) or two (days 0–4, 7–11) weeks. All fractionation protocols were concluded by a local test irradiation (day 7/14) using graded doses to generate complete dose–effect curves. Daily doses of unfractionated or low molecular weight heparin (40 or 200 I.U./mouse, respectively) were applied subcutaneously over varying time intervals. The incidence and the time course of mucosal ulceration, corresponding to confluent mucositis in patients (RTOG/EORTC grade 3), were analysed as clinically relevant endpoints.

Results

Systemic application of heparins significantly increased the iso-effective doses for the induction of mucosal ulceration, particularly in combination with fractionated irradiation protocols. Moreover, a tentative prolongation of the latent time and a pronounced reduction of the ulcer duration were observed.

Conclusion

These data provide the first evidence for a protective and/or mitigative effect of heparins for radiation-induced oral mucositis. Further studies are ongoing investigating the underlying mechanism.

     

Protective effects of systemic dermatan sulfate treatment in a preclinical model of radiation-induced oral mucositis

Purpose

Oral mucositis is a frequent, dose-limiting side effect of radio(chemo)therapy of head-and-neck malignancies. The epithelial radiation response is based on multiple tissue changes, which could offer targets for a biologically tailored treatment. The potential of dermatan sulfate (DS) to modulate radiation-induced oral mucositis was tested in an established preclinical mucositis model.

Methods

Irradiation was either applied alone or in combination with daily DS treatment (4?mg/kg, subcutaneously) over varying time intervals. Irradiation comprised single dose irradiation with graded doses to the lower tongue surface or daily fractionated irradiation of the whole tongue. Fractionation protocols (5?×?3?Gy/week) over one (days 0–4) or two weeks (days 0–4, 7–11) were terminated by an additional local single dose irradiation to a defined treatment field on the lower tongue surface to induce the mucosal radiation response. The additional single dose irradiation (top-up) on day 7 (after one week of fractionation) or day 14 (after 2 weeks of fractionation) comprised graded doses in order to generate full dose–effect curves. Ulceration of the epithelium of the lower tongue, corresponding to confluent mucositis, was analysed as clinically relevant endpoint. Additionally, the time course parameters, latent time and ulcer duration were analysed.

Results

DS treatment significantly reduced the incidence of ulcerations. DS application over longer time intervals resulted in a more pronounced reduction of ulcer frequency, increased latent times and reduced ulcer duration.

Conclusion

DS has a significant mucositis-ameliorating activity with pronounced effects on mucositis frequency as well as on time course parameters.

     

Autologous collagen-induced chondrogenesis technique (ACIC) for the treatment of chondral lesions of the talus

Purpose

Autologous collagen-induced chondrogenesis technique (ACIC) combines microfractures with the use of an injectable atelocollagen matrix that allows performing the whole cartilage repair treatment arthroscopically. The aim of this study was to evaluate the in vitro cytocompatibility of this biomaterial using human bone marrow mesenchymal stem cells and human chondrocytes. Moreover, the preliminary data of five patients affected by chondral lesion of the talus treated with the ACIC technique are shown.

Methods

Human bone marrow mesenchymal stem cells and human chondrocytes were seeded on solid and pre-solid atelocollagen scaffolds. Cell–scaffold constructs were cultured for 7 days and then prepared for histological analyses. Arthroscopic ACIC was performed in five patients affected by chondral lesions of the talus; they were clinically evaluated with AOFAS, VAS and Tegner score before and then after 6 months from surgery.

Results

In vitro results showed that both bone marrow mesenchymal stem cells and chondrocytes were able to efficiently colonize the whole construct, from the surface to the core, only when seeded on the pre-solid atelocollagen scaffold, but not on its solid form. No adverse events were observed in the patients treated with the ACIC technique; a significant improvement in VAS pain scale and in AOFAS score was found at 6 months follow up.

Conclusion

Injectable atelocollagen can be considered a feasible scaffold for cartilage repair treatment, in particular if used in its pre-solid form. ACIC leads to good clinical results in the treatment for chondral lesions of the talus even if longer follow-up and a higher number of patients are necessary to confirm these data.

Level of evidence

IV.     

