Phase I study with ONCOS-102 for the treatment of solid tumors - an evaluation of clinical response and exploratory analyses of immune markers.

BACKGROUND: We conducted a phase I study with a granulocyte macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, ONCOS-102, in patients with solid tumors refractory to available treatments. The objectives of the study were to determine the optimal dose for further use and to assess the safety, tolerability and adverse event (AE) profile of ONCOS-102. Further, the response rate and overall survival were evaluated as well as preliminary evidence of disease control. As an exploratory endpoint, the effect of ONCOS 102 on biological correlates was examined. METHODS: The study was conducted using a classic 3 + 3 dose escalation study design involving 12 patients. Patients were repeatedly treated intratumorally with ONCOS-102 plus daily low-dose oral cyclophosphamide (CPO). Tumor response was evaluated with diagnostic positron emission tomography (PET) and computed tomography (CT). Tumor biopsies were collected at baseline and after treatment initiation for analysis of immunological correlates. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and during the study to assess antigen specificity of CD8+ T cells by interferon gamma (IFNγ) enzyme linked immunospot assay (ELISPOT). RESULTS: No dose limiting toxicity (DLT) or maximum tolerated dose (MTD) was identified for ONCOS-102. Four out of ten (40 %) evaluable patients had disease control based on PET/CT scan at 3 months and median overall survival was 9.3 months. A short-term increase in systemic pro-inflammatory cytokines and a prominent infiltration of TILs to tumors was seen post-treatment in 11 out of 12 patients. Two patients showed marked infiltration of CD8+ T cells to tumors and concomitant systemic induction of tumor-specific CD8+ T cells. Interestingly, high expression levels of genes associated with activated TH1 cells and TH1 type immune profile were observed in the post-treatment biopsies of these two patients. CONCLUSIONS: ONCOS-102 is safe and well tolerated at the tested doses. All three examined doses may be used in further development. There was evidence of antitumor immunity and signals of clinical efficacy. Importantly, treatment resulted in infiltration of CD8+ T cells to tumors and up-regulation of PD-L1, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors. TRIAL REGISTRATION: NCT01598129. Registered 19/04/2012.

PET/CT Dose Planning for Volumetric Modulated Arc Radiation Therapy (VMAT) -Comparison with Conventional Approach in Advanced Prostate Cancer Patients.

Molecular imaging is the only way of defining biological target volume (BTV) for externalbeam radiation therapy (EBRT) and may be used for advanced targeting in dose planning and dose painting. There are, however, no reports about the EBRT response when dose planning is based on BTV target definition in advanced prostate cancer. Clinical and biochemical results of two clinically equal group of patients with advanced prostate cancer patients were compared. Both groups were treated with volumetric modulated arc therapy (VMAT) based on target definition by PET/CT (1(st) group) or conventional imaging (2(nd) group). Biochemical relapse occurred in 16.6% (in 1 out of 6) of the patients in the first group and 50% (3 out of 6) patients in the second group during the follow up period. Clinical manifestation of disease occurred in 33% (2 out of 6) patients of the first group and in 5 out of 6 (83,3%) patients in the second one. 4 patients in the first group had no biochemical relapse and no clinical manifestation during the follow up period. The difference in the duration of progression free period was statistically significant between the groups (p<0.010) being in the first group 16.5±5.4 (10-24) months and 4.6±2.9 (2-10) months in the second one. Because patients with PET/CT based VMAT had lower incidence of biochemical relapse, less clinical manifestations and longer, statistically significant duration of progression free period as compared to patients treated with VMAT based on conventional imaging, our preliminary results suggest introducing BTV definition based on PET imaging for VMAT in the EBRT of prostate cancer.

Immunological data from cancer patients treated with Ad5/3-E2F-Δ24-GMCSF suggests utility for tumor immunotherapy.

