The feasibility of prostate-specific membrane antigen positron emission tomography(PSMA PET/CT)-guided radiotherapy in oligometastatic prostate cancer patients

Background. To investigate the efficacy and toxicity of 68Ga-PSMA-HBED-CC (68Ga-PSMA) PET-CT-guided RT in the treatment of oligometastatic prostate cancer retrospectively. Methods. A total of 23 prostate cancer patients with biochemical relapse, of which 13 were castration sensitive (CS) and 10 castration resistant (CR), were treated with intensity-modulated and image-guided RT (IMRT-IGRT) on ≤3 metastases detected by 68Ga PSMA PET-CT. Androgen deprivation therapy was continued in CR patients. Results. A total of 38 metastases were treated. The involved sites were pelvic bone (n = 16), pelvic lymph nodes (n = 11), paraaortic lymph nodes (n = 6), ribs (n = 3) and vertebral body (n = 2). The median PSA prior to RT was 1.1 ng/mL (range 0.1-29.0 ng/mL). A median dose of 43.5 Gy (range 30-64 Gy) was delivered by IMRT-IGRT in 12-27 fractions. At a median follow-up of 7 months (range 2-17 months), 19 patients (83%) were in remission. Four patients (17%) developed distant recurrences. The actuarial 1-year LC, PFS and OS rates were 100, 51 (95% CI 8-83%) and 100%. Univariate analysis demonstrated a statistically significantly better PFS in CS patients as compared to CR patients (1-year PFS 67 vs. 0%, p < 0.01). One patient experienced grade 2 acute gastrointestinal toxicity. Grade 3 or more toxicity events were not observed. Conclusions. By providing optimal LC, low toxicity and a promising PFS in CS patients, the current retrospective study illustrated that 68Ga PSMA PET-CT-guided RT may be an attractive treatment strategy in patients with oligometastatic prostate cancer. Validation by randomized trials is eagerly awaited (AU)

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The feasibility of prostate-specific membrane antigen positron emission tomography(PSMA PET/CT)-guided radiotherapy in oligometastatic prostate cancer patients.

BACKGROUND: To investigate the efficacy and toxicity of 68Ga-PSMA-HBED-CC (68Ga-PSMA) PET-CT-guided RT in the treatment of oligometastatic prostate cancer retrospectively. METHODS: A total of 23 prostate cancer patients with biochemical relapse, of which 13 were castration sensitive (CS) and 10 castration resistant (CR), were treated with intensity-modulated and image-guided RT (IMRT-IGRT) on ≤3 metastases detected by 68Ga PSMA PET-CT. Androgen deprivation therapy was continued in CR patients. RESULTS: A total of 38 metastases were treated. The involved sites were pelvic bone (n = 16), pelvic lymph nodes (n = 11), paraaortic lymph nodes (n = 6), ribs (n = 3) and vertebral body (n = 2). The median PSA prior to RT was 1.1 ng/mL (range 0.1-29.0 ng/mL). A median dose of 43.5 Gy (range 30-64 Gy) was delivered by IMRT-IGRT in 12-27 fractions. At a median follow-up of 7 months (range 2-17 months), 19 patients (83%) were in remission. Four patients (17%) developed distant recurrences. The actuarial 1-year LC, PFS and OS rates were 100, 51 (95% CI 8-83%) and 100%. Univariate analysis demonstrated a statistically significantly better PFS in CS patients as compared to CR patients (1-year PFS 67 vs. 0%, p < 0.01). One patient experienced grade 2 acute gastrointestinal toxicity. Grade 3 or more toxicity events were not observed. CONCLUSIONS: By providing optimal LC, low toxicity and a promising PFS in CS patients, the current retrospective study illustrated that 68Ga PSMA PET-CT-guided RT may be an attractive treatment strategy in patients with oligometastatic prostate cancer. Validation by randomized trials is eagerly awaited.

Randomized phase II study of axitinib versus physicians best alternative choice of therapy in patients with recurrent glioblastoma.

