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PDF file - 95K, A panel of proinflammatory cytokines was analyzed to evaluate the safety of treatment.

PDF file - 100K, PBMCs were isolated from patients before and circa one month after treatment and pulsed with an adenovirus-derived peptide pool and analyzed with IFN-gamma ELISPOT.

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. Clin Cancer Res; 19(10); 2734–44. ©2013 AACR.

PDF file - 62K, Adverse reactions of all CGTG-102 patients.

PDF file - 67K, Adverse reactions in patients na�ve to oncolytic adenovirus.

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PDF file - 889K, Individual anti-tumor (survivin) and anti-viral (Ad5) ELISPOT results in single (A) and serial (B) treated patients.

PDF file - 71K, Characteristics of patients na�ve to oncolytic adenovirus.

PDF file - 94K, The phenotypic panel of circulating white blood cells.

PDF file - 141K, Example of progressive inflammation in serial treatment.

// Otto Hemminki 1 , Suvi Parviainen 1 , Juuso Juhila 1 , Riku Turkki 2 , Nina Linder 2 , Johan Lundin 2, 3 , Matti Kankainen 4 , Ari Ristimaki 5 , Anniina Koski 1 , Ilkka Liikanen 1 , Minna Oksanen 1 , Dirk M. Nettelbeck 6 , Kalevi Kairemo 7 , Kaarina Partanen 7 , Timo Joensuu 7 , Anna Kanerva 1, 8 , Akseli Hemminki 1, 7, 9 1 Cancer Gene Therapy Group, Transplantation Laboratory & Haartman Institute, University of Helsinki, Helsinki, Finland 2 Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland 3 Division of Global Health/IHCAR, Karolinska Institutet, Stockholm, Sweden 4 CSC - IT Center for Science Ltd, Helsinki, Finland 5 Department of Pathology, HUSLAB and Haartman Institute, Helsinki, University Central Hospital and Genome-Scale Biology, Research Programs Unit, University of Helsinki, Helsinki, Finland 6 German Cancer Research Center (DKFZ), Heidelberg, Germany 7 Docrates Cancer Center, Helsinki, Finland 8 Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland 9 TILT Biotherapeutics Ltd, Helsinki, Finland Correspondence to: Akseli Hemminki, e-mail: akseli.hemminki@helsinki.fi Keywords: Oncolytic, immunotherapy, cancer, ATAP Received: September 17, 2014 Accepted: December 14, 2014 Published: February 24, 2015 ABSTRACT 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.

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.

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.

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. 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). 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. 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. NCT01598129 . Registered 19/04/2012

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. Cancer Res; 72(7); 1621–31. ©2012 AACR.

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.

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.

To analyse the long term results of temporal lobe epilepsy surgery in a national epilepsy surgery centre for adults, and to evaluate preoperative factors predicting a good postoperative outcome on long term follow up.Longitudinal follow up of 140 consecutive adult patients operated on for drug resistant temporal lobe epilepsy.46% of patients with unilateral temporal lobe epilepsy became seizure-free, 10% had only postoperative auras, and 15% had rare seizures on follow up for (mean (SD)) 5.4 (2.6) years, range 0.25 to 10.5 years. The best outcome was after introduction of a standardised magnetic resonance (MR) imaging protocol (1993-99): in unilateral temporal lobe epilepsy, 52% of patients became seizure-free, 7% had only postoperative auras, and 17% had rare seizures (median follow up 3.8 years, range 0.25 to 6.5 years); in palliative cases (incomplete removal of focus), a reduction in seizures of at least 80% was achieved in 71% of cases (median follow up 3.1 years, range 1.1 to 6.8 years). Most seizure relapses (86%) occurred within one year of the operation, and outcome at one year did not differ from the long term outcome. Unilateral hippocampal atrophy with or without temporal cortical atrophy on qualitative MR imaging (p0.001, odds ratio (OR) 5.2, 95% confidence interval (CI) 2.0 to 13.7), other unitemporal structural lesions on qualitative MR imaging (por = 0.001, OR 6.9, 95% CI 2.2 to 21.5), onset of epilepsy before the age of five years (p0.05, OR 2.9, 95% CI 1.2 to 7.2), and focal seizures with ictal impairment of consciousness and focal ictal EEG as a predominant seizure type (p0.05, OR 3.4, 95% CI 1.2 to 9.1) predicted Engel I-II outcome. Hippocampal volume reduction of at least 1 SD from the mean of controls on the side of the seizure onset (p0.05, OR 3.1, 95% CI 1.1 to 9.2) also predicted Engel I-II outcome.Outcome at one year postoperatively is highly predictive of long term outcome after temporal lobe epilepsy surgery. Unitemporal MR imaging abnormalities, early onset of epilepsy, and seizure type predominance are factors associated with good postoperative outcome.