Oncolytic viruses that selectively replicate in tumor cells can be used for treatment of cancer. Accumulating data suggests that virus induced oncolysis can enhance anti-tumor immunity and break immune tolerance. To capitalize on the immunogenic nature of oncolysis, we generated a quadruple modified oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor (GMCSF). Ad5/3-E2F-Δ24-GMCSF (CGTG-602) was engineered to contain a tumor specific E2F1 promoter driving an E1 gene deleted at the retinoblastoma protein binding site ("Δ24"). The fiber features a knob from serotype 3 for enhanced gene delivery to tumor cells. The virus was tested preclinically in vitro and in vivo and then 13 patients with solid tumors refractory to standard therapies were treated. Treatments were well tolerated and frequent tumor- and adenovirus-specific T-cell immune responses were seen. Overall, with regard to tumor marker or radiological responses, signs of antitumor efficacy were seen in 9/12 evaluable patients (75%). The radiological disease control rate with positron emission tomography was 83% while the response rate (including minor responses) was 50%. Tumor biopsies indicated accumulation of immunological cells, especially T-cells, to tumors after treatment. RNA expression analyses of tumors indicated immunological activation and metabolic changes secondary to virus replication.

VMAT technique enables concomitant radiotherapy of prostate cancer and pelvic bone metastases.

BACKGROUND: Prostate cancer (PCa) patients with metastatic disease often suffer from skeletal pain and urinary retention impairing their quality of life. Prophylactic radiotherapy to bone metastases planned concomitantly with primary PCa radiotherapy could enable more precise control of combined dose in healthy tissues when compared to sequential palliative treatment. MATERIALS AND METHODS: Volumetric modulated arc therapy (VMAT) was planned for 14 PCa patients with primary bone metastases. The bone planning target volume (PTVbone) was contoured together with the PTVs of prostate (pr), pelvic lymph nodes (ln) and seminal vesicles (sv). Another virtual plan was calculated excluding PTVbone for dose volume histogram (DVH) comparison. DVHs were additionally compared to a set of actual VMAT treatment plans of a control cohort of 13 high risk PCa patients treated with PTVpr, PTVsv and PTVln. The prescribed doses varied between 42 and 76 Gy for PTVbone. RESULTS: Recommended healthy tissue tolerances (Quantec) were not exceeded except for one patient's rectum V50Gy value. Rectum doses did not increase significantly due to the inclusion of PTVbone. For bladder, there was a slight increase for V65Gy and V50Gy (2.7% and 7.4%). The DVHs of metastatic and non-metastatic patients were comparable. There were no differences in the PTVpr DVH parameters, while mean PTVln dose increased by 3.7 Gy-4.4 Gy due to the increased treatment volume related to PTVbone. All side effects were

Preliminary clinical experience of trans-1-Amino-3-(18)F-fluorocyclobutanecarboxylic Acid (anti-(18)F-FACBC) PET/CT imaging in prostate cancer patients.

BACKGROUND: In this retrospective analysis we assessed the role of [(18)F]-FACBC-PET/CT in the prostatic cancer staging. PROCEDURE: 30 first [(18)F]-FACBC-PET/CT images of 26 patients (68.1 ± 5.8 years) were analyzed. PET/CT findings were compared with PSA concentrations, with PSA doubling times (PDT), and with correlative imaging. RESULTS: On 16 [(18)F]-FACBC (53.3%) scans, 58 metabolically active lesions were found. 12 (20.7%) lesions corresponding to the local relapse were found in prostate/prostate bed and seminal vesicles, 9 (15.5%) lesions were located in regional lymph nodes, 10 (17.2%) were located in distal lymph nodes, and 26 (44.8%) metabolically active lesions were found in the skeleton. In one case, focal uptake was found in the brain, confirmed further on MRI as meningioma. The mean S-PSA level in patients with positive [(18)F]-FACBC findings was 9.5 ± 16.9 µ g/L (0.54-69 µ g/L) and in patients with negative [(18)F]-FACBC findings was 1.96 ± 1.87 µ g/L (0.11-5.9 µ g/L), but the difference was not statistically significant. However, the PSA doubling time (PDT) in patients with positive findings was significantly shorter than PDT in patients with negative findings: 3.25 ± 2.09 months (0.3-6 months) versus 31.2 ± 22.02 months (8-84 months), P < 0.0001. There was a strong positive correlation between PSA value and number of metabolically active lesions (R = 0.74) and a negative correlation between PDT and number of metabolically active lesions (R = -0.56). There was a weak negative correlation between PDT and SUVmax⁡ (R = -0.30). CONCLUSION: According to our preliminary clinical experience, [(18)F]-FACBC-PET may play a role in in vivo restaging of an active prostate cancer, especially in patients with a short S-PSA doubling time.

