Positive pivot shift after ACL reconstruction predicts later osteoarthrosis: 63 patients followed 5-9 years after surgery.

BACKGROUND: Rupture of the anterior cruciate ligament (ACL) may cause osteoarthrosis (OA) and functional impairment. We wanted to find out whether the degree of knee stability obtained after ACL reconstruction correlates with radiographic and clinical outcome. PATIENTS AND METHODS: We examined 63 patients 2 and 5-9 years after anterior cruciate ligament (ACL) reconstruction. Knee stability was assessed 2 years after surgery by recording AP laxity using radiostereometric technique (RSA) and by performing the pivot shift test. Degeneration of the knee joint was evaluated with bone scintigraphy, and radiographically. Functional outcome was assessed with Lysholm score, Tegner activity scale and with the one-leg hop test. RESULTS: Radiographic signs of osteoarthrosis at the most recent follow-up (5-9 years) did not correlate with knee stability. Patients with positive pivot shift test 2 years after surgery showed increased scintigraphic activity of the subchondral bone at the most recent follow-up, and inferior subjective functional outcome 2 years after surgery. Knees having had meniscus resections had more often OA. Radiographical signs of OA were associated with higher scintigraphic uptake in the operated knee relative to the contralateral knee. INTERPRETATION: The ability to obliterate the pivoting by ACL reconstruction appears to be more important than normalizing the AP laxity in order to prevent later OA.

Visual consciousness: dissociating the neural correlates of perceptual transitions from sustained perception with fMRI.

To investigate the possible dichotomy between the neurophysiological bases of perceptual transitions versus sustaining a particular percept over time, an fMRI study was conducted with subjects viewing fragmented pictures. Unlike most other perceptually unstable stimuli, fragmented pictures give rise to only one perceptual transition and a continuous period of sustained perception. Earlier research is inconclusive on the subject of which anatomical regions should be attributed to what temporal aspect of perception, and the aim of the present study was to shed more light on the subject. In this study occipitotemporal and fronto-parietal regions were found to be activated for both aspects. However, regions in the medial-temporal lobe were activated specifically for transitions, whereas medial and dorsolateral prefrontal regions were activated specifically for sustained perception. These results provide further support for the theory that the initial creation of perceptual awareness and upholding perceptual awareness over time are separate processes involving different brain regions.

Combined low dose radio- and radioimmunotherapy of experimental HeLa Hep 2 tumours.

Radiation therapy of malignant tumours can be delivered by external beam radiation (RT) or radioimmunotherapy (RIT), using nuclides attached to monoclonal antibodies (mAbs). These treatment modalities have now been combined in order to investigate putative therapeutic advantages and elucidate the biological responses involved. Nude mice were transplanted subcutaneously on the back with human HeLa Hep2 tumour cells. RT (3x5 Gy) and/or 100 microg (131)I-labelled mAb H7, against placental alkaline phosphatase, or (131)I-labelled mAb TS1, against cytokeratin, was administered separately or in combination (specific activity of 120-200 MBq/mg antibody). Significant tumour growth retardation was observed both with RT alone and with RIT alone. Combining these regimens enhanced the therapeutic effects further, and a significant reduction in tumour volume could be demonstrated. The tumours were subjected to extensive histochemical and immunohistochemical investigations in order to elucidate changes in biology and histology within them. The following stainings were used: haematoxylin-eosin (morphology), Ki67 (proliferation), M30 (apoptosis), TUNEL (apoptosis) and endoglin (vascularisation). Tumours in the control group grew fast, with an average tumour doubling time of 9 days. These tumours contained large viable tumour cell masses displaying vast proliferation zones of Ki67-positive tumour cells, as well as necrotic regions and small amounts of connective tissue. Apoptotic cells could be identified both with M30 and TUNEL staining. When RT was applied, the growth rate was significantly reduced (doubling time 19 days) and typical alterations in morphology were seen, with a relative increase in connective tissue and a decrease in necrotic regions. Apoptotic cells were identified and a decrease in cell density was also observed. When RIT alone was applied, the growth parameters indicated a longer lasting growth reduction, especially when TS1 was used separately or in combination with H7. The histological appearances of these tumours were somewhat different from the RT-treated tumours, with a larger portion of intratumoural cysts. These tumours also presented a reduced tumour cell density. Dramatic effects were observed when RT was combined with RIT, with a pronounced growth reduction seen in all combination treatment groups. Pronounced tumour volume reduction was also evident in both the RT + RIT ((131)I-TS1) group and RT + RIT ((131)I-TS1/(131)I-H7) group, and in some animals no tumour remained at all. The morphology of the tumour remnants at day 22 was chaotic with a drastically changed histology, with presence of abundant cysts, low fractions of Ki67-positive cells, reduction in cell density, increased amounts of connective tissue and a decrease in necrotic regions. Again, apoptotic cells could be identified, scattered throughout the viable regions. Combining RT and RIT seems to generate an efficient treatment with convincing and long-lasting tumour growth inhibition, which is reflected in a highly aberrant histology within the tumour. Results obtained in this study indicate that both necrosis and apoptosis may be involved in the process leading to this efficient therapy of epithelially derived tumours.