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.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.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).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.

Purpose: We evaluated the reproducibility of three visual scoring methods of emphysema and compared these methods with pulmonary function tests (VC, DLCO, FEV1 and FEV%) among farmer's lung patients and farmers. Material and Methods: Three radiologists examined high-resolution CT images of farmer's lung patients and their matched controls (n=70) for chronic interstitial lung diseases. Intraobserver reproducibility and interobserver variability were assessed for three methods: severity, Sanders' (extent) and Sakai. Pulmonary function tests as spirometry and diffusing capacity were measured. Results: Intraobserver κ-values for all three methods were good (0.51-0.74). Interobserver κ varied from 0.35 to 0.72. The Sanders' and the severity methods correlated strongly with pulmonary function tests, especially DLCO and FEV1. Conclusion: The Sanders' method proved to be reliable in evaluating emphysema, in terms of good consistency of interpretation and good correlation with pulmonary function tests.

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 < grade 3 during the mean follow-up duration of 25 months.Conclusions. VMAT offers a good optimization tool for adding extra PTVs to the radiotherapy plan. Radiotherapy of bone metastases concomitantly with irradiation of the primary prostate tumor is a safe and well-tolerated approach and deserves to be studied in a randomized setting.

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

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 colony‑stimulating 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.

Background.In this retrospective analysis we assessed the role of [18F]-FACBC-PET/CT in the prostatic cancer staging.Procedure.30 first [18F]-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 [18F]-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 [18F]-FACBC findings was 9.5 ± 16.9 μg/L (0.54–69 μg/L) and in patients with negative [18F]-FACBC findings was 1.96 ± 1.87 μg/L (0.11–5.9 μg/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 andSUVmax⁡(R=-0.30).Conclusion.According to our preliminary clinical experience, [18F]-FACBC-PET may play a role inin vivorestaging of an active prostate cancer, especially in patients with a short S-PSA doubling time.

Patients with drug-refractory temporal lobe epilepsy (TLE) often have hippocampal and amygdaloid damage. The present study investigated the factors associated with the occurrence and severity of damage in patients with partial epilepsy. Magnetic resonance imaging was used to measure the volumes of the hippocampus and the amygdala in 241 patients with different durations of epilepsy. We also investigated the association of damage with the location of seizure focus and clinical factors (age at onset of seizures, lifetime seizure number and medical history of complex febrile convulsions, intracranial infection or status epilepticus) with regression analysis. We found that high lifetime seizure number ( P P P P P

Neuronal damage has been observed in the medial temporal lobe of both humans and animals following status epilepticus. The aim of the present study was to investigate the occurrence of medial temporal lobe damage in status epilepticus patients treated in hospital with a predetermined protocol and to assess whether the changes progress in a long-term follow-up. The volumes of the hippocampus, amygdala, entorhinal and perirhinal cortices were measured using magnetic resonance imaging (MRI) in nine adult patients with status epilepticus 3 weeks, 6 and 12 months after the insult. The control group included 20 healthy subjects. The etiology of status epilepticus was an acute process in one patient and a chronic process in eight cases. The mean duration of secondarily generalized tonic-clonic status epilepticus episodes was 1 h and 44 min. Volumetric MRI indicated that none of the patients developed marked volume reduction in the hippocampus, amygdala, or the entorhinal and perirhinal cortices during the 1-year follow-up period. Status epilepticus does not invariably lead to a progressive volume reduction in the medial temporal lobe structures of adult patients treated promptly in hospital with a predetermined protocol for rapid cessation of seizure activity.