Local treatment of a pleural mesothelioma tumor with ONCOS-102 induces a systemic antitumor CD8+ T-cell response, prominent infiltration of CD8+ lymphocytes and Th1 type polarization.

Late stage cancer is often associated with reduced immune recognition and a highly immunosuppressive tumor microenvironment. The presence of tumor infiltrating lymphocytes (TILs) and specific gene-signatures prior to treatment are linked to good prognosis, while the opposite is true for extensive immunosuppression. The use of adenoviruses as cancer vaccines is a form of active immunotherapy to initialise a tumor-specific immune response that targets the patient's unique tumor antigen repertoire. We report a case of a 68-year-old male with asbestos-related malignant pleural mesothelioma who was treated in a Phase I study with a granulocyte-macrophage colony­stimulating factor (GM-CSF)-expressing oncolytic adenovirus, Ad5/3-D24-GMCSF (ONCOS-102). The treatment resulted in prominent infiltration of CD8+ lymphocytes to tumor, marked induction of systemic antitumor CD8+ T-cells and induction of Th1-type polarization in the tumor. These results indicate that ONCOS-102 treatment sensitizes tumors to other immunotherapies by inducing a T-cell positive phenotype to an initially T-cell negative tumor.

[(18)F]-fluorodeoxyglucose positron emission tomography and computed tomography in response evaluation of oncolytic adenovirus treatments of patients with advanced cancer.

Computed tomography (CT) is the most commonly used radiological response evaluation method in contemporary oncology. However, it may not be optimally suitable for assessment of oncolytic virus treatments because of paradoxical inflammatory tumor swellings, which result from virus treatments, particularly when viruses are armed with immunostimulatory molecules. Here we investigated the prognostic utility of CT and [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) in oncolytic virus treatments. We also investigated possible appearance of false-positive FDG signals in FDG-PET imaging of humans and hamsters treated with oncolytic adenoviruses. First, immunocompetent Syrian hamsters were treated with intratumoral adenovirus injections, tumor growth was followed up, and [(18)F]-FDG-uptake was quantitated with small animal PET/CT. Second, we describe a retrospective patient series, essentially 17 individual case reports, of advanced cancer patients treated with oncolytic adenoviruses in the context of an Advanced Therapy Access Program (ATAP) who underwent radiological response evaluation with both contrast-enhanced CT and FDG-PET. Third, we collected a retrospective case series of radiological response and survival data of 182 patients treated with oncolytic adenoviruses in ATAP to evaluate the prognostic reliability of CT and FDG-PET. Overall, responses in CT and FDG-PET correlated well with each other and were equally reliable as prognostic markers for long survival after oncolytic adenovirus treatment. Interestingly, we observed that new FDG-avid lymph nodes appearing in FDG-PET after virus treatments may represent inflammatory responses and therefore should not be interpreted as treatment failure in the absence of other signs or verification of disease progression. We also observed indications that FDG-PET might be more sensitive in detection of responses than tumor size.

Oncolytic adenovirus with temozolomide induces autophagy and antitumor immune responses in cancer patients.

Oncolytic adenoviruses and certain chemotherapeutics can induce autophagy and immunogenic cancer cell death. We hypothesized that the combination of oncolytic adenovirus with low-dose temozolomide (TMZ) is safe, effective, and capable of inducing antitumor immune responses. Metronomic low-dose cyclophosphamide (CP) was added to selectively reduce regulatory T-cells. Preclinically, combination therapy inhibited tumor growth, increased autophagy, and triggered immunogenic cell death as indicated by elevated calreticulin, adenosine triphosphate (ATP) release, and nuclear protein high-mobility group box-1 (HMGB1) secretion. A total of 41 combination treatments given to 17 chemotherapy-refractory cancer patients were well tolerated. We observed anti- and proinflammatory cytokine release, evidence of virus replication, and induction of neutralizing antibodies. Tumor cells showed increased autophagy post-treatment. Release of HMGB1 into serum--a possible indicator of immune response--increased in 60% of treatments, and seemed to correlate with tumor-specific T-cell responses, observed in 10/15 cases overall (P = 0.0833). Evidence of antitumor efficacy was seen in 67% of evaluable treatments with a trend for increased survival over matched controls treated with virus only. In summary, the combination of oncolytic adenovirus with low-dose TMZ and metronomic CP increased tumor cell autophagy, elicited antitumor immune responses, and showed promising safety and efficacy.

