Impact of several histopathological prognosticators and local tumour extension on oncological outcome in pT3b/c N0M0 renal cell carcinoma

OBJECTIVE

To investigate the prognostic relevance of different histopathological features and local tumour extension in patients with pT3b/c N0M0 renal cell carcinoma (RCC), as recently new proposals of reclassifying tumour fat invasion in pT3b/c RCC have been made but the effect of other histopathological tumour characteristics and combinations thereof with tumour invasion has yet to be determined in these patients.

PATIENTS AND METHODS

Between 1990 and 2006, 1943 patients underwent surgical treatment for renal tumours in our institution, of which 175 patients (8.7%) had pT3b/c RCC. After exclusion of 57 patients (32.6%) with lymph node and/or distant metastases at the time of diagnosis, 118 (67.4%) remained for retrospective analysis. Different histopathological features and local tumour extension were studied for their association with cancer‐specific‐survival (CSS) and progression‐free‐survival (PFS) by univariate and multivariate analyses. Histopathology was reviewed and revised according to the 2002 Tumour‐Nodes‐Metastasis (TNM) classification system by one pathologist (S.B.). CSS and PFS were estimated by the Kaplan–Meier method.

RESULTS

Follow‐up data were obtained from 110 patients at a median (range) of 3.2 (0.3–16.1) years. In univariate analysis, microvascular invasion (MVI) and capsular invasion increased the risk of tumour progression by 2.05‐ and 2.72‐times (P = 0.037 and P < 0.001). Overall, tumour fat invasion (TFI) and the presence of areas composed by cells with eosinophilic cytoplasm were associated with a higher risk of progression (P = 0.001 and P = 0.011) and reduced CSS (P = 0.037 and P = 0.017). In multivariate analysis, MVI and capsular invasion were associated with a two‐fold increased risk of dying from cancer (hazard risk ratio, HR 2.22, P = 0.045 and HR 2.31, P = 0.011). TFI in general (P = 0.004) and specifically coexistent perirenal fat invasion (PFI) and renal sinus fat invasion (RSFI) were associated with a three‐fold increased risk of developing tumour progression (HR 3.36, P = 0.001). The 10‐year CSS and PFS rates were 39% and 36% for all patients, 47% and 45% for pT3b/c RCC with no PFI or RSFI, and 25% and 10% for PFI + RSFI.

CONCLUSION

Patients with pT3b/c RCC with MVI, capsular invasion, TFI and especially PFI + RSFI, have a markedly reduced prognosis compared with patients with pT3b/c RCC without these features. When these results are corroborated by additional studies and external validation, modification of the TNM classification system would be a sensible consequence.     

Adjuvant therapy with recombinant interferon alfa-2a in metastasized malignant melanoma

Recombinant alpha-2a interferon (IFN alpha-2a; Roferon-A) was administered as adjuvant therapy in 21 patients with malignant melanoma stage IIa or IIb after surgical removal of all detectable metastases. Patients received 9 x 10(6) units of IFN alpha-2a s.c. 3 times weekly over 6 months. One patient was treated over 12 months. Relapses occurred in 5 of the 21 patients during therapy, and 10 patients developed new metastases a few weeks or months after the end of therapy. Of the 15 patients with recurrent disease, 9 have since died. One patient without any relapse died of a myocardial infarction 5 months after the start of therapy. Comparison of the 21 treated patients with an untreated historical matched control group did not show any prolongation of the recurrence-free period in the interferon-treated group.     

Comparison of prognostic usefulness (three years) of computed tomographic angiography versus 64-slice computed tomographic calcium scanner in subjects without significant coronary artery disease