Objective: To detect reduced [11C]flumazenil in patients with temporal lobe epilepsy (TLE) and to relate binding to histopathology.Methods: The authors studied 16 patients who underwent epilepsy surgery because of drug-resistant TLE using [11C]flumazenil PET and quantitative MRI. In 12 patients, resected hippocampus was available for histologic analysis. [11C]Flumazenil binding potential (fitted BP) was assessed with the simplified reference tissue model.Results: [11C]Flumazenil fitted BP in the medial temporal lobe was reduced in all patients with abnormal hippocampal volumetry or T2 relaxometry on MRI. Fitted BP was also reduced in 46% of the patients with hippocampal volume within the normal range and in 38% of patients with less than 2 SD T2 prolongation. In all MRI-negative/PET-positive patients, the histologic analysis verified hippocampal damage. Also, [11C]flumazenil fitted BP correlated with the severity of reduced hippocampal volume, T2 prolongation, and histologically assessed neuronal loss and astrogliosis.Conclusion: [11C]Flumazenil PET provides a useful tool for investigating the hippocampal damage in vivo even in patients with no remarkable hippocampal abnormalities on quantitative MRI.

The entorhinal cortex (Brodmann’s area 28) is located at the anterior aspect of the parahippocampal gyrus ventral to the amygdala and the hippocampus. It is reciprocally interconnected with the hippocampus via glutamatergic pathways. We investigated whether the entorhinal cortex is damaged in human temporal lobe epilepsy (TLE). The volume of the entorhinal cortex was measured using magnetic resonance imaging (MRI) in 36 patients with cryptogenic TLE and in 21 controls. The mean volumes of the entorhinal cortex on the focal side did not differ from controls. In 11 of 36 patients, however, the entorhinal cortex volume was reduced by 25%. Entorhinal volume correlated with hippocampal volume in TLE (ipsilaterally, r= 0.454, P< 0.01; contralaterally, r= 0.340, P< 0.05). Further, 64% of patients with 25% entorhinal cortex damage had ipsilateral hippocampal atrophy. On the other hand, right focal TLE patients with hippocampal atrophy had a 19% volume reduction of the ipsilateral entorhinal cortex (P< 0.05). The volume of the entorhinal cortex correlated with the duration of TLE (r= −0.335, P< 0.05). The present study indicates that the entorhinal cortex might be damaged in a subpopulation of patients with cryptogenic TLE. In most cases, volume reduction was associated with hippocampal damage. These data suggest that entorhinal damage contributes to the symptomatology in TLE.

Verbal fluency tests (VFTs) are suggested to assess frontal lobe function. This view is supported by functional imaging studies that report left frontal activation during VFTs. VFTs require retrieval of semantically associated words from long-term memory storage. The neural networks that participate in this process, however, are largely unknown. These neural networks are of interest, given that patients with early Alzheimer's disease, typically without frontal pathology, are often impaired in VFTs. In the present study, functional magnetic resonance imaging was performed to determine brain activation areas during VFTs in young subjects. In the activation task, category fluency was contrasted with orderly listing of numbers. As judged from using this comparison, there was activation in the left medial temporal lobe, in the inferior frontal and retrosplenial cortices bilaterally, and in the left superior parietal lobule. Left medial temporal lobe activation was present in 13 of the 14 study subjects either in the hippocampal formation (11 of 14) or in the posterior parahippocampal gyrus (12 of 14). These results suggest that the medial temporal lobe is required for the process of retrieval by category. Functional magnetic resonance imaging combined with a category fluency task may provide a new method to study patients with early Alzheimer's disease.

Background: Due to the progressive nature of Alzheimer’s disease (AD), it has been proposed that serial imaging studies tracking the course of progression might improve the diagnostic accuracy of AD. Methods: Longitudinal changes in hippocampal volumes were evaluated using magnetic resonance imaging (MRI) over a period of 3 years in 27 AD patients and 8 control subjects. Results: A statistically nonsignificant trend towards accelerated volume loss in the AD group compared to control subjects was observed. During the study period, the average shrinkage of the hippocampal volume ranged from −2.2% to −5.8% in control subjects, and from −2.3% to −15.6% in AD patients. Conclusions: The observed changes at an individual level were small, and within the accuracy range of the measurements. Therefore, serial MRI of the hippocampus did not offer any advantage over a single MRI to support the diagnosis of AD in this study sample.