Effects of interferon-alpha, verapamil and dacarbazine in the treatment of advanced malignant melanoma.

Treatment of patients with metastatic melanoma with either dacarbazine (DTIC) or interferon-alpha (IFNalpha) as single drugs, or in combination, results in a response rate of approximately 15-20%. This study evaluated the activity and toxicity following treatment with a combination of DTIC, IFNalpha2b and verapamil (VPL). Thirty patients with disseminated metastatic melanoma received DTIC 250 mg/m(2) on days 1-5 of a 4 week schedule, IFNalpha2b 3 MIU on days 1-5 each week, and VPL 80 mg three times a day throughout the cycle, until either disease progression or serious toxicity was observed. Among the 28 evaluable patients, there were four complete responses (CRs), five partial responses (PRs) and eight patients with stable disease (SD). The overall response rate (CR + PR) was 32%. Two patients with a CR were long-term survivors (45 and 34 months) and a third is still in complete remission after 49 months. The fourth CR patient relapsed and died with progressive brain metastases after 8 months. Among the eight patients with SD, one survived for 22 months and another for 34 months. Despite one toxic death, these results suggest that this treatment regimen is well tolerated and seems to be more effective than DTIC alone in a subset of patients. A controlled randomized study would be required to determine the value of adding VPL and IFNalpha2b to DTIC.

The combination of external beam radiotherapy and experimental radioimmunotargeting with a monoclonal anticytokeratin antibody.

BACKGROUND: Doses to tumors of up to 80 grays (Gy) have been postulated to eradicate solid experimental tumors with radiommunotargeting, but this value has proved difficult to reach. Combining two treatment modalities, external beam radiotherapy and radioimmunotargeting, could potentially give rise to a number of advantages. METHODS: The purpose of this study was to detect potential benefits with different treatment timing strategies when combining external beam radiotherapy and radioimmunotargeting, with the anticytokeratin monoclonal antibody (MAb) TS1 injected into a nude mouse model carrying subcutaneous human HeLa Hep 2-cell tumors. Cytokeratins are present in necrotic regions within tumors, thereby providing a potential increase in binding sites for TS1 if combined with external beam radiotherapy. External beam radiotherapy was given before, after, and simultaneously with injection of radiolabeled MAb. RESULTS: The highest yields in terms of total accumulated dose (Gy), percentage of injected activity per gram of tumor tissue, and accumulated dose per injected activity (Gy/MBq) were seen in the group receiving external beam radiotherapy prior to MAb-injection. CONCLUSIONS: Enhanced effects may be achievable by combining external beam radiotherapy with experimental radioimmunotargeting using the monoclonal anticytokeratin antibody TS1, if the radiotherapy is given prior to MAb injection.