We conducted a randomized, non-comparative, multi center, phase II clinical trial in order to investigate the efficacy of axitinib, an oral small molecule tyrosine kinase inhibitor with high affinity and specificity for the vascular endothelial growth factor receptors, in patients with recurrent glioblastoma following prior treatment with radiation and temozolomide. Forty-four patients were randomly assigned to receive treatment with axitinib (5 mg BID starting dose; N = 22) or "physicians best alternative choice of therapy" that consisted of bevacizumab (N = 20) or lomustine (N = 2). Six-month progression-free survival served as the primary endpoint. The estimated 6-month progression-free survival rate was 34 % (95 % CI 14-54) for patients treated with axitinib and 28 % (95 % CI 8-48) with best alternative treatment; median overall survival was 29 and 17 weeks, respectively. Objective responses according to RANO criteria were documented in 28 % of patients treated with axitinib and 23 % of patients treated with best alternative therapy. A decrease in maximal uptake of 18F-fluoro-ethyL-tyrosine (18F-FET) by the glioblastoma on PET imaging was documented in 85 % of patients at the time of response on axitinib. Corticosteroid treatment could be stopped in four and tapered in seven out of the 15 patients who were treated with steroids at baseline in the axitinib cohort. Most frequent axitinib related grade ≥3 adverse events consisted of fatigue (9 %), diarrhea (9 %), and oral hyperesthesia (4.5 %). We conclude that axitinib has single-agent clinical activity and a manageable toxicity profile in patients with recurrent glioblastoma.

Comparison of ventilation-perfusion single-photon emission computed tomography (V/Q SPECT) versus dual-energy CT perfusion and angiography (DECT) after 6 months of pulmonary embolism (PE) treatment.

BACKGROUND: The natural evolution of treated symptomatic pulmonary embolism shows often incomplete resolution of pulmonary thrombi. The prevalence of perfusion defects depend on the image modality used. This study directly compares V/Q SPECT with DECT. METHODS: A single-center prospective observational cohort study of patients with intermediate risk PE, reassessed at the end of treatment with V/Q SPECT. Abnormal V/Q SPECT images were compared with DECT. RESULTS: We compared DECT en V/Q SPECT in 28 consecutive patients with persistent V/Q mismatch on V/Q SPECT, 13 men and 15 woman, mean age 60 (+17), range 23-82 year. One patient was excluded from the final analysis due to inferior quality DECT. In 18/27 (66.7%) the results were concordant between CTPA (persistent embolus visible), DECT (segmentary defects on iodine map) and V/Q SPECT (segmentary ventilation-perfusion mismatch). In 3/18 (11.1% of the total group) the partialy matched V/Q SPECT defect could be explained on DECT lung images by lung infarction. In 6/27 (22.1%) only hypoperfusion was seen on DECT iodine map. In 3/27 (11.1%) results were discordant between V/Q SPECT and DECT images. CONCLUSION: Six months after diagnosis of first or recurrent PE, residual pulmonary perfusion-defects encountered on V/Q-SPECT corresponds in the majority of patients with chronic thromboembolic disease seen on DECT. In 22.1% of patients V/Q SPECT mismatch only corresponds with hypoperfusion on iodine map DECT scan. Some (11.1%) of the chronic thromboembolic lesions seen on V/Q SPECT can not be explained by DECT results.

Erdheim-Chester disease detected with 99mTc MDP bone SPECT/CT.

Erdheim-Chester disease (ECD) is a rare non-Langerhans' cell histiocytosis. Mild but permanent juxta-articular bone pain in mainly knees and ankles is the most frequent associated symptom. Despite the pathognomonic radiographic findings, most cases are still diagnosed by the pathologist.The lesions consist of lipid-storing CD 68 +/CD 1a--non-Langerhans' cell histiocytes, most frequently localized in bone but also involving multiple organ systems in the body. We present a case report in which the diagnosis of ECD was established with 99mTc MDP bone SPECT/CT.

Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu.