Background. To compare antepartum ultrasonography with magnetic resonance imaging for prenatal diagnosis of malformations in the fetal urinary tract in high risk patients during the last trimester. Materials and methods. The study involved 22 women and 24 fetuses with either severe oligohydramnios or ultrasonographically or clinically suspected abnormality of urinary tract. Ultrasound examination was carried out with 5 MHz abdominal convex probe and magnetic resonance imaging with superconductive 1.5 T equipment. Postnatal findings were used as reference. Results. Correct diagnosis of urinary tract anomaly was done in 15 fetuses on ultrasound and in 20 fetuses on magnetic resonance imaging. Both methods enabled correct diagnosis in 12, only ultrasound in three and only magnetic resonance imaging in eight fetuses. Both methods imaged equivocally in one case. The additional information by magnetic resonance imaging was gained from five fetuses out of 12 pregnancies with oligohydramnios and from three fetuse...

Background. There is little evidence to support possible structural changes in the amygdala and hippocampus of patients with severe depression.Methods. Quantitative MRI of the amygdala and hippocampus, as well as proton spectroscopy (MRS) of mesial temporal structures were studied in 34 drug-resistant in-patients with major depression and compared with 17 age-matched controls. Volumetric MRI data were normalized for brain size.Results. The volume of the left hippocampus was significantly smaller in the patients compared with the controls. Both groups exhibited similar significant hippocampal asymmetry (left smaller than right). The patients, but not the controls, had significant asymmetry of the amygdalar volumes (right smaller than left). No differences were observed between the patients and controls in the T2 relaxation times for the hippocampus and amygdala. Mesial temporal lobe MRS revealed a significantly elevated choline/creatine ratio in the patients compared with the controls.Conclusions. This quantitative MRI study provides support for a possible association between structural and biochemical substrates and severe drug-resistant major depression.

To compare antepartum ultrasonography with magnetic resonance imaging for prenatal diagnosis of malformations in the fetal urinary tract in high risk patients during the last trimester.The study involved 22 women and 24 fetuses with either severe oligohydramnios or ultrasonographically or clinically suspected abnormality of urinary tract. Ultrasound examination was carried out with 5 MHz abdominal convex probe and magnetic resonance imaging with superconductive 1.5 T equipment. Postnatal findings were used as reference.Correct diagnosis of urinary tract anomaly was done in 15 fetuses on ultrasound and in 20 fetuses on magnetic resonance imaging. Both methods enabled correct diagnosis in 12, only ultrasound in three and only magnetic resonance imaging in eight fetuses. Both methods imaged equivocally in one case. The additional information by magnetic resonance imaging was gained from five fetuses out of 12 pregnancies with oligohydramnios and from three fetuses out of ten pregnancies with normal amount of amniotic fluid.MRI is a valuable additional method to ultrasonography of fetal urinary tract if resolution of ultrasound is impaired for reason of oligohydramnios or technical deterioration.

Background. Double reading is a widely used criterion standard in breast cancer screening despite a lack of evidence of the cost‐effectiveness of the second reading. This study evaluates the incremental cost‐effectiveness of such a strategy. Design. Cost‐effectiveness analysis: Nationwide population‐based semi‐annual screening program for women aged 50–59 in Finland. Participation rate was 91%. All mammograms (95,423) performed during 1990–1995 in three screening centers of the Finnish Cancer Society were read by two radiologists with gradings recorded. The effectiveness of the double reading was the difference in cancers detected in the double compared to that of the single reading. Incremental costs of the double reading for the health care and non‐health care and the time costs were estimated. The main outcome measure was the incremental cost per additional cancer found as a result of the double‐reading strategy. Results. The total number of cancers detected with the double and single reading were 290 and 261, respectively. A significantly higher ratio of carcinoma in situ was the causative pathology in cancers detected only by the second reader. The cost per cancer detected with a single reading was US$ 18,340. The incremental cost of any additional cancer found was US$ 25,523, that is, a 39% higher cost per additional cancer found by double reading. Conclusions. The additional cost per cancer detected by double reading is not drastically higher than with single reading. However, the additional cost per life year saved may be much higher.