Antiviral and antitumor T-cell immunity in patients treated with GM-CSF-coding oncolytic adenovirus.

PURPOSE: Multiple injections of oncolytic adenovirus could enhance immunologic response. In the first part of this article, the focus was on immunologic aspects. Sixty patients previously naïve to oncolytic virus and who had white blood cells available were treated. Thirty-nine of 60 were assessed after a single virus administration, whereas 21 of 60 received a "serial treatment" consisting of three injections within 10 weeks. In the second part, we focused on 115 patients treated with a granulocyte macrophage colony-stimulating factor (GM-CSF)-coding capsid chimeric adenovirus, CGTG-102. RESULTS: Following serial treatment, both increase and decrease in antitumor T cells in blood were seen more frequently, findings which are compatible with induction of T-cell immunity and trafficking of T cells to tumors, respectively. Safety was good in both groups. In 115 patients treated with CGTG-102 (Ad5/3-D24-GMCSF), median overall survival was 111 days following single and 277 days after serial treatment in nonrandomized comparison. Switching the virus capsid for avoiding neutralizing antibodies in a serial treatment featuring three different viruses did not impact safety or efficacy. A correlation between antiviral and antitumor T cells was seen (P = 0.001), suggesting that viral oncolysis can result in epitope spreading and breaking of tumor-associated immunologic tolerance. Alternatively, some patients may be more susceptible to induction of T-cell immunity and/or trafficking. CONCLUSIONS: These results provide the first human data linking antiviral immunity with antitumor immunity, implying that oncolytic viruses could have an important role in cancer immunotherapy.

Ad3-hTERT-E1A, a fully serotype 3 oncolytic adenovirus, in patients with chemotherapy refractory cancer.

Twenty-five patients with chemotherapy refractory cancer were treated with a fully serotype 3-based oncolytic adenovirus Ad3-hTERT-E1A. In mice, Ad3 induced higher amounts of cytokines but less liver damage than Ad5 or Ad5/3. In humans, the only grade 3 adverse reactions were self-limiting cytopenias and generally the safety profile resembled Ad5-based oncolytic viruses. Patients that had been previously treated with Ad5 viruses presented longer lasting lymphocytopenia but no median increase in Ad3-specific T-cells in blood, suggesting immunological activity against antigens other than Ad3 hexon. Frequent alterations in antitumor T-cells in blood were seen regardless of previous virus exposure. Neutralizing antibodies against Ad3 increased in all patients, whereas Ad5 neutralizing antibodies remained stable. Treatment with Ad3-hTERT-E1A resulted in re-emergence of Ad5 viruses from previous treatments into blood and vice versa. Signs of possible efficacy were seen in 11/15 (73%) patients evaluable for tumor markers, four of which were treated only intravenously. Particularly promising results were seen in breast cancer patients and especially those receiving concomitant trastuzumab. Taken together, Ad3-hTERT-E1A seems safe for further clinical testing or development of armed versions. It offers an immunologically attractive alternative, with possible pharmacodynamic differences and a different receptor compared to Ad5.

Oncolytic immunotherapy of advanced solid tumors with a CD40L-expressing replicating adenovirus: assessment of safety and immunologic responses in patients.

