Preoperative (neoadjuvant) systemic treatment of breast cancer

Preoperative systemic treatment (PST) is a valid option not only for advanced breast cancer stages but also for operable breast cancer. We know that disease-free and overall survival after PST are equivalent to those after adjuvant therapy. Furthermore, PST is able to improve surgical treatment by increasing the rate of breast conservation surgery, which minimises psychological distress for patients fearing mastectomy. Response to PST is a predictor of long-term outcome and gives prognostic information after a short-term interval in contrast to adjuvant trials, which do not show their results until after a 5- to 10-year follow-up. More often, endocrine non-responsive tumours demonstrate a pathological complete response (pCR). Thus, PST can change the formerly bad prognostic marker into one that indicates a favourable prognosis if pCR is achieved by PST. If PST is performed outside clinical trials, anthracycline/taxane-based regimens should be used, especially in sequential prolonged schedules. The use of aromatase inhibitors in preoperative endocrine therapy in elderly postmenopausal patients with endocrine-responsive breast cancer yields a larger proportion of local response than tamoxifen. The duration of PST is not well established, but at least four cycles of chemotherapy should be administered and endocrine therapy needs a minimal time to show greatest benefit when given for at least 3-4 months . The concurrent use of chemotherapy and endocrine drugs did not show any benefit, even in endocrine-responsive tumours and should therefore be avoided. Sentinel node biopsy is a reasonable approach, but this technique should be reserved for experienced surgeons. PCR is the most important surrogate marker of PST, demonstrating an improved disease-free and overall survival. But even if pCR of the primary tumour is achieved, the detection of lymph node metastases is the most important prognostic factor, indicating a substantial risk of cancer recurrence. PST will lead to individualised (tailored) treatment in patients with primary breast cancer.     

Heat shock protein 60 is released in immune-mediated glomerulonephritis and aggravates disease: in vivo evidence for an immunologic danger signal

Heat shock proteins (Hsp) are ubiquitous intracellular proteins that can be released in various forms of cellular stress. Some Hsp, such as Hsp60, have been shown to stimulate directly T cell-mediated immune responses in vitro. Here, it is demonstrated that Hsp60 is released from the kidneys and excreted into the urine of mice with nephrotoxic nephritis (NTN), a model of rapidly progressive glomerulonephritis. For examining the functional relevance of Hsp60 release, this protein was injected into mice with subnephritogenic NTN, in which only transient proteinuria and minimal organ damage occur that do not progress to terminal kidney failure. Injection of Hsp60 strikingly aggravated disease, as evidenced by global glomerular necrosis, tubulointerstitial damage, and complete anuria after 10 to 12 d. This effect was mediated neither by endotoxin contaminations of Hsp60 nor by autologous antibodies. It was strictly T cell dependent but not associated with a systemic Th1/Th2 shift. Thus, Hsp60 is an endogenous mediator stimulating immune effector mechanisms that contribute to the progression of NTN. These findings demonstrate in vivo that Hsp60 fulfills criteria of immunologic danger signals and suggest that such signals may be involved in immune-mediated kidney disease.     

On the substrate specificity of the digitoxigenin monodigitoxoside conjugating UDP-glucuronyltransferase in rat liver

The aim of the present study was to investigate the specificity of the UDP-glucuronosyltransferase (EC 2.4.1.17) involved in the conjugation of digitoxigenin monodigitoxoside. By in vitro assays with detergent activated liver musomes it was found that (1) digitoxigenin monodigitoxoside is by far the best substrate of all cardenolides and cardenolide digitoxosides tested. (2) In the presence of saturating UDP-glucuronate concentrations an apparent K_m of 5.8 μM was obtained from linear Lineweaver-Burk plots together with a V_max of about 150 pmoles/mg musomal protein/min. (3) Neither phenobarbital nor polycyclic aromatic hydrocarbons caused a considerable induction of the enzyme without change of the apparent K_m, but spironolactone did. (4) The conjugation of the substrate (4 μM) could only be inhibited by the 3'-epi-digitoxoside of digitoxigenin. (5) 25–50 μM substrate inhibited only the conjugation of the 3'-epimer and that of digoxigenin monodigitoxoside. It is suggested that there is a form of glucuronyltransferase which specifically conjugates digitoxigenin monodigitoxoside.     