Coronary computerized tomographic angiography (CTA) has been used as a noninvasive method for ruling out high-grade stenoses. Even in the absence of such stenoses, analysis of coronary atherosclerosis may provide for important prognostic information, and this may be superior to exclusive coronary artery calcium scoring. We tested this hypothesis in patients undergoing CTA for clinical indications who had no stenoses requiring revascularization. From December 2004 to December 2006, 706 consecutive patients who underwent CTA but had no high-grade stenoses were included (58% men, mean age 59 ± 11 years). CTA and coronary artery calcium scoring (Agatston method) were performed using a 64-slice CT scanner with a gantry rotation time of 330 ms. CT angiograms were categorized as completely normal (group 1), showing minor plaque (group 2), or showing intermediate stenoses (group 3). Follow-up information was obtained in 670 patients (95%) over a mean of 3.2 years. There were 31 major adverse events (5%), namely 9 deaths (all noncoronary), 2 myocardial infarctions, 5 strokes, 13 coronary revascularization procedures (percutaneous or surgical > 6 months after CTA), and 2 peripheral percutaneous interventions. Coronary status as defined by CTA was predictive of major events after adjustment for age and gender. In group 1, the probability of event-free survival at 3 years was 100%; in group 2, it was 96%; and in group 3, it was 91%. Compared to group 1, the risk in group 2 was increased 2.3-fold, and in group 3, it was increased 5.6-fold after adjusting for age and gender. However, after addition of the coronary artery calcium score to the regression analysis, CT angiographic status no longer appeared to be predictive. In conclusion, the risk of a major adverse cardiovascular event or death increased in a graded manner with degree of coronary atherosclerosis as defined by CTA even in the absence of high-grade coronary stenoses. However, in the absence of high-grade stenoses, we were unable to demonstrate a superior prognostic value of CTA compared to coronary artery calcium.     

TP53 and ovarian cancer

Ovarian cancer represents the fourth most frequent type of cancer among females and is the leading cause of death from gynecological cancer in the western world. This review describes gene alterations in ovarian cancer. Specific emphasis is placed on genetic alterations and the prevalence of TP53 (p53) gene alterations in the distinct biological ovarian tumors (benign, borderline, and malignant) and histological subtypes (serous, mucinous, endometrioid, clear cell), as well as in BRCA1-associated hereditary ovarian cancer. Although multi-modality treatment regimens, including cytoreductive surgery and cisplatin-containing combination chemotherapy, have usefully prolonged survival, the overall cure rate of the disease has not changed dramatically. Ovarian cancer is difficult to eradicate completely by surgery and many patients have only a partial response to postoperative chemotherapy and/or many will develop chemotherapy resistance. All these important factors contribute to the poor prognosis of ovarian cancer patients. In this review, the putative prognostic or predictive value of TP53 in ovarian cancer is addressed.     

Competition-based cellular peptide binding assays for 13 prevalent HLA class I alleles using fluorescein-labeled synthetic peptides

We report the development, validation, and application of competition-based peptide binding assays for 13 prevalent human leukocyte antigen (HLA) class I alleles. The assays are based on peptide binding to HLA molecules on living cells carrying the particular allele. Competition for binding between the test peptide of interest and a fluorescein-labeled HLA class I binding peptide is used as read out. The use of cell membrane-bound HLA class I molecules circumvents the need for laborious biochemical purification of these molecules in soluble form. Previously, we have applied this principle for HLA-A2 and HLA-A3. We now describe the assays for HLA-A1, HLA-A11, HLA-A24, HLA-A68, HLA-B7, HLA-B8, HLA-B14, HLA-B35, HLA-B60, HLA-B61, and HLA-B62. Together with HLA-A2 and HLA-A3, these alleles cover more than 95% of the Caucasian population. Several allele-specific parameters were determined for each assay. Using these assays, we identified novel HLA class I high-affinity binding peptides from HIVpol, p53, PRAME, and minor histocompatibility antigen HA-1. Thus these convenient and accurate peptide-binding assays will be useful for the identification of putative cytotoxic T lymphocyte epitopes presented on a diverse array of HLA class I molecules.     

An open,randomized single-centre study to compare the efficacy and convenience of follitropin beta administered by a pen device with follitropin alpha administered by a conventional syringe in women undergoing ovarian stimulation for IVF/ICSI

BACKGROUND: A pen device, similar to an insulin pen, has been recently marketed for the administration of follitropin beta in cartridges. A randomized controlled trial was performed to compare the efficacy and convenience of this pen device delivering follitropin beta with a conventional syringe delivering follitropin alpha. METHODS: A total of 200 patients needing IVF/ICSI treatment and willing to self-inject were enrolled in the study. All subjects had ovarian stimulation according to a long protocol and were randomized to the pen or the conventional syringe group during down-regulation by means of a computer-generated randomization list using random numbers. Patients were asked to fill in a daily local tolerance book after each injection. On the day of hCG the patients scored a Visual Analogue Scale (VAS) for pain and convenience. RESULTS: The average duration, total dose of recombinant FSH and number of cumulus oocyte complexes retrieved were 10.8/12.0 days (P = 0.001), 1880/2226 IU (P < 0.001) and 15.2/13.1 respectively in the pen device and conventional syringe groups; the presence of pain after the daily injection was significantly higher in the conventional syringe group (P = 0.027); the visual analogue scale score was similar for pain but significantly more convenient for the pen device (P < 0.001). The live birth rate per embryo transfer was 32.9 and 34.4% respectively in the pen device and conventional syringe groups. CONCLUSIONS: Self-injection with the pen device is safe and easy, more convenient and less painful for the patient, requires less FSH and shortens the treatment duration.     