Early inflammatory changes in radiation-induced oral mucositis

Purpose

Early inflammation is a major factor of mucosal reactions to radiotherapy. Pentoxifylline administration resulted in a significant amelioration of radiation-induced oral mucositis in the mouse tongue model. The underlying mechanisms may be related to the immunomodulatory properties of the drug. The present study hence focuses on the manifestation of early inflammatory changes in mouse tongue during daily fractionated irradiation and their potential modulation by pentoxifylline.

Materials and methods

Daily fractionated irradiation with 5 fractions of 3 Gy/week (days 0–4, 7–11) was given to the snouts of mice. Groups of 3 animals per day were euthanized every second day between day 0 and 14. Pentoxifylline (15?mg/kg, s.?c.) was administered daily from day 5 to the day before sacrifice. The expression of the inflammatory proteins TNFα, NF-κB, and IL-1β were analysed.

Results

Fractionated irradiation increased the expression of all inflammatory markers. Pentoxifylline significantly reduced the expression of TNFα and IL-1β, but not NF-κB.

Conclusion

Early inflammation, as indicated by the expression of the inflammatory markers TNFα, NF-κB, and IL-1β, is an essential component of early radiogenic oral mucositis. Pentoxifylline differentially modulated the expression of different inflammatory markers. The mucoprotective effect of pentoxifylline does not appear to be based on modulation of NF-κB-associated inflammation.

     

Autologous mesenchymal stem cell endografting in experimental cerebrovascular aneurysms

Introduction

Coiling is the gold standard for the treatment of intracranial aneurysms. However, some issues associated with endovascular treatment limit its long-term efficiency. Recanalization with coil compaction is certainly the most important. New approaches may be considered to promote thrombus colonization by mesenchymal cells and aneurysm healing. In the present study, we have percutaneously delivered autologous bone marrow mesenchymal stem cells (BMSCs) to an elastase-induced rabbit carotid aneurysm model in vivo.

Methods

Autologous mesenchymatous stem cells were obtained after femoral puncture and bone marrow aspiration. After 2 weeks of in vitro cell culture, five million BMSCs were grafted in the carotid aneurysm using an endovascular approach.

Results

We demonstrated the feasibility of in vivo percutaneous seeding of autologous BMSCs in the aneurysm by positive Hoechst fluorostaining. Two weeks later, conventional angiography showed an increase in median aneurysmal surface in the sham group, whereas this surface was decreased in the group treated with BMSCs, +28.4 versus ?26.4 %, respectively (p?=?0.01). BMSC seeding resulted in intimal hyperplasia with cell colonization and disappearance of the thrombus.

Conclusion

In conclusion, percutaneous seeding of BMSCs may colonize and heal the arterial wall thus limiting aneurysm expansion.     

Fractionated stereotactic radiotherapy in the treatment of pituitary adenomas

Purpose

The purpose of this work was to evaluate tumor control and side effects associated with fractionated stereotactic radiotherapy (FSRT) in the management of residual or recurrent pituitary adenomas.

Patients and methods

We report on 37 consecutive patients with pituitary adenomas treated with FSRT at our department. All patients had previously undergone surgery. Twenty-nine patients had nonfunctioning, 8 had hormone-producing adenoma. The mean total dose delivered by a linear accelerator was 49.4 Gy (range 45–52.2 Gy), 5?×?1.8 Gy weekly. The mean PTV was 22.8 ccm (range 2.0–78.3 ccm). Evaluation included serial imaging tests, endocrinologic and ophthalmologic examination.

Results

Tumor control was 91.9?% for a median follow-up time of 57 months (range 2–111 months). Before FSRT partial hypopituitarism was present in 41?% of patients, while 35?% had anterior panhypopituitarism. After FSRT pituitary function remained normal in 22?%, 43?% had partial pituitary dysfunction, and 35?% had anterior panhypopituitarism. Visual acuity was stable in 76?% of patients, improved in 19?%, and deteriorated in 5?%. Visual fields remained stable in 35 patients (95?%), improved in one and worsened in 1 patient (2.7?%).

Conclusion

FSRT is an effective and safe treatment for recurrent or residual pituitary adenoma. Good local tumor control and preservation of adjacent structures can be reached, even for large tumors.     

Whole-body MRI for the detection of bone marrow involvement in lymphoma: prospective study in 116 patients and comparison with FDG-PET

Objective

To assess and compare the value of whole-body MRI with FDG-PET for detecting bone marrow involvement in lymphoma.