The immunosuppressive environment of advanced tumors is a primary obstacle to the efficacy of immunostimulatory and vaccine approaches. Here, we report an approach to arm an oncolytic virus with CD40 ligand (CD40L) to stimulate beneficial immunologic responses in patients. A double-targeted chimeric adenovirus controlled by the hTERT promoter and expressing CD40L (CGTG-401) was constructed and nine patients with progressing advanced solid tumors refractory to standard therapies were treated intratumorally. No serious adverse events resulting in patient hospitalization occurred. Moderate or no increases in neutralizing antibodies were seen, suggesting effective Th1 immunologic effects. An assessment of the blood levels of virus indicated 17.5% of the samples (n = 40) were positive at a low level early after treatment, but not thereafter. In contrast, high levels of virus, CD40L, and RANTES were documented locally at the tumor. Peripheral blood mononuclear cells were analyzed by IFN-γ ELISPOT analysis and induction of both survivin-specific and adenovirus-specific T cells was seen. Antitumor T-cell responses were even more pronounced when assessed by intracellular cytokine staining after stimulation with tumor type-specific peptide pools. Of the evaluable patients, 83% displayed disease control at 3 months and in both cases in which treatment was continued the effect was sustained for at least 8 months. Injected and noninjected lesions responded identically. Together, these findings support further clinical evaluation of CGTG-401.

Integrin targeted oncolytic adenoviruses Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of patients with advanced chemotherapy refractory solid tumors.

The safety of oncolytic viruses for treatment of cancer has been shown in clinical trials while antitumor efficacy has often remained modest. As expression of the coxsackie-adenovirus receptor may be variable in advanced tumors, we developed Ad5-D24-RGD, a p16/Rb pathway selective oncolytic adenovirus featuring RGD-4C modification of the fiber. This allows viral entry through alpha-v-beta integrins frequently highly expressed in advanced tumors. Advanced tumors are often immunosuppressive which results in lack of tumor eradication despite abnormal epitopes being present. Granulocyte-macrophage colony stimulating factor (GMCSF) is a potent activator of immune system with established antitumor properties. To stimulate antitumor immunity and break tumor associated immunotolerance, we constructed Ad5-RGD-D24-GMCSF, featuring GMCSF controlled by the adenoviral E3 promoter. Preliminary safety of Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of human cancer was established. Treatments with Ad5-D24-RGD (N = 9) and Ad5-RGD-D24-GMCSF (N = 7) were well tolerated. Typical side effects were grade 1-2 fatigue, fever and injection site pain. 77% (10/13) of evaluable patients showed virus in circulation for at least 2 weeks. In 3 out of 6 evaluable patients, disease previously progressing stabilized after a single treatment with Ad5-RGD-D24-GMCSF. In addition, 2/3 patients had stabilization or reduction in tumor marker levels. All patients treated with Ad5-D24-RGD showed disease progression in radiological analysis, although 3/6 had temporary reduction or stabilization of marker levels. Induction of tumor and adenovirus specific immunity was demonstrated with ELISPOT in Ad5-RGD-D24-GMCSF treated patients. RGD modified oncolytic adenoviruses with or without GMCSF seem safe for further clinical development.

Immunological effects of low-dose cyclophosphamide in cancer patients treated with oncolytic adenovirus.

Patients with advanced solid tumors refractory to and progressing after conventional therapies were treated with three different regimens of low-dose cyclophosphamide (CP) in combination with oncolytic adenovirus. CP was given with oral metronomic dosing (50 mg/day, N = 21), intravenously (single 1,000 mg dose, N = 7) or both (N = 7). Virus was injected intratumorally. Controls (N = 8) received virus without CP. Treatments were well tolerated and safe regardless of schedule. Antibody formation and virus replication were not affected by CP. Metronomic CP (oral and oral + intravenous schedules) decreased regulatory T cells (T(regs)) without compromising induction of antitumor or antiviral T-cell responses. Oncolytic adenovirus given together with metronomic CP increased cytotoxic T cells and induced Th1 type immunity on a systemic level in most patients. All CP regimens resulted in higher rates of disease control than virus only (all P < 0.0001) and the best progression-free (PFS) and overall survival (OS) was seen in the oral + intravenous group. One year PFS and OS were 53 and 42% (P = 0.0016 and P < 0.02 versus virus only), respectively, both which are unusually high for chemotherapy refractory patients. We conclude that low-dose CP results in immunological effects appealing for oncolytic virotherapy. While these first-in-human data suggest good safety, intriguing efficacy and extended survival, the results should be confirmed in a randomized trial.

Safety of glucocorticoids in cancer patients treated with oncolytic adenoviruses.