Lectin histochemistry of the lymphoid organs of the chicken

Cellular interactions within the immune system are in part mediated via the carbohydrate-rich coat of the cell membrane, the glycocalyx, of which the terminal carbohydrate residues are of particular functional importance. Thus, these carbohydrate residues from thymus, bursa of Fabricius, spleen and bone marrow of 2- and 30-day-old chickens were investigated by lectin histochemistry. In the thymus, mannose as well as N-acetyl-glucosamine (glcNAc)-specific lectins labelled macrophages, epithelial reticulum cells and lymphocytes within the cortex. In the bursa of Fabricius, the brush border of the lining epithelium, the macrophages and the endothelium were labelled by mannose-specific lectins. The follicle-associated epithelium was labelled by a broad spectrum of lectins. Epithelial cells that separated the cortex from the medulla and large mononuclear cells in the cortex were only being labelled by N-acetyl-galactosamine (galNAc)-specific and glcNAc-specific lectins, respectively. In the spleen, lymphocytes of the peri-ellipsoid lymphocyte sheaths and macrophages of the red pulp were labelled by lectins of nearly all sugar specificities. In general, glycotopes of these organs were more intensively labelled in the 2-day-old chicken than in the 30-day-old chicken, indicating changes in glycotope expression during post-hatching development. Thus, cells of the avian immune system are as rich and diverse in their lectin binding sites as their mammalian counterparts, indicating that similar carbohydrate lectin interactions between cells and matrices take place in birds as well.     

Transmaternal cell flow leads to antigen-experienced cord blood

Umbilical cord blood (UCB) is used for HSCT. It is known that UCB can comprise Ag-specific T cells. Here we question whether solely transmaternal cell flow may immunize UCB. Twenty-three female UCB samples were collected from healthy mothers and analyzed for minor histocompatibility Ag HY-specific responses. Forty-two of 104 tetramer(pos) T-cell clones, isolated from 16 of 17 UCB samples, showed male-specific lysis in vitro. Male microchimerism was present in 6 of 12 UCB samples analyzed. In conclusion, female UCB comprises HY-specific cytotoxic T cells. The immunization is presumably caused by transmaternal cell flow of male microchimerism present in the mother. The presence of immune cells in UCB that are not directed against maternal foreign Ags is remarkable and may explain the reported clinical observation of improved HSCT outcome with younger sibling donors.     

Apolipoprotein M binds oxidized phospholipids and increases the antioxidant effect of HDL

ObjectiveOxidation of LDL plays a key role in the development of atherosclerosis. HDL may, in part, protect against atherosclerosis by inhibiting LDL oxidation. Overexpression of HDL-associated apolipoprotein M (apoM) protects mice against atherosclerosis through a not yet clarified mechanism. Being a lipocalin, apoM contains a binding pocket for small lipophilic molecules. Here, we report that apoM likely serves as an antioxidant in HDL by binding oxidized phospholipids, thus enhancing the antioxidant potential of HDL.Methods and resultsHDL was isolated from wild type mice, apoM-deficient mice, and two lines of apoM-Tg mice with ～2-fold and ～10-fold increased plasma apoM, respectively. Increasing amounts of HDL-associated apoM were associated with an increase in the resistance of HDL to oxidation with Cu²⁺ or 2,2′-azobis 2-methyl-propanimidamide, dihydrochloride (AAPH) and to an increased ability of HDL to protect human LDL against oxidation. Oxidized phospholipids, but not native phospholipids, quenched the intrinsic fluorescence of recombinant human apoM and the quenching could be competed with myristic acid suggesting selective binding of oxidized phospholipid in the lipocalin-binding pocket of apoM.ConclusionsThe results suggest that apoM can bind oxidized phospholipids and that it increases the antioxidant effect of HDL. This new mechanism may explain at least part of the antiatherogenic potential of apoM.