Methods

A total of 116 patients with newly diagnosed lymphoma prospectively underwent whole-body MRI and blind bone marrow biopsy (BMB) of the posterior iliac crest. Of 116 patients, 80 also underwent FDG-PET. Patient-based sensitivities of whole-body MRI for detecting bone marrow involvement were calculated using BMB as reference standard and compared with FDG-PET in aggressive and indolent lymphomas separately.

Results

Sensitivity of whole-body MRI in all lymphomas was 45.5 % [95 % confidence interval (CI): 29.8–62.0 %]. Sensitivity of whole-body MRI in aggressive lymphoma [88.9 % (95 % CI: 54.3–100 %)] was significantly higher (P?=?0.0029) than that in indolent lymphoma [23.5 % (95 % CI: 9.1–47.8 %)]. Sensitivity of FDG-PET in aggressive lymphoma [83.3 % (95 % CI: 41.8–98.9 %)] was also significantly higher (P?=?0.026) than that in indolent lymphoma [12.5 % (95 % CI: 0–49.2 %)]. There were no significant differences in sensitivity between whole-body MRI and FDG-PET (P?=?1.00)

Conclusion

Sensitivity of whole-body MRI for detecting lymphomatous bone marrow involvement is too low to (partially) replace BMB. Sensitivity of whole-body MRI is significantly higher in aggressive lymphoma than in indolent lymphoma and is equal to FDG-PET in both entities.

Key Points

? Bone marrow involvement in lymphoma has prognostic and therapeutic implications. ? Blind bone marrow biopsy (BMB) is standard for bone marrow assessment. ? Neither whole-body MRI nor FDG-PET can yet replace BMB. ? Both techniques have higher sensitivity in aggressive than in indolent lymphoma. ? Both imaging techniques are complementary to BMB.     

Image quality and radiation dose of low tube voltage 3rd generation dual-source coronary CT angiography in obese patients: a phantom study

Objectives

To assess the influence of tube potential on radiation dose and image quality of third-generation dual-source coronary CT angiography (CTA) in a phantom simulating an obese patient.

Methods

A thoracic phantom was equipped with tubular inserts containing iodine solution and water. A soft-tissue-equivalent ring around the phantom simulated an obese patient. Images were acquired at tube potentials of 80, 100, 120 and 140 kV with second-generation dual-source CT (DSCT) and 70–150 kV (in 10-kV increments) with third-generation DSCT. Contrast-to-noise ratio (CNR) was calculated and CT dose index was recorded.

Results

With second-generation DSCT, CNR was highest for 120 kV (19.0) and decreased with lower tube potential (12.0 at 80 kV) owing to disproportionately increased image noise. With third-generation DSCT, 70- and 80-kV acquisitions showed a smaller increase in noise. CNRs for third-generation DSCT were highest for 70 and 80 kV (21.1 and 21.2, respectively). Compared to 120 kV, radiation dose was 68 % and 49 % lower at 70 kV and 80 kV, respectively.

Conclusion

Third-generation DSCT enables one to perform coronary CTA at 70–80 kV in obese patients without compromising CNR and thus reduces radiation dose by 49–68 %.

Key points

? Low tube potential CT angiography is currently not suitable for obese patients. ? Third-generation DSCT offers substantially increased tube power at low tube potential. ? This enables one to perform coronary CT angiography at 70–80 kV in obese patients. ? Signal-to-noise ratio is maintained owing to increased tube current. ? This approach can be expected to reduce radiation dose by 49–68 %.     

Predictive patient-specific dosimetry and individualized dosing of pretargeted radioimmunotherapy in patients with advanced colorectal cancer

Purpose

Pretargeted radioimmunotherapy (PRIT) with bispecific antibodies (bsMAb) and a radiolabeled peptide reduces the radiation dose to normal tissues. Here we report the accuracy of an ¹¹¹In-labeled pretherapy test dose for personalized dosing of ¹⁷⁷Lu-labeled IMP288 following pretargeting with the anti-CEA × anti-hapten bsMAb, TF2, in patients with metastatic colorectal cancer (CRC).

