T-cell depletion and graft survival induced by anti-human CD3 immunotoxins in human CD3epsilon transgenic mice

BACKGROUND: Anti-CD3 immunotoxins are broad-spectrum immunosuppressive agents in a wide range of organ transplantation animal models with potential use in eliciting antigen-specific tolerance. However, the anti-CD3 immunotoxins used in animal studies do not cross-react with human T cells, limiting extrapolation to humans and hindering clinical development. METHODS: Three anti-human CD3-directed immunotoxins, DT389-scFv(UCHT1), scFv(UCHT1)-PE38, and UCHT1-CRM9, were compared in vitro and in transgenic mice, tg(epsilon)600+/-, that have T cells expressing both human and murine CD3epsilon antigens. RESULTS: These immunotoxins were extraordinarily potent in vitro against human or transgenic mouse T cells, with IC50 values in cellular assays ranging from pM to fM. Systemic administration of these immunotoxins dose-dependently depleted >99% of tg(epsilon)600+/- lymph node and spleen T cells in vivo. Depletion was specific for T cells. The loss of the concanavalin A-induced, but not the lipopolysaccharide-induced, splenic proliferative response from immunotoxin-treated animals further demonstrated specific loss of T-cell function. Immunotoxin treatment prolonged fully allogeneic skin graft survival in tg(epsilon)600+/- recipients to 25 days from 10 days in untreated animals. T-cells recovered to approximately 50% of normal levels after approximately 22 days in animals with or without skin grafts; T-cell recovery correlated with skin graft rejection. All three immunotoxins elicited >100 day median survival of fully allogeneic heterotopic heart grafts. By 100 days, T cells recovered to normal numbers in these animals, but the grafts showed chronic rejection. CONCLUSION: These immunotoxins profoundly deplete T cells in vivo and effectively prolong allogeneic graft survival.     

High dose rate brachytherapy of localized prostate cancer

OBJECTIVE: We evaluated the safety and efficacy of high dose rate (HDR) brachytherapy using Iridium-192 (Ir 192) and 3D conformal external beam radiotherapy in patients with localized prostate cancer. METHODS: A total of 444 patients with localized prostate cancer underwent combined radiotherapy with interstitial Ir 192 and 3D conformal external beam radiotherapy between December 1992 and March 2001. The 230 patients, treated between December 1992 and December 1997 were analyzed. All patients underwent laparoscopic pelvic lymph node dissection to exclude patients with lymphatic involvement. Ir 192 was delivered twice with a 1-week interval in HDR remote control technique. The interstitial dose from December 1992 to December 1993 was 10Gy, after December 1993 the dose was reduced to 9Gy per treatment session. The interstitial application was followed by external beam radiation of 45Gy for cT1-cT2 and 50.4Gy for cT3 tumor (40Gy from December 1992 to December 1993). Progression was defined as biochemical failure according to ASTRO criteria, e.g. three consecutive PSA rises following the PSA nadir. RESULTS: The median PSA value decreased from 12.8 to 0.93ng/ml 12 months after treatment. Median PSA value was 0.47 after 24 months, 0.30ng/ml after 36 months and 0.18ng/ml after 60 months. 68% of the biopsies were negative 24 months after therapy. Progression-free rate was 100% for cT1 tumors, 75% for cT2 and 60% for stage-cT3 on 5-year follow-up. Five-year overall survival was 93%, 5-year disease-specific survival was 98%. Initial PSA value <10ng/ml, low stage and low grade were significantly related to 5-year progression-free survival. CONCLUSIONS: Combined HDR brachytherapy with Ir 192 is an alternative treatment option especially for patients with cT3 prostate cancer. Initial PSA value, stage and grade, are important prognostic factors.     

Brain death impairs coronary endothelial function

BACKGROUND: To characterize the impact of brain death (BD) on endothelial dysfunction after cardiac transplantation we investigated coronary circulation and vasomotor function in a canine model. METHODS: Left ventricular pressure-volume data (conductance catheter) and coronary blood flow (CBF) were monitored continuously. Endothelium-dependent vasodilatation after acetylcholine and endothelium-independent vasodilation after sodium nitroprusside were assessed before and 3 hr after BD induction (inflation of a subdural balloon). RESULTS: BD led to an initial hyperdynamic reaction with significant (P<0.05) increase of CBF. After 3 hr, CBF decreased significantly (P<0.05). Although before BD, application of acetylcholine led to a monophasic vasodilatative response, after BD a short mild vasodilatation was followed by a longer vasoconstriction. Endothelium-independent vasodilatation remained unchanged. CONCLUSIONS: BD affects coronary circulation by two means: (1) impairment of CBF to decrease in parallel in afterload with consecutive hemodynamic deterioration and (2) severe endothelial dysfunction that may be a contributing factor to posttransplant outcome.     

A comparison of the laryngeal tube with the laryngeal mask airway during routine surgical procedures