Oncolytic adenoviruses are an emerging treatment option for advanced and refractory cancer. Such patients are often treated with corticosteroids to ameliorate tumor associated symptoms. Thus, it is important to evaluate whether safety is affected by immunosuppression possibly induced by corticosteroids. Concurrent low-dose cyclophosphamide, appealing for its immunomodulatory effects, could also impact safety. In a retrospective case-control study, we evaluated the effect of systemic corticosteroid use in cancer patients receiving oncolytic virotherapy. Four treatment groups were identified: (1) oncolytic adenovirus with oral glucocorticoids, (2) virus alone, (3) virus with glucocorticoids and cyclophosphamide and (4) virus with cyclophosphamide. Adverse events, neutralizing antibody titers, viral DNA in circulation and tumor responses were evaluated. The most common adverse effects were grade 1-2 fatigue, nausea, fever and abdominal pain. Common asymptomatic findings included self-limiting grade 1-3 hyponatremia and aspartate aminotransferase increase. Safety was good and no significant differences were observed between the groups. All patients had an increase in neutralizing antibody titers post-treatment, and no trends for differences between groups were observed. There were fewer post-treatment virus genomes circulating in patients receiving glucocorticoids when compared to their control groups. Overall, glucocorticoid use in cancer patients receiving oncolytic adenovirus, with or without low-dose cyclophosphamide, seems safe.

Treatment of cancer patients with a serotype 5/3 chimeric oncolytic adenovirus expressing GMCSF.

Augmenting antitumor immunity is a promising way to enhance the potency of oncolytic adenoviral therapy. Granulocyte-macrophage colony-stimulating factor (GMCSF) can mediate antitumor effects by recruiting natural killer cells and by induction of tumor-specific CD8(+) cytotoxic T-lymphocytes. Serotype 5 adenoviruses (Ad5) are commonly used in cancer gene therapy. However, expression of the coxsackie-adenovirus receptor is variable in many advanced tumors and preclinical data have demonstrated an advantage for replacing the Ad5 knob with the Ad3 knob. Here, a 5/3 capsid chimeric and p16-Rb pathway selective oncolytic adenovirus coding for GMCSF was engineered and tested preclinically. A total of 21 patients with advanced solid tumors refractory to standard therapies were then treated intratumorally and intravenously with Ad5/3-D24-GMCSF, which was combined with low-dose metronomic cyclophosphamide to reduce regulatory T cells. No severe adverse events occurred. Analysis of pretreatment samples of malignant pleural effusion and ascites confirmed the efficacy of Ad5/3-D24-GMCSF in transduction and cell killing. Evidence of biological activity of the virus was seen in 13/21 patients and 8/12 showed objective clinical benefit as evaluated by radiology with Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Antiadenoviral and antitumoral immune responses were elicited after treatment. Thus, Ad5/3-D24-GMCSF seems safe in treating cancer patients and promising signs of efficacy were seen.

Hippocampus and entorhinal cortex in mild cognitive impairment and early AD.

Magnetic resonance imaging (MRI) has been suggested as a useful tool in early diagnosis of Alzheimer's disease (AD). Based on MRI-derived volumes, we studied the hippocampus and entorhinal cortex (ERC) in 59 controls, 65 individuals with mild cognitive impairment (MCI) and 48 patients with AD. The controls and individuals with MCI were derived from population-based cohorts. Volumes of the hippocampus and ERC were significantly reduced in the following order: control > MCI > AD. Stepwise discriminant function analysis showed that the most efficient overall classification between controls and individuals with MCI subjects was achieved with ERC measurements (65.9%). However, the best overall classification between controls and AD patients (90.7%), and between individuals with MCI and AD patients (82.3%) was achieved with hippocampal volumes. Our results suggest that the ERC atrophy precedes hippocampal atrophy in AD. The ERC volume loss is dominant over the hippocampal volume loss in MCI, whereas more pronounced hippocampal volume loss appears in mild AD.

Encoding of novel picture pairs activates the perirhinal cortex: an fMRI study.