The amygdala complex is one component of the temporal lobe that may be damaged unilaterally or bilaterally in children and adults with temporal lobe epilepsy (TLE) or following status epilepticus. Most MR (magnetic resonance) imaging studies of epileptic patients have shown that volume reduction of the amygdala ranges from 10-30%. In the human amygdala, neuronal loss and gliosis have been reported in the lateral and basal nuclei. Studies in rats have more specifically identified the amygdaloid regions that are sensitive to status epilepticus-induced neuronal damage. These areas include the medial division of the lateral nucleus, the parvicellular division of the basal nucleus, the accessory basal nucleus, the posterior cortical nucleus, and portions of the anterior cortical and medial nuclei. Otherwise, other amygdala nuclei, such as the magnocellular and intermediate divisions of the basal nucleus and the central nucleus, remain relatively well preserved. Amygdala kindling studies in rats have shown that the density of a subpopulation of GABAergic inhibitory neurons that also contain somatostatin may be reduced even after a low number of generalized seizures. While analyses of histological sections and MR images indicate that in approximately 10% of TLE patients, seizure-induced damage is isolated to the amygdala, more often amygdala damage is combined with damage to the hippocampus and/or other brain areas. Moreover, recent data from rodents and nonhuman primates suggest that structural and functional alterations caused by seizure activity originating in the amygdala are not limited to the amygdala itself, but may also affect other temporal lobe structures. The information gathered so far on damage to the amygdala in epilepsy or after status epilepticus suggests that local alterations in inhibitory circuitries may contribute to a lowered seizure threshold and greater excitability within the amygdala. Furthermore, damage to select nuclei in the amygdala may predict impairment of performance in behavioral tasks that depend on the integrity of the amygdaloid circuits.

We evaluated the long-term outcome of farmer's lung (FL) patients and matched control farmers using high-resolution computed tomography (HRCT). The study population consisted of 88 FL patients and 83 control farmers, matched by age, sex, and smoking habits. The mean time after the first diagnosed episode of FL was 14 yr. The great majority, 82%, of the studied subjects were nonsmokers. Clinical studies included HRCT, spirometry, and pulmonary diffusing capacity. Emphysema was found significantly more often (23%) in FL patients than in control farmers (7%) (p = 0.006). The presence of emphysema was 18% in nonsmoking and 44% in smoking FL patients, the respective values being 4% and 20% in control farmers. Patients with recurrent attacks of FL tended to have emphysema more often (p = 0. 08) than patients who had experienced only a single attack. Fibrosis was observed in 17% of the FL patients and in 10% of the control farmers (p = 0.2). Miliary changes were found in 12% of the FL patients compared with 4% of the control farmers (p = 0.07). Both emphysematous and fibrotic but not miliary changes correlated significantly with impaired pulmonary function. In conclusion, farmer's lung disease seems to be associated with an increased risk of developing emphysema.

To investigate whether recurrent seizures cause hippocampal damage in temporal lobe epilepsy (TLE).Eighteen patients with newly diagnosed cryptogenic TLE, 14 patients with chronic well-controlled cryptogenic TLE, 32 patients with chronic drug-resistant cryptogenic TLE, and 25 healthy subjects were studied.Hippocampal MRI volumetry and T2 relaxometry were used.Chronic drug-resistant patients with seizure focus in the left temporal lobe had an 18% smaller left hippocampus and chronic drug-resistant patients with seizure focus in the right temporal lobe had a 14% smaller right hippocampus than did the control group (p0.05). Chronic drug-resistant patients with seizure focus on the left side had longer T2 relaxation times in the body of the left hippocampus than did the control group (p0.001) and chronic drug-resistant patients with seizure focus on the right side had longer T2 relaxation times in the body of the right hippocampus than did the control subjects (p0.01). In all patients with a left seizure focus, the left hippocampal volume correlated inversely with the estimated total number of partial (r = -0.391, p0.01) or generalized (r = -0.312, p0.05) seizures the patient had experienced. The prolongation of the left T2 relaxation time in the body of the hippocampus correlated with the total number of both partial (r = 0.670, p0.001) and generalized (r = 0.481, p0.001) seizures and with the duration of TLE symptoms (r = 0.580, p0.001).In patients with cryptogenic epilepsy, recurrent seizures may cause damage to the hippocampus throughout the lifetime of the patient.

