Immunohistochemical detection of p53 in Wilms' tumors correlates with unfavorable outcome.

The role of p53 in the pathogenesis and progression of Wilms' tumors is only partly understood. Although p53 mutations were initially reported only in anaplastic Wilms' tumors, we had reported that, of two of twenty-one cases that had a p53 mutation, one tumor showed no evidence of anaplasia. To determine the significance of p53 expression in all clinical stages of Wilms' tumor, twenty-eight cases were analyzed for p53 immunoreactivity. Paraffin sections were immunolabeled with two different monoclonal antibodies, recognizing both mutant and wild-type p53. Fifteen of sixteen tumors in the recurrent/metastatic group and three of twelve tumors in the nonmetastatic/nonrecurrent group showed p53 immunopositivity. Only one of three positive tumors in the latter group showed moderate to strong positivity, whereas twelve of sixteen metastatic/recurrent tumors revealed a similar degree of p53 positivity. The positivity was stronger in the metastasis/recurrences as compared with the corresponding primary tumor. Western blot analysis revealed p53 expression in all of the Wilms' tumors tested, suggesting its involvement in the development of Wilms' tumors. Single-strand conformation polymorphism analysis performed on twenty-three of these tumors revealed p53 mutations in four of fourteen recurrent/metastatic tumors and none in the nonmetastatic/nonrecurrent group. Our results show that, whereas 60% of cases were immunopositive for p53 protein, mutations were detected in only 16% of tumors, indicating that wild-type p53 protein is retained in the other tumors. We conclude that p53 immunopositivity strongly correlates with recurrence/metastasis in Wilms' tumors. Furthermore, the accumulation of p53 in these tumors is not only due to mutations but may also involve stabilization of normal p53 with other proteins.     

A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma.

PURPOSE: Localized pancreatic carcinoma is rarely resectable and is resistant to conventional therapies. ONYX-015 (dl1520) is an E1B-55kD gene-deleted replication-selective adenovirus that preferentially replicates in and kills malignant cells. Endoscopic ultrasound (EUS) has the potential to conveniently and accurately deliver local therapy to the pancreas. Therefore, we undertook a trial of the feasibility, tolerability, and efficacy of EUS injection of ONYX-015 into unresectable pancreatic carcinomas. EXPERIMENTAL DESIGN: Twenty-one patients with locally advanced adenocarcinoma of the pancreas or with metastatic disease, but minimal or absent liver metastases, underwent eight sessions of ONYX-015 delivered by EUS injection into the primary pancreatic tumor over 8 weeks. The final four treatments were given in combination with gemcitabine (i.v., 1,000 mg/m(2)). Patients received 2 x 10(10) (n = 3) or 2 x 10(11) (n = 18) virus particles/treatment. RESULTS: After combination therapy, 2 patients had partial regressions of the injected tumor, 2 had minor responses, 6 had stable disease, and 11 had progressive disease or had to go off study because of treatment toxicity. No clinical pancreatitis occurred despite mild, transient elevations in lipase in a minority of patients. Two patients had sepsis before the institution of prophylactic oral antibiotics. Two patients had duodenal perforations from the rigid endoscope tip. No perforations occurred after the protocol was changed to transgastic injections only. CONCLUSIONS: This study indicates that ONYX-015 injection via EUS into pancreatic carcinomas by the transgastic route with prophylactic antibiotics is feasible and generally well tolerated either alone or in combination with gemcitabine. Transgastric EUS-guided injection is a new and practical method of delivering biological agents to pancreatic tumors.     

Use of immunoadsorption columns in ABO-incompatible renal transplantation: A prospective study at a tertiary care center in India

BackgroundWe present our experience of ABO-incompatible renal transplant using immunoadsorption (IA) columns. We have compared efficacy of two commercially available columns.MethodsThis single-center prospective study was conducted at Army Hospital Research and Referral, Delhi. All consecutive ABO-incompatible renal transplants from January 2014 to February 2018 were analyzed. Of 30 patients who underwent transplantations, 28 underwent antibody depletion with immunoadsorption columns. Of them, 14 cases were in the “Glycosorb group,” while 14 in the “Adsopak group.”ResultsThe donors in the Adsopak group were older than those in the Glycosorb group (p < 0.05). Both groups had spousal donors in majority. The cutoff for the antibody titer was 1:8. The median titer in the Adsopak group was 128 (range, 1:4 to 1:2048), while that in the Glycosorb group was 24 (range, 1:8 to 1:128). All patients in the Glycosorb group had baseline titers ≤1:128, while 13 patients in the Adsopak group had baseline titers ≤1:512. Nil titer was achievable with Glycosorb® (50%,7/14) but not with Adsopak® (P < 0.01). Around 4 sessions were required for the Glycosorb group, while around 8 sessions were required for the Adsopak group before transplantation (p < 0.001). The Glycosorb group was advantageous in terms of graft failure because no rejection was noticed in these patients in their follow-up period. Three patients in the Adsopak group developed rejection (two had mixed rejection, and one had antibody-mediated rejection). Four patients died of sepsis (three in the Glycosorb and one in the Adsopak group). Lower baseline serum creatinine level was achieved in the Glycosorb group.ConclusionsResults of ABO-incompatible renal transplantation were satisfactory, and the use of immunoadsorption columns could effectively deplete antibody titers. Glycosorb columns were more efficient than Adsopak columns. Graft survival was better with Glycosorb. Posttransplant infections were a major cause of mortality.     