Tumor necrosis factor receptor 1 and 2 proteins are differentially regulated during Wallerian degeneration of mouse sciatic nerve

The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF) is involved in injury-induced peripheral nerve pathology and in the generation of neuropathic pain. Here, we investigated local protein levels of the two known TNF receptors, TNF receptor 1 and 2 (TNFR1, TNFR2), on days 0, 1, 3, 7, 14, and 28 after unilateral crush or chronic constriction injury (CCI) of mouse sciatic nerves using enzyme-linked immunoassay. Both receptors were detectable at a low level in nerve homogenates from naive mice. After crush or CCI, TNFR1 increased by 2-fold on days 3 and day 7. Unlike TNFR1, TNFR2 was markedly upregulated already on day 1 after crush or CCI. TNFR2 increased by 7-fold on days 3 and 7, and remained elevated at a lower level until day 28 after both CCI and crush injury. These data indicate that endoneurial TNFR1 and TNFR2 proteins are differentially regulated during Wallerian degeneration.     

Imaging of macrophages in soft-tissue infection in rats: relationship between ultrasmall superparamagnetic iron oxide dose and MR signal characteristics

PURPOSE: To describe dose-dependent signal intensity (SI) characteristics of experimentally induced soft-tissue abscesses on 1.5-T T1- and T2*-weighted magnetic resonance (MR) images obtained 24 hours after administration of ultrasmall superparamagnetic iron oxide (USPIO) and to describe the relationship between SI and amount of USPIO uptake and macrophage iron content. MATERIALS AND METHODS: Local institutional review committee on animal care approved the experiments, which were performed according to the guidelines of the National Institutes of Health and the committee on animal research at our institution. Unilateral calf muscle abscesses were induced in 21 rats with an injection of a Staphylococcus aureus suspension. The rats were divided into three groups of seven animals each: low USPIO dose (50 micromol of iron per kilogram of body weight), high USPIO dose (150 micromol Fe/kg), and control (saline solution). All rats were imaged before and 24 hours after USPIO administration at 1.5 T (transverse T1-weighted spin-echo, T2*-weighted fast gradient-echo, and short inversion time inversion-recovery sequences). Images were analyzed quantitatively and qualitatively with regard to SI and signal pattern. Temporal variation of calculated contrast-to-noise ratios was analyzed with the Wilcoxon signed rank test. MR findings were correlated with histopathologic findings, including those of electron microscopy. RESULTS: Twenty-four hours after USPIO administration in the high-dose group, susceptibility effects were present in abscess periphery on postcontrast T2*-weighted images (P=.04), and SI enhancement was noted on postcontrast T1-weighted images within both abscess wall and abscess center (P=.04 for both). In the low-dose group, SI enhancement was noted in entire abscess on T1-weighted postcontrast images (P=.03). Neither significant SI loss (P=.09) nor susceptibility effects were detected in periphery or center of any abscess on postcontrast T2*-weighted images. There was no obvious difference in total amount of macrophages among the groups, but there was a clear difference with regard to individual iron content of iron-positive macrophages between the USPIO dose groups. CONCLUSION: At 1.5 T, SI characteristics of abscesses on T1- and T2*-weighted images obtained 24 hours after USPIO injection strongly depend on administered dose of the contrast agent. At low doses, T1 effects were stronger than T2* effects.     

A novel flexible, retrievable endovascular stent system for small-vessel anatomy: preliminary in vivo data

BACKGROUND AND PURPOSE: This study assessed the in vivo delivery, retrievability, short-term patency, and cellular response to a new flexible endovascular stent system in a rabbit model. The stent is designed for delivery through a microcatheter and is fully retrievable with electrolytic detachment from a delivery wire. METHODS: We successfully deployed nine stents (range of sizes, 2.5-4 mm diameter, 15-35 mm length) in six straight (carotid) and three angled (subclavian) arteries of six Chinchilla Bastard rabbits. Serial imaging was performed by using intravenous digital subtraction angiography (IVDSA), contrast-enhanced MR angiography (CEMRA), time-of-flight MR angiography (TOF), and CT-angiography 3 days and 4 weeks after stent deployment. Subjects were euthenized after 4 weeks (n = 5), and stents were removed for histologic analysis. RESULTS: Stent deployment was feasible in all cases. After initial deployment, all stents could be fully retrieved within the microcatheter. The detachment zone and the distal stent marker were easily visible under fluoroscopy, and final detachment occurred reliably in all cases. We observed no procedural complications. Noninvasive imaging by using IVDSA, MR angiography, and CT angiography was feasible in this stent system and demonstrated all arteries patent and not narrowed at 3 days and 4 weeks, findings that were confirmed by histologic analysis. CONCLUSION: This electrolytically detachable stent is promising as a treatment for intracranial arteries, because it can be delivered through microcatheters small enough for intracranial navigation. It is fully retrievable, thus providing greater control than currently available stents. Noninvasive imaging by using IVDSA, MR angiography, and CT angiography is feasible in this stent system and may be useful for follow-up. Further long-term data are needed.     

