Results of a single-arm pilot study of 32P microparticles in unresectable locally advanced pancreatic adenocarcinoma with gemcitabine/nab-paclitaxel or FOLFIRINOX chemotherapy.

BACKGROUND: Unresectable locally advanced pancreatic cancer (LAPC) is generally managed with chemotherapy or chemoradiotherapy, but prognosis is poor with a median survival of ∼13 months (or up to 19 months in some studies). We assessed a novel brachytherapy device, using phosphorous-32 (32P) microparticles, combined with standard-of-care chemotherapy. PATIENTS AND METHODS: In this international, multicentre, single-arm, open-label pilot study, adult patients with histologically or cytologically proven unresectable LAPC received 32P microparticles, via endoscopic ultrasound-guided fine-needle implantation, planned for week 4 of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) or gemcitabine/nab-paclitaxel chemotherapy, per investigator's choice. The primary endpoint was safety and tolerability measured using Common Terminology Criteria for Adverse Events version 4.0. The lead efficacy endpoint was local disease control rate at 16 weeks. RESULTS: Fifty patients were enrolled and received chemotherapy [intention-to-treat (ITT) population]. Forty-two patients received 32P microparticle implantation [per protocol (PP) population]. A total of 1102 treatment-emergent adverse events (TEAEs) were reported in the ITT/safety population (956 PP), of which 167 (139 PP) were grade ≥3. In the PP population, 41 TEAEs in 16 (38.1%) patients were possibly or probably related to 32P microparticles or implantation procedure, including 8 grade ≥3 in 3 (7.1%) patients, compared with 609 TEAEs in 42 (100%) patients attributed to chemotherapy, including 67 grade ≥3 in 28 patients (66.7%). The local disease control rate at 16 weeks was 82.0% (95% confidence interval: 68.6% to 90.9%) (ITT) and 90.5% (95% confidence interval: 77.4% to 97.3%) (PP). Tumour volume, carbohydrate antigen 19-9 levels, and metabolic tumour response at week 12 improved significantly. Ten patients (20.0% ITT; 23.8% PP) had surgical resection and median overall survival was 15.2 and 15.5 months for ITT and PP populations, respectively. CONCLUSIONS: Endoscopic ultrasound-guided 32P microparticle implantation has an acceptable safety profile. This study also suggests clinically relevant benefits of combining 32P microparticles with standard-of-care systemic chemotherapy for patients with unresectable LAPC.

Allosensitization Following Bone Graft.

It is recognized that patients may become sensitized to donor-specific HLA antigens as a result of previous antigenic exposures, classically through previous transplantation, pregnancy, or blood transfusion. We present an unusual case of a patient who unexpectedly developed a range of anti-HLA antibodies following orthopedic surgery where a bone graft was deployed intraoperatively. We describe the case of a 52-year-old man awaiting a renal transplantation, undergoing elective orthopedic surgery requiring a small-volume bone graft. His postoperative antibody profile was found to be substantially changed compared to his previous negative samples, with the presence of HLA-DR, DQ, and DP specificities, at levels that would be likely to give a positive flow cytometry crossmatch and therefore according to local procedures required listing as unacceptable antigens for organ allocation. We perform a literature review of all previous cases of allosensitization following bone graft. This case is the first to demonstrate allosensitization following minor surgery with ;low-volume bone graft. Previous evidence is very limited and pertains only to massive osteochondral surgery for trauma or malignancy, and is confounded by potential concomitant blood transfusion. Clinicians should be aware of the risk of allosensitization where bone grafts are used.

Skeletal and Appendage Diversity as Design Elements in the Synthesis of a Discovery Library of Nonaromatic Polycyclic 5-Iminooxazolidin-2-ones, Hydantoins, and Acylureas.