Human epidermal growth factor receptor (HER)2/neu kinase domain mutations are found in approximately 1-4% of lung adenocarcinomas with a similar phenotype to tumors with epidermal growth factor receptor (EGFR) mutations. Afatinib is a potent irreversible ErbB family blocker. We determined the tumor genomic status of the EGFR and HER2 genes in non- or light smokers with lung adenocarcinoma in patients who were entered into an exploratory Phase II study with afatinib. Five patients with a non-smoking history and metastatic lung adenocarcinomas bearing mutations in the kinase domain of HER2 gene were identified, three of which were evaluable for response. Objective response was observed in all three patients, even after failure of other EGFR- and/or HER2-targeted treatments; the case histories of these patients are described in this report. These findings suggest that afatinib is a potential novel treatment option for this subgroup of patients, even when other EGFR and HER2 targeting treatments have failed.

An unusual cause of subtalar pain and instability: accessory calcaneus.

We report on a 45-yr-old male sports instructor with chronic pain and instability of the ankle. He was a recreational basketball player, but because of repeated ankle sprains and chronic subtalar pain this activity became impossible. The radiologic findings were compatible with the diagnosis of accessory calcaneus. In an initial therapeutic approach the patient was treated conservatively with taping and physical therapy, but this failed to relieve the symptoms. Next, a ligamentoplasty was performed. The instability improved, but the pain remained the same. Finally the accessory calcaneus was resected and short term follow-up was unremarkable. Accessory calcaneus is an uncommon anatomical variation that may cause subtalar pain and instability. Resection of the accessory bone may be necessary to provide relief of symptoms. Accessory calcaneus can be well demonstrated on CT, SPECT-CT, and MR. MR and nuclear medicine can indicate instability of the accessory bone by showing bone marrow edema on MR or uptake on fusion imaging.

The influence of headspace and dissolved oxygen level on growth and haemolytic BL enterotoxin production of a psychrotolerant Bacillus weihenstephanensis isolate on potato based ready-to-eat food products.

The major objective of this study was to determine the influence of the initial headspace and dissolved O(2) level and vacuum packaging on growth and diarrhoeal enterotoxin production by Bacillus weihenstephanensis on potato based ready-to-eat food products. In general, the lower the initial headspace or dissolved O(2) level the slower the maximum growth rate (µ(max), log(10) CFU g(-1) d(-1)), the longer the lag phase duration (λ, d) and the smaller the maximum population density (N(max), log(10) CFU g(-1)) became. The slowest µ(max), the longest λ and the smallest N(max) were generally found for growth under vacuum packaging. This implies shorter shelf-lives will occur at higher initial headspace or dissolved O(2) levels as the growth of B. weihenstephanensis to the infective dose of 10(5) CFU g(-1) in such atmospheres takes a shorter time. Significant consumption of dissolved O(2) only occurred when growth shifted from the lag to the exponential phase and growth generally transitioned from the exponential to the stationary phase when the dissolved O(2) levels fell below ca. 75 ppb. Diarrhoeal enterotoxin production (determined via detection of the L2 component of haemolytic BL) was similar for growth under initial headspace O(2) levels of 1-20.9%, and was only reduced when growth took place under vacuum packaging. The reduction in L2 production when growth took place under vacuum was most probably related to the low final cell densities observed under this condition. Both growth and L2 production were inhibited over a 32-day incubation period at 7 °C by 40% CO(2) irrespective of the headspace or dissolved O(2) levels. The results illustrate the importance of residual O(2) and CO(2) on the shelf-stability and safety of modified atmosphere packaged potato based ready-to-eat food products with regards to B. weihenstephanensis.

Phase II study of sunitinib malate in patients with recurrent high-grade glioma.