Interferon-gamma expression in jejunal biopsies in experimental human cryptosporidiosis correlates with prior sensitization and control of oocyst excretion

To investigate the role of interferon (IFN)-gamma in human cryptosporidiosis, jejunal biopsies from experimentally infected volunteers and chronically infected AIDS patients were examined for IFN-gamma expression by in situ hybridization. IFN-gamma expression was compared with oocyst excretion, baseline serum anti-Cryptosporidium antibody, and symptoms. IFN-gamma mRNA was detected in biopsies from 13 of 26 volunteers after experimental infection but not in biopsies taken before C. parvum exposure or in biopsies from patients with AIDS-associated cryptosporidiosis. After challenge, 9 of 10 volunteers with baseline C. parvum antibody produced IFN-gamma, compared with 4 of 16 volunteers without baseline antibody (P<.01). Furthermore, IFN-gamma mRNA was detected in 9 of 13 volunteers who did not excrete oocysts, compared with 4 of 13 with organisms (P<.05). Thus, expression of IFN-gamma in the jejunum was associated with prior sensitization and absence of oocyst shedding. IFN-gamma production may explain the resistance to infection noted in sensitized persons but may not be involved in control of human primary infection.     

Ring-opening cyclization of activated spiro-aziridine oxindoles with heteroarenes: a facile synthetic approach to spiro-oxindole-fused pyrroloindolines

Herein, we report a facile tandem approach for the synthesis of both spiro-oxindole-fused pyrroloindolines and benzofurano-pyrrolidines via a Lewis acid-catalyzed domino ring-opening with concomitant ring annulation using activated spiro-aziridines and heteroarenes. This method offers a new class of novel spiro-fused polycyclic pyrrolidines in a one-pot and sustainable manner with good yields and high diastereoselectivity. In addition, the structure of 3d was confirmed by single X-ray crystallography analysis.

Herein, we report a facile tandem approach for the synthesis of both spiro-oxindole-fused pyrroloindolines and benzofurano-pyrrolidines via a Lewis acid-catalyzed domino ring-opening annulation using activated spiro-aziridines and heteroarenes.     

A randomised prospective evaluation of ceramic-on-ceramic and ceramic-on-highly cross-linked polyethylene bearings in the same patients with primary cementless total hip arthroplasty

Purpose

Very few studies have compared alumina-on-alumina ceramic and alumina-on-highly cross-linked polyethylene bearings in the same patient. The purpose of this prospective randomised study was to compare the clinical and radiographic results and the prevalence of osteolysis in cementless total hip arthroplasty using an alumina-on-alumina and alumina-on-highly cross-linked polyethylene bearings in young active patients.

Methods

We prospectively compared the results of 100 patients (200 hips) who had undergone a cementless total hip arthroplasty with an alumina-on-alumina ceramic bearing in one hip and an alumina-on-highly cross-linked polyethylene in the other. There were 66 men and 34 women with a mean age of 45.3 years (range, 21–49 years) at the time of surgery. The mean follow-up was 12.4 years (range, 11–13 years). The patients were assessed clinically and radiographically at three months, one year, and annually thereafter.

Results

Harris hip, Western Ontario and McMaster Universities Osteoarthritis Index, and University of California, Los Angeles activity scores did not show statistically significant differences between the two groups of bearings preoperatively or at the time of final follow-up. Radiographic findings of the component were not significantly different between the two groups. The mean polyethylene linear penetration was 0.031?±?0.004 mm per year. No hips in either group displayed osteolysis. The Kaplan-Meier survivorship with revision as the end point at 12.4 years was 100 % (95 % confidence interval [CI], 94–100 %) for the femoral component in both groups and 99 % (95 %CI, 93–100 %) for the acetabular component.

Conclusion

The clinical and radiographic results of using an alumina-on-alumina ceramic and alumina-on-highly cross-linked polyethylene bearings were similar.