The laryngeal mask airway (LMA; Laryngeal Mask Company, Henley-on-Thames, UK) is an established airway device, whereas the laryngeal tube (LT) is relatively new and therefore not as well investigated. Therefore, the purpose of the present prospective, randomized, controlled trial was to compare the LT with the LMA in routine clinical practice. In 50 patients undergoing general anesthesia for minor routine surgery, standardized anesthesia was induced and maintained with alfentanil and propofol. Patients were randomized to controlled ventilation (fraction of inspired oxygen = 0.4; fraction of inspired nitrous oxide = 0.6; tidal volume = 7 mL/kg; respiratory rate = 10 breaths/min) with the LT (n = 25) or the LMA (n = 25). Oxygen saturation was recorded before the induction of anesthesia and after the administration of oxygen. After 2 and 10 min of ventilation with the LT or LMA, oxygen saturation, end-expiratory carbon dioxide, expiratory tidal volume, and peak airway pressure were recorded. Capillary blood gas samples were taken before the induction of anesthesia and after 10 min of ventilation. Time of insertion and airway leak pressure of each device were measured. The time of insertion was comparable with both devices (LT versus LMA, median 21 s versus 19 s; P = not significant). Blood gas samples and ventilation variables revealed sufficient ventilation and oxygenation with either device (P = not significant). Peak airway pressure (LT, 17 +/- 3 cm H(2)O; LMA, 15 +/- 3 cm H(2)O) and airway leak pressure (LT, 36 +/- 3 cm H(2)O; LMA, 22 +/- 3 cm H(2)O) were significantly (P < 0.05) higher when using the LT compared with the LMA. In conclusion, using the LT and LMA resulted in comparable ventilation and oxygenation variables in this model of ASA physical status I and II patients undergoing routine surgical procedures. The newly developed LT may be a simple alternative device to secure the airway. IMPLICATIONS: The laryngeal tube, a newly developed airway device, and the laryngeal mask airway were used to ventilate patients in the operating room. Both airway devices proved to be effective and safe; however, the laryngeal tube allowed greater airway pressure during ventilation.     

The frequency and clinical significance of congenital defects of the posterior and anterior arch of the atlas

OBJECT: In this study the authors investigated the anatomical, clinical, and imaging features as well as incidence of congenital defects of the C-1 arch. METHODS: The records of 1104 patients who presented with various medical problems during the time between January 2006 and December 2006 were reviewed retrospectively. The craniocervical computed tomography (CT) scans obtained in these patients were evaluated to define the incidence of congenital defects of the posterior arch of C-1. In addition, 166 dried C-1 specimens and 84 fresh human cadaveric cervical spine segments were evaluated for anomalies of the C-1 arch. RESULTS: Altogether, 40 anomalies (2.95%) were found in 1354 evaluated cases. Of the 1104 patients in whom CT scans were acquired, 37 (3.35%) had congenital defects of the posterior arch of the atlas. The incidence of each anomaly was as follows: Type A, 29 (2.6%); Type B, six (0.54%); and Type E, two (0.18%). There were no Type C or D defects. One patient (0.09%) had an anterior arch cleft. None of the reviewed patients had neurological deficits or required surgical intervention for their anomalies. Three cases of Type A posterior arch anomalies were present in the cadaveric specimens. CONCLUSIONS: Most congenital anomalies of the atlantal arch are found incidentally in asymptomatic patients. Congenital defects of the posterior arch are more common than defects of the anterior arch.     

T cell memory,anergy and immunotherapy in breast cancer

T cell immunity in breast cancer is suggested to play a role in tumor dormancy, a period of stability which can correspond to the time interval between primary treatment and tumor recurrence. Bone marrow in breast cancer patients seems to be particularly important because it is highly enriched with cancer specific memory T cells. Similar cells can be found in peripheral blood, but these appear to be functionally anergic. The immune system of primary operated breast cancer patients does not seem to be completely anergized. Bone marrow derived memory T cells can be reactivated ex vivo and show functional reactivity, including tumor rejection in NOD/SCID mice. Promising results were obtained from a postoperative phase-II active specific immunotherapy study. In this study, 32 patients treated with an optimal formulation of a virus-modified autologous tumor vaccine (ATV-NDV) appeared to have a significant 5-year survival benefit. Our results suggest that cancer reactive memory T cells which are enriched in the bone marrow of breast cancer patients, can be activated ex vivo via autologous dendritic cells pulsed with breast cancer tumor antigens, or they can be activated in situ via a tumor vaccine, which combines tumor antigens with virus infection. The findings should encourage further studies in breast cancer on active specific immunotherapy with tumor vaccines or adoptive immunotherapy with activated memory T cells.     

Acute paranoid psychosis as sole clinical presentation of hepatic artery thrombosis after living donor liver transplantation

Background  

Hepatic artery thrombosis is a devastating complication after orthotopic liver transplantation often requiring revascularization or re-transplantation. It is associated with considerably increased morbidity and mortality. Acute cognitive dysfunction such as delirium or acute psychosis may occur after major surgery and may be associated with the advent of surgical complications.     

Malfunction of a Heimlich flutter valve causing tension pneumothorax: case report of a rare complication

Background  

Thoracic injuries play an important role in major trauma patients due to their high incidence and critical relevance. A serious consequence of thoracic trauma is pneumothorax, a condition that quickly can become life-threatening and requires immediate treatment.     

Virtual placement of posterior C1-C2 transarticular screw fixation

We wanted to evaluate how often safe and effective posterior C1-C2 transarticular screw placement is realizable when it is performed according to guidelines given in the literature. In 50 adult patients, computerized tomography scan data from C0 to C3 were transformed into a 3D spine model. Virtually, bilateral screws were placed from the medial third of the C2-C3 facet joint towards the rim of the C1 anterior arc parallel to midline. Three categories of virtual screw position were rated: optimal (virtual screw inside the C2 pars interarticularis, transversing the middle third of the atlantoaxial joint, and sparing the vertebral artery canal), suboptimal (virtual screw violating the C2 pars interarticularis, and/or transversing the lower or upper third of the C1-C2 joint, and sparing vertebral artery canal), and unacceptable (virtual screw breaching the vertebral artery canal). Optimal placement was seen in 74, suboptimal placement in 11, and unacceptable locations in 15 sites. We conclude that due to the variability of the anatomy of the upper cervical spine, optimal transarticular C1-C2 screw placement is not possible in up to 26%, and even hazardous in up to 15%. This paper was presented in part at the Jahrestagung der Deutschen Gesellschaft für Neurochirurgie, May 25–28, 2003, Saarbrücken, Germany