Receptor tyrosine kinase signaling causes profound neo-angiogenesis in high-grade gliomas (HGG). The KIT, PDGFR-α, and VEGFR2 genes are frequently amplified and expressed in HGG and are molecular targets for therapeutic inhibition by the small-molecule kinase inhibitor sunitinib malate. Twenty-one patients with progressive HGG after prior radiotherapy and chemotherapy received a daily dose of 37.5 mg sunitinib until progression or unacceptable toxicity. Magnetic resonance imaging (MRI) and dynamic susceptibility contrast (DSC)-enhanced perfusion measurements were performed before and during therapy. Cerebral blood volume (CBV) and cerebral blood flow (CBF) lesion-to-normal-white matter ratios were measured to evaluate the antiangiogenic effects of sunitinib. The most frequent grade ≥3 adverse events were skin toxicity, neutropenia, thrombocytopenia, and lymphocytopenia. None of the patients achieved an objective response, whereas a decrease in CBV and CBF within the lesion compared with the normal brain was documented in four out of 14 (29%) patients evaluable for DSC-enhanced perfusion measurements. All patients experienced progression of their disease before or after eight weeks of therapy. Median time-to-progression and overall survival were 1.6 (95%CI 0.8-2.5) and 3.8 (95% CI 2.2-5.3) months, respectively. No correlation could be established between VEGFR2, PDGFR-α, and KIT gene copy numbers or protein expression and the effects of sunitinib. Single-agent sunitinib at 37.5 mg/day had insufficient activity to warrant further investigation of this monotherapy regimen in recurrent HGG.

Phase II study of helical tomotherapy for oligometastatic colorectal cancer.

BACKGROUND: To evaluate the efficacy and toxicity of helical tomotherapy in the treatment of oligometastatic colorectal cancer (CRC) patients who were not amenable for metastasectomy and/or (further) systemic treatment. PATIENTS AND METHODS: CRC patients with five or less metastases were enrolled. No limitations concerning dimension or localization of the metastases were imposed. Patients were treated with intensity-modulated and image-guided radiotherapy using helical tomotherapy, delivering a total dose of 40 Gy in fractions of 4 Gy. Positron emission tomography-computed tomography (PET-CT) was carried out at baseline and 3 months after the initiation of radiotherapy to evaluate the metabolic response rate according to PET Response Criteria in Solid Tumors (PERCIST) version 1.0. Side-effects were scored using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTC AE) version 3.0. RESULTS: Twenty-three patients were enrolled. A total of 52 metastases were treated. One patient (4%) experienced grade 3 vomiting; two patients (9%) grade 2 diarrhea and dysphagia, respectively. Twenty-two patients were evaluated by post-treatment PET-CT. Five (23%) and seven patients (32%) achieved a complete and partial metabolic response, respectively, resulting in an overall metabolic response rate of 55%. The actuarial 1-year local control, progression-free survival, and overall survival were 54%, 25% and 86%, respectively. CONCLUSION: The use of helical tomotherapy in oligometastatic CRC patients resulted in a promising metabolic response rate of 55%.

Complete metabolic tumour response, assessed by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET), after induction chemotherapy predicts a favourable outcome in patients with locally advanced non-small cell lung cancer (NSCLC).

BACKGROUND: 18FDG-PET and multislice computerized axial tomography (CT) scan are used for diagnosis, staging and response evaluation in NSCLC patients. The correlation between the response assessment by both imaging techniques and survival was assessed in patients with unresectable stage III NSCLC treated with induction chemotherapy followed by consolidation radiotherapy. METHODS: Thirty-one patients, enrolled in a phase II study evaluating the efficacy and toxicity of a novel triplet induction chemotherapy (paclitaxel, carboplatin and gemcitabine) (PACCAGE) before consolidation radiotherapy, were evaluated by CT and 18FDG-PET at baseline and after three cycles of chemotherapy. The correlation between CT and 18FDG-PET response and time to progression and overall survival was analyzed using the Kaplan-Meier estimates of survival and the log rank test. RESULTS: Ten patients with a complete response (CR) on 18FDG-PET had a significantly longer time to progression and overall survival than patients with a non-CR (median 19.9 months versus 9.8 months, p=0.026, and median >49 months versus 14.4 months, p=0.004, respectively). Twenty patients with a partial CT response (PR) had a significantly longer time to progression (median 15 months versus 9.4 months, p=0.001) than patients with a non-PR but the difference in overall survival only showed a trend (23.3 months versus 14.4 months, p=0.093). CONCLUSIONS: A CR on 18FDG-PET following induction chemotherapy for locally advanced, unresectable NSCLC seems to be a more powerful prognostic marker for survival compared to PR on CT.