Introduction of transperitoneal lymphadenectomy in a gynecologic oncology center: analysis of 650 laparoscopic pelvic and/or paraaortic transperitoneal lymphadenectomies

OBJECTIVE: Lymphadenectomy is an integral part of staging and treatment of gynecologic malignancies. We evaluated the feasibility and oncologic value of laparoscopic transperitoneal pelvic and paraaortic lymphadenectomy in correlation to complication rate and body mass index. METHODS: Between August 1994 and September 2003, pelvic and/or paraaortic transperitoneal laparoscopic lymphadenectomy was performed in 650 patients at the Department of Gynecology of the Friedrich-Schiller University of Jena. Retrospective and prospective data collection and evaluation of videotapes were possible in 606 patients. Laparoscopic lymphadenectomy was part of the following surgical procedures: staging laparoscopy in patients with advanced cervical cancer (n = 133) or early ovarian cancer (n = 44), trachelectomy in patients with early cervical cancer (n = 42), laparoscopic-assisted radical vaginal hysterectomy in patients with cervical cancer (n = 221), laparoscopy before exenteration in patients with pelvic recurrence (n = 20), laparoscopic-assisted vaginal hysterectomy or laparoscopic-assisted radical vaginal hysterectomy in patients with endometrial cancer (n = 112), and operative procedures for other indications (n = 34). RESULTS: After a learning period of approximately 20 procedures, a constant number of pelvic lymph nodes (16.9-21.9) was removed over the years. Pelvic lymphadenectomy took 28 min, and parametric lymphadenectomy took 18 min for each side. The number of removed paraaortic lymph nodes increased continuously over the years from 5.5 to 18.5. Right-sided paraaortic, left-sided inframesenteric and left-sided infrarenal lymphadenectomy took an average of 36, 28, and 62 min, respectively. The number of removed lymph nodes was independent from the body mass index of the patient. Duration of pelvic lymphadenectomy was independent of body mass index, but right-sided paraaortic lymphadenectomy lasted significantly longer in obese women (35 vs. 41 min, P = 0,011). The overall complication rate was 8.7% with 2.9% intraoperative (vessel or bowel injury) and 5.8% postoperative complications. No major intraoperative complication was encountered during the last 5 years of the study. CONCLUSION: By transperitoneal laparoscopic lymphadenectomy, an adequate number of lymph nodes can be removed in an adequate time and independent from body mass index. The complication rate is low and can be minimized by standardization of the procedure.     

The laryngeal mask airway Unique versus the Soft Seal laryngeal mask: a randomized, crossover study in paralyzed, anesthetized patients

We tested the hypothesis that ease of insertion, oropharyngeal leak pressure, fiberoptic position, ease of ventilation, and mucosal trauma are different for the Soft Seal laryngeal mask airway (SSLM) and the laryngeal mask airway Unique (LMA-U). Ninety paralyzed, anesthetized adult patients (ASA I-II; 18-80 yr old) were studied. Both devices were inserted into each patient in random order. Oropharyngeal leak pressure and fiberoptic position were determined during cuff inflation from 0-40 mL in 10-mL increments and at an intracuff pressure of 60 cm H(2)O. Ease of ventilation was determined by controlling ventilation for 10 min at 8 and 12-mL/kg tidal volume and recording hemoglobin oxygen saturation, end-tidal CO(2), leak fraction, peak airway pressure, and the presence or absence of gastric insufflation. Mucosal trauma was determined by examining the first randomized device for the presence of visible and occult blood. Insertion time was shorter (P = 0.0001) and fewer attempts were required (P = 0.005) for the LMA-U. There were no failed uses of either device. Oropharyngeal leak pressures were similar, but fiberoptic position was superior with the LMA-U (P < or = 0.0003). There were no differences in hemoglobin oxygen saturation, end-tidal CO(2), leak fraction, or peak airway pressure at either tidal volume. Gastric insufflation was not detected in either group at either tidal volume. The frequency of visible (P = 0.009) and occult blood (P = 0.0001) was less with the LMA-U. We conclude that the LMA-U is superior to the SSLM in terms of ease of insertion, fiberoptic position, and mucosal trauma, but similar in terms of oropharyngeal leak pressure and ease of ventilation.