Amino acid-derived cross-conjugated trienes were used as a starting point for the synthesis of a discovery library of over 200 polycyclic 5-iminooxazolidin-2-ones, hydantoins, and acylureas. The main feature of this library synthesis is a triple branching strategy which provides efficient access to five skeletally diverse scaffolds. In addition, four sets of building blocks were applied in both a front end and a back end diversification strategy. Multiple fused rings were obtained by cyclization of diamides with phosgene and stereoselective Diels-Alder reactions with maleimides. The 5-iminooxazolidin-2-one scaffold was rearranged into the isomeric hydantoin scaffold through a sequence of ring opening and ring closing reactions.

Major histocompatibility complex susceptibility genes and immune thrombocytopenic purpura in Caucasian adults.

Immune thrombocytopenic purpura (ITP) is a heterogeneous disorder with wide variability in response rates to treatments including corticosteroids, splenectomy and intravenous immune globulins. The nature of the underlying predisposing causes for this autoimmune disorder are not known. We have HLA typed 71 adult Caucasian patients with chronic primary ITP, and compared the data with 750 control samples. In this association study, we were not able to identify a significant immunogenetic susceptibility factor for ITP with HLA class I and class II alleles. However, it appeared that there might be an association between HLA-A2 and ITP, particularly in female patients, who are the predominantly affected group; and HLA-A2 was also present at increased frequency in patients with chronic ITP progressing to splenectomy. These findings are reviewed in the context of other similar reported HLA studies in ITP. Further studies based on larger groups of patients will be necessary to identify genetic susceptibility factors for this disease.

Polymorphism in the promoter region of the gene encoding human allograft inflammatory factor-1.

We have identified a new single nucleotide polymorphism within the promoter region of the human allograft inflammatory factor (AIF-1) gene. The polymorphism, defined by Genbank accession number AF097515, was characterized as a C/T single base pair substitution at position -932. The T allele is associated with both HLA-DR2 and HLA-B7. Also, this allele creates the consensus binding site for the E-box that has high affinity for the basic helix-loop-helix (bHLH) family of transcription factors.

Tumor necrosis factor-alpha gene polymorphism and death due to acute cellular rejection in a subgroup of heart transplant recipients.

Irreversible acute rejection of the transplanted heart usually has a fatal outcome. Predicting which recipients are most likely to reject might allow closer monitoring and modification of treatment protocols to prevent graft loss. Recipients genetically predisposed to produce more TNF-alpha are those who suffer the most acute rejection episodes. Here we show that TNF-alpha genotype is strongly associated with death due to acute cell-mediated heart transplant rejection (Chi-square = 28.57, p < 0.0001). This subgroup of recipients should be given optimally tissue matched transplants and should be treated with the most effective immunosuppressive regimens.

Mutation frequency is reduced in the cerebellum of Big Blue mice overexpressing a human wild type SOD1 gene.

Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder caused by motor neuron degeneration. A similar disease phenotype is observed in mice overexpressing a mutant human hSOD1 gene (G93A, 1Gurd(1)). Mice transgenic for lacI (Big Blue) and human mutant (1Gurd(1), Mut hSOD1) or wild type (2Gur, Wt hSOD1) SOD1 genes were used to examine spontaneous mutation, oxidative DNA damage, and neurodegeneration in vivo. The frequency and pattern of spontaneous mutation were determined for forebrain (90% glia), cerebellum (90% neurons) and thymus from 5-month-old male mice. Mutation frequency is not elevated significantly and mutation pattern is unaltered in Mut hSOD1 mice compared to control mice. Mutation frequency is reduced significantly in the cerebellum of Wt hSOD1 mice (1.6x10(-5); P=0.0093; Fisher's Exact Test) compared to mice without a human transgene (2.7x10(-5)). Mutation pattern is unaltered. This first report of an endogenous factor that can reduce in vivo, the frequency of spontaneous mutation suggests potential strategies for lowering mutagenesis related to aging, neurodegeneration, and carcinogenesis.

A novel HLA allele, B*4104, identified in a cord blood donor.

Results from a number of HLA typing methods prompted the DNA sequencing (SBT) of a cord blood sample at the HLA-B locus. A novel HLA-B allele, B*4104, was identified. This was confirmed by sequencing the mother of the cord blood unit for HLA-B.