Methods

In 20 patients bone marrow absorbed doses (BMD) and doses to the kidneys were predicted based on blood samples and scintigrams acquired after ¹¹¹In-IMP288 injection for individualized dosing of PRIT with ¹⁷⁷Lu-IMP288. Different dose schedules were studied, varying the interval between the bsMAb and peptide administration (5 days vs. 1 day), increasing the bsMAb dose (75 mg vs. 150 mg), and lowering the peptide dose (100 μg vs. 25 μg).

Results

TF2 and ¹¹¹In/¹⁷⁷Lu-IMP288 clearance was highly variable. A strong correlation was observed between peptide residence times and individual TF2 blood concentrations at the time of peptide injection (Spearman’s ρ?=?0.94, P?<?0.0001). PRIT with 7.4 GBq ¹⁷⁷Lu-IMP288 resulted in low radiation doses to normal tissues (BMD <0.5 Gy, kidney dose <3 Gy). Predicted ¹⁷⁷Lu-IMP288 BMD were in good agreement with the actual measured doses (mean?±?SD difference ?0.0026?±?0.028 mGy/MBq). Hematological toxicity was mild in most patients, with only two (10 %) having grade 3–4 thrombocytopenia. A correlation was found between platelet toxicity and BMD (Spearman’s ρ?=?0.58, P?=?0.008). No nonhematological toxicity was observed.

Conclusion

These results show that individual high activity doses in PRIT in patients with CEA-expressing CRC could be safely administered by predicting the radiation dose to red marrow and kidneys, based on dosimetric analysis of a test dose of TF2 and ¹¹¹In-IMP288.     

Proton beam therapy for malignancy in Bloom syndrome

Background and purpose

Bloom syndrome is a DNA repair disorder that is hypersensitive to radiotherapy. We describe the first case in which proton beam therapy (PBT) was used in a patient with Bloom syndrome to treat oropharyngeal cancer.

Patients and methods

The patient was a 32-year-old woman with Bloom syndrome who was diagnosed with oropharyngeal cancer staged as T2N2bM0 poorly differentiated squamous cell carcinoma. The primary tumor was located on the right tongue base and extended to the right lateral pharyngeal wall. Several right upper region lymph nodes were positive for metastases.

Results

We selected PBT in anticipation of dose reduction to normal tissue. The clinical target volume was defined as the area of the primary tumor and lymph node metastases plus an 8-mm margin. After treatment with 36 GyE (Gray equivalent) in 20 fractions (4–5 fractions per week), dietary intake was decreased by mucositis and intravenous hyperalimentation was started. Termination of treatment for 2.5 weeks was required to relieve mucositis. Administration of 59.4 GyE in 33 fractions markedly reduced the size of the primary tumor, but also caused moderate mucositis that required termination of PBT. One month later, lung metastases and breast cancer developed and the patient died 9 months after PBT. At this time the reduction in size of the primary tumor was maintained without severe late toxicity.

Conclusion

We obtained almost complete response for a radiosensitive patient with a deficiency of DNA repair, indicating the excellent dose concentration of proton beam therapy.     

Low-dose fractionated radiotherapy and concomitant chemotherapy for recurrent or progressive glioblastoma

Backgroud

Evaluated in this study were the feasibility and the efficacy of concurrent low dose fractionated radiotherapy (LD-FRT) and chemotherapy as palliative treatment for recurrent/progressive glioblastoma multiforme (GBM).

Patients and methods

Eligible patients had recurrent or progressive GBM, Karnofsky performance status ≥?70, prior surgery, and standard radiochemotherapy treatment. Recurrence/progression disease during temozolomide (TMZ) received cisplatin (CDDP; 30 mg/m² on days 1, 8, 15), fotemustine (FTM; 40 mg/m² on days 2, 9, 16), and concurrent LD-FRT (0.3 Gy twice daily); recurrence/progression after 4 months from the end of adjuvant TMZ were treated by TMZ (150/200 mg/m² on days 1–5) concomitant with LD-FRT (0.4 Gy twice daily). Primary endpoints were safety and toxicity.

Results

A total of 32 patients were enrolled. Hematologic toxicity G1–2 was observed in 18.7?% of patients and G3–4 in 9.4?%. One patient (3.1?%) had complete response, 3 (9.4?%) had partial response, 8 (25?%) had stable disease for at least 8 weeks, while 20 patients (62.5?%) experienced progressive disease. The clinical benefit was 37.5?%. Median progression-free survival (PFS) and overall survival (OS) were 5 and 8 months, respectively. Survival rate at 12 months was of 27.8?%.