Antepartum diagnosis of placenta accreta on the scarred myometrium of the isthmus uteri after previous cesarean section was made in 2 pregnancies. Antepartum sonographic examination revealed abnormal bulging of placental tissue toward the bladder cavity and arcuate arteries within the bladder wall. Magnetic resonance imaging revealed the depth and extent of placental invasion into the myometrium of the isthmus and the bladder muscular layer. Low-resistance pulsatile intervillous flow was recorded within the placenta in 1 case. Both magnetic resonance imaging and contrast-enhanced color Doppler sonography were informative in the other of these cases, in which the patient was conservatively managed during pregnancy and after delivery. © 1998 John Wiley & Sons, Inc. J Clin Ultrasound26: 90–94, 1998.

We measured the volumes of the entorhinal, perirhinal, and temporopolar cortices on magnetic resonance images by using a recently designed histology-based protocol in 30 patients with early Alzheimer's disease (AD) and 32 healthy control subjects. Compared to the controls, all of these cortical regions were significantly atrophied in AD patients (p < 0.0001). However, the entorhinal cortex was the most severely involved brain region studied, with 40% volume loss, and this region provided the highest discriminative accuracy (92%) in separating patients with AD from healthy control subjects. Importantly, the entorhinal volume loss was evident already in mild AD. In addition, the volume of the entorhinal cortex was not dependent on age, but it did correlate significantly with the severity of the disease. Because it assesses the major site of initial neuropathological changes in AD, magnetic resonance imaging volumetric measurement of the entorhinal cortex can offer a tool for distinguishing AD patients even in the very early stages of the disease from healthy aged subjects.

In this study, magnetic resonance imaging (MRI) of the hippocampus for the diagnosis of early Alzheimer's disease (AD) is evaluated. We measured hippocampal volumes and the area of the medial hippocampus with a 1.5 T MR imager in 160 subjects: 55 patients with probable AD according to the NINCDS-ADRDA criteria, 43 subjects fulfilling the NIMH criteria of age-associated memory impairment (AAMI), 42 cognitively normal elderly controls, and 20 controls younger than 50 years. Three methods for normalization were compared. The hippocampi were atrophied in the AD patients, but not in the AAMI subjects or the elderly controls. There was no significant correlation between hippocampal volumes and age in the nondemented subjects. The discrimination based on volumetry resulted in an overall correct classification of 92% of AD patients vs. nondemented elderly subjects, whereas discrimination based on hippocampal area was less accurate, producing a correct classification in 80% of the subjects. We conclude that the hippocampus as assessed by MRI volumetry is atrophied early in AD, and spared by aging or AAMI. A brief critical review of previous studies is in concordance with the presented data: all the previous studies that have used volumetry, have similarly ended up with a good classification, whereas simpler or subjective measurements, subject to various sources of bias, have produced most variable results.

Little is known about the appearance and severity of amygdaloid damage in temporal lobe epilepsy, particularly in its early stages. In the present magnetic resonance imaging study, we measured amygdaloid volumes and T2 relaxation times in 29 patients with newly diagnosed and in 54 patients with chronic temporal lobe epilepsy. The control population included 25 normal subjects. In the newly diagnosed patients, the mean amygdaloid volume did not differ from that in controls. Also, in the chronic patients the mean amygdaloid volume did not differ from that in controls or in newly diagnosed patients. However, in 19% of the chronic patients the amygdaloid volume was reduced by at least 20%. Moreover, in all of the epilepsy patients, both chronic and newly diagnosed, we found an inverse correlation between the number of epileptic seizures the patient had experienced and the amygdaloid volume on the focal side (focus on the left, r = -0.371, P0.01; focus on the right, r = -0.348, P0.05). The mean T2 relaxation time in newly diagnosed or chronic patients did not differ from each other or from control values. However, the T2 relaxation time of the left amygdala wasor = 111 msec (i.e.,or = 2 S.D. over the mean T2 time of the left amygdala in control subjects) in seven (10%) patients, one of which was newly diagnosed and six were chronic. The T2 time of the right amygdala was prolonged in eight (12%) patients, three of which were newly diagnosed and five were chronic. We did not find any clear asymmetries in amygdaloid volumes or T2 relaxation times between the ipsilateral and contralateral sides relative to seizure focus. According to the present findings, signs of amygdaloid damage were observed in approximately 20% of patients with temporal lobe epilepsy, most of which had chronic epilepsy.