It is well established in nonhuman primates that the medial temporal lobe (MTL) structures, the hippocampus and the entorhinal and perirhinal cortices, are necessary for declarative memory encoding. In humans, the neuropathological and neuropsychological changes in early Alzheimer's disease (AD) further support a role for the rhinal cortex in the consolidation of new events into long-term memory. Little is known, however, regarding the function of the rhinal cortex in humans in vivo. To examine the participation of the interconnected MTL structures as well as the whole-brain network of activated brain areas in visual associative long-term memory, functional magnetic resonance imaging (fMRI) was used to determine the brain regions that are activated during encoding and retrieval of paired pictures in 12 young control subjects. The most striking finding in the MTL activation pattern was the consistent activation of the perirhinal cortex in the encoding-baseline and encoding-retrieval comparisons with a strict statistical threshold (P < 0.00001). In contrast, no perirhinal cortex activation was detected in the retrieval-baseline or retrieval-encoding comparisons even with a low statistical threshold (P < 0.05). The location of the perirhinal activation area was in the transentorhinal part of the perirhinal cortex, in the medial bank of the collateral sulcus. The hippocampus and the more posterior parahippocampal gyrus were activated in both encoding and retrieval conditions. During the encoding processing, MTL activations were more consistent and the hippocampal activation area located more anteriorly than during retrieval. The frontal, parietal, temporal, and occipital association cortices were also activated in the encoding-baseline and retrieval-baseline comparisons. The data suggest that encoding, but not retrieval, of novel picture pairs activates the perirhinal cortex. To our knowledge, this is the first fMRI study reporting encoding activation in this transentorhinal part of the perirhinal cortex, the site of the very earliest neuropathological changes in AD.

Visual processing of coherent rotation in the central visual field: an fMRI study.

Functional magnetic resonance imaging was used to determine the brain areas that process coherent motion. To reduce the activity related to eye-movement planning and self-motion perception, rotation was used as coherent motion and the stimulus was restricted to the central visual field. Coherent rotation relative to incoherent random-dot motion resulted in consistent activation in the superior parietal lobule (SPL), in the lateral occipital gyrus (presumptive kinetic occipital region, KO), and in the fusiform gyrus (FG). The main novel finding in present study is the bilateral SPL activation, which has not been found in any previous study contrasting coherent and incoherent motion. It is suggested that the SPL activation is related to form-from-motion processing. The stimulus modification that prevented abrupt appearances of dots at the borders of the stimulus field increased the strength of rolling disk-like percept of the coherent stimulus. This perception of form may also be at least partly responsible for the activation in KO and FG. With this explanation, our three consistent activation areas are in line with previous findings. Furthermore, these results demonstrate that even delicate changes in some stimulus aspects can lead to significant changes in the activation of the brain.

Patients with acute flank pain: comparison of MR urography with unenhanced helical CT.

PURPOSE: To compare unenhanced helical computed tomography (CT) and magnetic resonance (MR) urography, by using T2-weighted and contrast material-enhanced T1-weighted imaging to examine patients with acute flank pain, with reference to excretory urography and final clinical diagnosis. MATERIALS AND METHODS: Forty-nine patients underwent CT, MR urography (with T2-weighted and gadopentetate dimeglumine-enhanced T1-weighted sequences), and excretory urography. CT and MR urographic findings were evaluated separately and independently by two radiologists each (CT, observers A and B; MR urography, observers C and D) for the presence, cause, level, and degree of obstruction. The final conclusive diagnosis was based on the combination of excretory urographic, clinical, and interventional results. RESULTS: At final diagnosis, 32 (65%) patients were found to have ureteral stones causing unilateral obstruction. In ureteral stone detection, the sensitivity and specificity of CT were 90.6% (29 of 32 patients) and 100.0% (17 of 17 patients), respectively (observer A) and 90.6% (29 of 32 patients) and 94.1% (16 of 17 patients), respectively (observer B), while those of MR urography were 93.8% (30 of 32 patients) and 100.0% (17 of 17 patients), respectively (observer C) and 100.0% (32 of 32 patients) and 100.0% (17 of 17 patients), respectively (observer D). Spearman correlation coefficients for stone size at CT were 0.76 (P <.001) and 0.75 (P <.001) and at MR urography, 0.49 (P =.005) and 0.51 (P =.004). CONCLUSION: In routine clinical practice, CT is the modality of choice in the evaluation of patients with acute flank pain. MR urography is an accurate and suitable alternative imaging technique in selected patients.