Conclusion

LD-FRT and chemotherapy for recurrent/progressive GBM have a good toxicity profile and clinical outcomes, even though further investigation of this novel palliative treatment approach is warranted.     

Bone marrow changes related to disuse

Objectives

To evaluate bone marrow changes on knee magnetic resonance imaging (MRI) in patients with 3- to 6-week-long period of unloading.

Methods

MRI knee examinations were performed in 30 patients (14 men, 16 women; aged 20–53 years) at baseline and 5–10 weeks after immobilisation of the ipsilateral lower extremity; subsets of patients were examined at additional time-points. Ten volunteers (4 men, 6 women; aged 20–50 years) were studied as control cohort at two time-points. Bone marrow signal abnormalities were analysed according to: (1) severity, (2) signal alteration relative to hyaline cartilage, (3) morphology, (4) increased vascularity in the knee joint and (5) T1-signal alteration. Spearman’s rank correlation test (SRC) and Kendall’s tau (KT) were used to compare individual scores.

Results

All 30 patients presented abnormal bone marrow findings after unloading, which reached a peak at 10–25 weeks (P <0.001). These findings decreased within 1 year (P?<?0.001). High scores of severity were associated with confluent and patchy patterns of bone marrow (SCR?=?0.923, P?<?0.001 and KT?=?0.877, P <0.001).

Conclusions

Signal abnormalities of the bone marrow related to unloading are consistent findings and most prominent 10–25 weeks following immobilisation when both confluent and patchy hyperintense patterns are present.

Key Points

? Disuse is associated with hyperintense MRI signal alteration on fluid-sensitive sequence. ? Disuse findings are more prominent at the patella and femoral epiphyses. ? Disuse MRI findings appear to be characterised by a specific chronological pattern.     

Concurrent hyperfractionated accelerated radiotherapy with 5-FU and once weekly cisplatin in locally advanced head and neck cancer

Purpose

In this study, the acute toxicity and long-term outcome of a hyperfractionated accelerated chemoradiation regimen with cisplatin/5-fluorouracil (5-FU) in patients with locally advanced squamous cell carcinomas of head and neck were evaluated.

Patients and methods

From 2000–2002, 38 patients with stage III (5.3?%) and stage IV (94.7?%) head and neck cancer were enrolled in a phase II study. Patients received hyperfractionated-accelerated radiotherapy with 72 Gy in 15 fractions of 2 Gy followed by 1.4 Gy twice daily with concurrent, continuous infusion 5-FU of 600 mg/m² on days 1–5 and 6 cycles of weekly cisplatin (30 mg/m²). Acute toxicities (CTCAEv2.0), locoregional control (LRC), metastases-free (MFS), and overall survival (OS) were analyzed and exploratively compared with the ARO 95-06 trial.

Results

Median follow-up was 11.4 years (95?% CI 8.6–14.2) and mean dose 71.6 Gy. Of the patients, 82?% had 6 (n?=?15) or 5 (n?=?16) cycles of cisplatin, 5 and 2 patients received 4 and 3 cycles, respectively. Grade 3 anemia, leukopenia, and thrombocytopenia were observed in 15.8, 15.8, and 2.6?%, respectively. Grade 3 mucositis in 50?%, grade 3 and 4 dysphagia in 55 and 13?%. The 2-, 5-, and 10-year LRC was 65, 53.6, and 48.2?%, the MFS was 77.5, 66.7, and 57.2?% and the OS 59.6, 29.2, and 15?%, respectively.

Conclusion

Chemoradiation with 5-FU and cisplatin seems feasible and superior in terms of LRC and OS to the ARO 95-06C-HART arm at 2 years. However, this did not persist at the 5- and 10-year follow-ups.     

Evaluation of image quality and lesion perception by human readers on 3D CT colonography: comparison of standard and low radiation dose

Aims

We compared the prevalence of noise-related artefacts and lesion perception on three-dimensional (3D) CT colonography (CTC) at standard and low radiation doses.