Background and material. In order to evaluate cerebral blood flow changes associated with fetal intracranial hemorrhages, ultrasound and MRI examinations were carried out in four pregnancies with this complication. Results. Increased resistance indices of the blood flow profile of the middle cerebral artery were detected in three of the fetuses, two of them presenting retrograde diastolic flow. Flow became normalized in one case within four weeks, changing on the contralateral side to an increased diastolic flow pattern. Conclusion. Increased intracranial pressure can cause these flow changes, but cerebral blood flow autoregulation need not be completely ruined in this complication.

To determine the long-term outcome of 12 youthful patients with lumbar disc herniation, who, at the time of surgery, were 15 years old or younger (mean age at operation 14.3 years), we assessed their current clinical condition (mean follow-up time 6 years) with a questionnaire inquiring about symptoms and disability, and radiologically with an MRI of the lumbar spine. Clinically, only five patients (40%) were totally asymptomatic and seven patients (60%) had recurring symptoms, both pain and disability. On MRI, seven patients (60%) had persistent stenosing changes at the operated disc levels and eight patients (65%) also had disc degeneration at other lumbar levels. Despite the symptoms and quite severe radiological findings, the long-term outcome was assessed as good or moderate in eleven patients (90%). As far as comparisons are reasonable, our results appear somewhat less favourable than those in two previous paediatric series, but they agree with those in two recent large series of adults.

Objectives:To examine the interobserver variability in measuring the abdominal aorta by ultrasound (US) and computed tomography (CT).Design:A prospective clinical study in a university hospital.Materials:Thirty-three patients whose abdominal aortas were scanned both with CT and US as a part of aneurysm investigation or for a variety of other reasons.Methods:Three radiologists measured abdominal aortic diameters by US and CT. The interobserver differences (IOD) in US and CT and intraobserver differences for CT-US-pairs were analysed by various statistical methods. A new concept of “clinically acceptable difference” (CAD) was adopted denoting differences of less than 5mm.Results:The IOD in US was 2mm or less in 65% of the anteroposterior and 61% of the transverse measurements and 5mm or more in 11% of the anteroposterior and 14% in the transverse measurements in 102 observer pairs for all aortas. The IODs were significantly larger in measuring the aneurysmal aortas compared with normal aortas (p < 0.001). The CAD-value for the aneurysmal aortas was 84% in the anteroposterior and 82% in the transverse directions. In CT the IODs were 2mm or less in 62% of the anteroposterior and 66% of the transverse measurements and 5mm or more in 12% of both anteroposterior and transverse measurements in 94 observer pairs for all aortas. The CAD-value in the aneurysmal aortas was 91% in the anteroposterior and 85% in the transverse directions. There was no significant difference between the US and CT CAD-levels. The absolute CT-US difference of an individual observer was 2mm or less in 54%, 5mm or more in 17% and 10mm or more in 2% of the anteroposterior measurements in the 95 CT-US pairs. In the transverse direction the corresponding figures were: 2mm or less in 63%, 5mm or more 13% and 10mm or more in 2% of the pairs. The diameters obtained by US were smaller in 84% of the cases compared with those of CT in measuring the maximum aortic diameter in anteroposterior direction, whereas the same figure for the transverse measurements was 59%.Conclusions:Both US and CT measurements are subject to significant interobserver variability that must be taken into account in the clinical follow-up of small abdominal aortic aneurysms and in screening studies. Neither of these methods can be considered as a ‘gold standard’.