Aortoesophageal fistula following endovascular exclusion of a thoracic aneurysm.

The aim of this study was to report a case of aortoesophageal fistula following endovascular exclusion of a thoracic aneurysm, treated conservatively with fatal outcome. Endovascular exclusion of a thoracic aneurysm was performed in a 64-year-old female patient. Three months later the diagnosis of an aortoesophageal fistula was made and minimal surgery (cervicotomy and jejunostomy) was performed, combined with antibiotherapy and catheter flushing of the infected excluded aneurysm thrombus. The patient died in septic shock 9 weeks later. As reported, following conventional thoracic aortic aneurysm surgery, endovascular stenting of the thoracic aorta can be complicated by aortoesophageal fistula. Management should be surgical, since the outcome under conservative management seems invariably fatal. However, it looks as if the poor condition of these patients may not permit open surgical treatment.

In vivo visualization of 111In labeled CD133+ peripheral blood stem cells after intracoronary administration in patients with chronic ischemic heart disease.

AIM: Stem cell homing to injured tissue is necessary for local tissue repair. But homing of stem cells in chronic ischemic heart disease (CIHD) is poorly understood. This study investigated homing of peripheral blood stem cells (PBSC) expressing the CD133 antigen. After intracoronary injection. The cells were (111)In labeled for in vivo visualization. METHODS: PBSC were mobilized with granulocyte-colony stimulating factor and collected by apheresis on d-1. On d0, CD133+ cells were enriched up to a median purity of 89% (range: 79-97%) with an immunomagnetic separation device (CliniMACS, Miltenyi). A fraction of the cells was radiolabeled with [(111)In]oxine in 0.1 M TRIS at pH 7.4 for 45-60 min. Cell viability after labeling was assessed using trypan-blue. The cells were injected at a radioactive concentration of 0.9 MBq/10(6) cells into the target open coronary vessel through a balloon catheter. During balloon inflation [(99m)Tc]sestamibi was injected intravenously to identify the myocardium and the target vascular territory. Eight patients (mean age: 53 years; range: 50-72 years) with stable CIHD and reduced left ventricular function (NYHA class I-II) after acute myocardial infarction (>12 months) were studied. After a first cohort of 3 patients received an injectate of 5-10 x 10(6) cells, our final protocol was applied in 5 patients in whom an average of 34.4 x 10(6) (range: 18.6-49.4) CD133+ cells was injected. Whole body and single photon emission computed tomography (SPECT) scans were acquired at different time points after injection (energy windows set at 140, 171 and 245 keV). Residual activity in the heart was assessed by drawing a region of interest around the heart on the anterior whole body views. RESULTS: Mean labeling efficiency of [111In]oxine labeling was 51.2% and cell viability after labeling averaged 88%. In the 5 patients receiving the higher amount of labeled cells, a clear (111)In-signal was observed in the heart region up to 3 days after administration. Fused [(99m)Tc]sestamibi/(111)In SPECT images demonstrated that the regional distribution of the transplanted cells within the target zone, as delineated by the flow tracer, remained unchanged over time. A biodistribution study in 2 patients showed a residual activity in the heart, liver and spleen of 6.9-8%, 23.1-26.8%, 3.1-3.7%, respectively, after 1-2 h and 2.3-3.2% 23.8-28.3%, 3.5-3.8%, respectively, after 12 h (decay corrected and expressed as a percentage of total body initial activity). No adverse events were observed during the procedure and up to 3 months follow-up. CONCLUSIONS: Radiolabeling with [(111)In]oxine is a suitable method for follow-up of cell distribution during the first days after transplantation. A significant amount of CD133+ PBSC home to the heart after intracoronary injection in patients with CIHD. The results of this study are useful for the design of trials that evaluate the tissue repair potential of CD133+ PBSC in the setting of CIHD.