Methods

Forty-eight patients underwent CTC (64?×?0.625 mm collimation; tube rotation time 0.5 s; automatic tube current modulation: standard dose 40–160 mA, low dose 10–50 mA). Low- and standard-dose acquisitions were performed in the supine position, one after the other. The presence of artefacts (cobblestone and snow artefacts, irregularly delineated folds) and the presence of polyps were evaluated by five radiologists on 3D images at standard dose, the original low dose and a modified low dose, i.e. after manipulation of opacity on 3D.

Results

The mean effective dose was 3.9?±?1.3 mSv at standard dose and 1.03?±?0.4 mSv at low dose. The number of images showing cobblestone artefacts and irregularly delineated folds at original and modified low doses was significantly higher than at standard dose (P?<?0.0001). Most of the artefacts on modified low-dose images were mild. No significant difference in sensitivity between the dose levels was found for polyps ≥6 mm.

Conclusions

Reduction of the effective dose to 1 mSv significantly affects image quality on 3D CTC, but the perception of ≥6 mm lesions is not significantly impaired.     

Positron emission tomography based in-vivo imaging of early phase stem cell retention after intramyocardial delivery in the mouse model

Purpose

To establish PET as a tool for in-vivo quantification and monitoring of intramyocardially transplanted stem cells after labelling with FDG in mice with induced myocardial infarction.

Methods

After inducing myocardial infarction in C57BL/6 mice, murine embryonic stem cells were labelled with FDG and transplanted into the border zone of the infarction. Dynamic PET scans were acquired from 25 to 120 min after transplantation, followed by a scan with 20 MBq FDG administered intravenously for anatomical landmarking. All images were reconstructed using the OSEM 3D and MAP reconstruction algorithms. FDG data were corrected for cellular tracer efflux and used as marker for cellular retention. FACS analysis of transplanted cells expressing enhanced green fluorescent protein was performed to validate the PET data.

Results

We observed a rapid loss of cells from the site of transplantation, followed by stable retention over 120 min. Amounts of retention were 5.3?±?1.1 % at 25 min, 5.0?±?0.9 % at 60 min and 5.7?±?1.2 % at 120 min. FACS analysis showed a high correlation without significant differences between the groups (P?>?0.05). FDG labelling did not have any adverse effects on cell proliferation or differentiation.

Conclusion

Up-to-date imaging is a powerful method for tracking and quantifying intramyocardially transplanted stem cells in vivo in the mouse model. This revealed a massive cell loss within minutes, and thereafter a relatively stable amount of about 5 % remaining cells was observed. Our method may become crucial for further optimization of cardiac cell therapy in the widely used mouse model of infarction.     

Feasibility of 6-month maintenance cetuximab after adjuvant concurrent chemoradiation plus cetuximab in squamous cell carcinoma of the head and neck

Background

Close resection margins <?5 mm (CM) or extra capsular extent at the lymph nodes (ECE) impair the prognosis of patients with squamous cell cancer of the head and neck (SCCHN) scheduled for adjuvant radiochemotherapy. We conducted a multicenter phase II study to investigate toxicity and efficacy of additional cetuximab administered concomitantly and as maintenance for the duration of 6 months following adjuvant radiochemotherapy., Ppreliminary results on feasibility and acute toxicity on skin and mucosa are presented in this article.

Methods

Patients with SCCHN following CM resection or with ECE were eligible for the study. In all, 61.6 Gy (1.8/2.0/2.2 Gy, days 1–36) were administered using an integrated boost intensity-modulated radiotherapy (IMRT) technique. Cisplatin (20 mg/m², days 1–5 and days 29–33) and 5-fluorouracil (5-FU) as continuous infusion (600 mg/m², days 1–5 + days 29–33) were given concurrently. Cetuximab was started 7 days prior to radiochemotherapy at 400 mg/m² followed by weekly doses of 250 mg/m². Maintenance cetuximab began after radiochemotherapy at 500 mg/m² every 2 weeks for 6 months.