A prolonged MR T 2 relaxation time was proposed to mark the presence and severity of Alzheimer's disease (AD). We studied the value of T 2 relaxometry in diagnosing early AD. T 2 was measured from 54 patients with AD, 25 subjects with age-associated memory impairment (AAMI), 18 elderly and 16 young controls. The AD patients had longer T 2 in the right hippocampal head (104 ± 11 ms) and tail (98 ± 10 ms) than age-matched controls (95 ± 5 and 92 ± 9 ms, respectively). This prolongation was not related to age. In the AD group, the T 2 of the left hippocampal head also correlated with the clinical severity. The T 2 of the amygdala did not differ across the groups. Increased T 2 in the temporal and parietal white matter and the thalamus related to increasing age rather than to the diagnostic category. The AAMI subjects had T 2 comparable with those of age-matched controls. Despite the prolongation of T 2 in the AD group the possible diagnostic value was compromized by a substantial overlap between the study groups. We, thus, conclude that the T 2 relaxometry is not a reliable method for diagnosing early AD.

We analyzed hippocampal volumes and T sub 2 relaxation times by MRI from 78 control subjects, 24 patients with temporal lobe epilepsy, and 55 patients with Alzheimer's disease (AD).In the epilepsy group, the hippocampal volumes were 27% smaller than in control subjects (p < 0.001). The T2 relaxation times were prolonged (8 to 20 ms compared with control subjects) in the head, body, and tail portions of the hippocampus on the focal side (p < 0.01) and also on the contralateral side (p < 0.05) compared with control subjects. In the epilepsy group, the prolongation of T2 relaxation time correlated inversely with the hippocampal volume (p < 0.05). In the AD group, the hippocampal volumes were 35% smaller than in control subjects (p < 0.01). The T2 relaxation times were slightly prolonged (5 to 6 ms) in the head and tail portions of the right hippocampus (p < 0.01), but the T2 relaxation times did not correlate with the hippocampal volumes. These data show that the degree of prolongation of T2 relaxation time is associated with severity of hippocampal atrophy in temporal lobe epilepsy but not in AD.NEUROLOGY 1996;46: 1724-1730

Hippocampal atrophy detected by volumetric MRI is a sensitive feature of early Alzheimer's disease (AD), but there are no studies evaluating hippocampal atrophy by MR volumetry in other dementing diseases. We therefore compared hippocampal volumes in a total of 113 subjects: 50 patients with mild to moderate AD, 9 patients with vascular dementia (VaD), 12 patients with idiopathic Parkinson's disease (PD) without dementia, 8 patients with PD and dementia (PDD), and 34 elderly control subjects. Thin, coronal, contiguous images were obtained by a 1.5-T MR imager. All patient groups had significantly smaller volumes of the hippocampus compared with the control group. In the PDD group, the absolute volumes were even smaller than in the AD group. In the PD group, the volumes were diminished to a lesser but significant extent. The volumes in the VaD group varied: of nine patients, two had no atrophy, three had unilateral, and four had bilateral atrophy. We postulate that hippocampal atrophy does not seem to be a specific phenomenon of dementia in AD but also occurs in VaD and PDD, and even in PD when no dementia is present. However, coexistence of AD pathology in our PD and VaD patients cannot be ruled out. Further studies with access to neuropathologic data are needed.

To evaluate the frequency of subclinical cerebral complications of carotid endarterectomy, 19 patients were studied before and 1 month after surgery. Significant neurological complications were detected only in 1 patient (5%), while neuropsychological deterioration was found in 12 patients (63%) as compared to 5 (29%) of 17 control subjects undergoing other vascular surgery procedures (p < 0.05). MRI detected new cerebral lesions in 3 (16%) patients, who also showed a decline in cerebral perfusion reserve in the peri-infarct area as assessed by acetazolamide-enhanced SPET. Global cerebral perfusion reserve declined in three patients. Quantitative EEG did not reveal deterioration in any patients. The possible prognostic significance of these sublinical complications should be defined.

To evaluate the frequency of subclinical cerebral complications of carotid endarterectomy, 19 patients were studied before and 1 month after surgery. Significant neurological complications were detected only in 1 patient (5%), while neuropsychological deterioration was found in 12 patients (63%) as compared to 5 (29%) of 17 control subjects undergoing other vascular surgery procedures (p < 0.05). MRI detected new cerebral lesions in 3 (16%) patients, who also showed a decline in cerebral perfusion reserve in the peri-infarct area as assessed by acetazolamide-enhanced SPET. Global cerebral perfusion reserve declined in three patients. Quantitative EEG did not reveal deterioration in any patients. The possible prognostic significance of these sublinical complications should be defined.