Results

Of the 55 patients (46 male, 9 female, mean age 55.6, range 29–70 years) who finished radiochemotherapy, 50 were evaluable for acute toxicity concerning grade III/IV toxicities of skin and mucosa. Grade 3–4 (CTC 3.0) mucositis, radiation dermatitis, and skin reactions outside the radiation portals were documented for 46, 28, and 14?% of patients, respectively. One toxic death occurred (peritonitis at day 57). Cetuximab was terminated in 5 patients due to allergic reactions after the first application. In addition, 22?% of patients discontinued cetuximab within the last 2 weeks or at the end of radiochemotherapy. Of patients embarking on maintenance treatment, 80?% were still on cetuximab at 3 months and 63?% at 5 months. Concurrent and maintenance treatment with cetuximab could be administered as scheduled in 48?% of patients.

Conclusion

Adjuvant radiochemotherapy with concomitant and maintenance cetuximab is feasible and acute toxicities are within the expected range. Compliance within the first 3–5 months is moderate.     

Multidetector CT radiation dose optimisation in adults: short- and long-term effects of a clinical audit

Objective

To report short- and long-term effects of an audit process intended to optimise the radiation dose from multidetector row computed tomography (MDCT).

Methods

A survey of radiation dose from all eight MDCT departments in the state of Luxembourg performed in 2007 served as baseline, and involved the most frequently imaged regions (head, sinus, cervical spine, thorax, abdomen, and lumbar spine). CT dose index volume (CTDIvol), dose–length product per acquisition (DLP/acq), and DLP per examination (DLP/exa) were recorded, and their mean, median, 25th and 75th percentiles compared. In 2008, an audit conducted in each department helped to optimise doses. In 2009 and 2010, two further surveys evaluated the audit’s impact on the dose delivered.

Results

Between 2007 and 2009, DLP/exa significantly decreased by 32–69 % for all regions (P?<?0.001) except the lumbar spine (5 %, P?=?0.455). Between 2009 and 2010, DLP/exa significantly decreased by 13–18 % for sinus, cervical and lumbar spine (P ranging from 0.016 to less than 0.001). Between 2007 and 2010, DLP/exa significantly decreased for all regions (18–75 %, P?<?0.001). Collective dose decreased by 30 % and the 75th percentile (diagnostic reference level, DRL) by 20–78 %.

Conclusions

The audit process resulted in long-lasting dose reduction, with DRLs reduced by 20–78 %, mean DLP/examination by 18–75 %, and collective dose by 30 %.

Key points

? External support through clinical audit may optimise default parameters of routine CT. ? Reduction of 75th percentiles used as reference diagnostic levels is 18–75?%. ? The effect of this audit is sustainable over time. ? Dose savings through optimisation can be added to those achievable through CT.     

Moderately hypofractionated radiotherapy for localized prostate cancer

Purpose

To evaluate long-term outcome after dose-escalated, moderately hypofractionated radiotherapy for prostate cancer.

Methods

Since 2005, 150 consecutive patients were treated with primary radiotherapy for localized prostate cancer. Intensity modulated radiotherapy (IMRT) using the simultaneous integrated boost (SIB) technique was practiced in all patients and doses of 73.9 Gy (n?=?41) and 76.2 Gy (n?=?109) were delivered in 32 and 33 fractions, respectively. The pelvic lymph nodes were treated in 41 high-risk patients. Treatment was delivered using cone-beam CT based image-guided radiotherapy (IGRT). Toxicity was assessed prospectively using CTCAE 3.0; biochemical failure was defined according to the Phoenix definition of nadir +?2 ng/ml.

Results

Median follow-up of living patients was 50 months. Gastrointestinal (GI) toxicity was mild with >?80?% of the patients free from any GI toxicity during follow-up and no time trend to increased rates or to higher grade of GI toxicity. Two patients suffered from late grade 3 GI toxicity. Acute genitourinary (GU) toxicity grade 1–2 was observed in 85?% of the patients; most patients recovered quickly within 6 weeks after treatment. The rate of GU toxicity grade ≥?2 was <?10?% at 6–12 month but increased continuously to 22.4?% at 60 months; grade 3 GU toxicity remained below 5?% during follow-up. The 5-year freedom from biochemical failure (FFBF) was 82?% for all patients and 88, 80, and 78?% for low-, intermediate-, and high-risk disease.

Conclusion

Favorable FFBF with simultaneously low rates of toxicity was observed after moderately hypofractionated radiotherapy with 2 Gy-equivalent doses ≥?80 Gy. Conformal IMRT planning and accurate IGRT treatment delivery may have contributed to these results.