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.

HLA-A typing by reference strand-mediated conformation analysis (RSCA) using a capillary-based semi-automated genetic analyser.

HLA typing of class I loci by reference strand-mediated conformation analysis (RSCA) using a slab gel genetic analyser has been described. This study adapted the method for use in the capillary based ABI PRISM 310. Control DNA samples were used to create a database of mobility values for 37 HLA-A alleles. The technique was validated by comparing RSCA and sequence-specific oligonucleotide probe (SSOP)/sequence-specific primer amplification (SSP) HLA-A locus typing results from 214 cord blood samples. Of the samples tested, 6.5% required confirmatory typing by SSP, compared with a repeat rate of 10-40% for SSOP. In 200 samples where no SSP was necessary, there was 100% concordance between RSCA and previous results. The ABI PRISM 310 RSCA method defines HLA-A types at medium resolution and is quick and easy to implement.

Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation.

BACKGROUND: Transforming growth factor (TGF)-beta1 is a profibrogenetic cytokine that has been implicated in the development of fibrosis in transplanted tissues. In this study, we have analyzed the genetic regulation of TGF-beta1 production in lung transplant recipients. METHOD: A polymerase chain reaction-single-stranded conformational polymorphism technique was used to detect polymorphisms in the TGF-beta1 gene from genomic DNA. Polymorphisms were shown to correlate with in vitro TGF-beta1 production by stimulated lymphocytes. A single-specific oligonucleotide probe hybridization method was devised to screen for these polymorphisms in lung transplant groups and controls. RESULTS: We have identified five polymorphisms in the TGF-beta1 gene: two in the promoter region at positions -800 and -509, one at position +72 in a nontranslated region, and two in the signal sequence at positions +869 and +915. The polymorphism at position +915 in the signal sequence, which changes codon 25 (arginine-->proline), is associated with interindividual variation in levels of TGF-beta1 production. Stimulated lymphocytes of homozygous genotype (arginine/arginine) from control individuals produced significantly more TGF-beta1 in vitro (10037+/-745 pg/ml) compared with heterozygous (arginine/proline) individuals (6729+/-883 pg/ml; P<0.02). In patients requiring lung transplantation for a fibrotic lung condition, there was an increase in the frequency of the high-producer TGF-beta1 allele (arginine). This allele was significantly associated with pretransplant fibrotic pathology (P<0.02) (n=45) when compared with controls (n=107) and with pretransplant nonfibrotic pathology (P<0.004) (n=50). This allele was also associated with allograft fibrosis in transbronchial biopsies when compared with controls (P<0.03) and with nonallograft fibrosis (P<0.01). CONCLUSION: The production of TGF-beta1 is under genetic control, and this in turn influences the development of lung fibrosis. Hence, the TGF-beta1 genotype has prognostic significance in transplant recipients.

An investigation of polymorphism in the interleukin-10 gene promoter.

Interleukin-10 (IL-10) has been described as an anti-inflammatory cytokine and B-cell proliferation factor and has been implicated in autoimmunity, tumorigenesis and transplantation tolerance. We have identified three single base pair substitutions in the IL-10 gene promoter and have investigated whether this polymorphism correlates with IL-10 protein production in vitro.

Natural product source material use in the pharmaceutical industry: the Glaxo experience.

Glaxo PLC has had a significant involvement with Natural Product Source Materials for all of its commercial history and, most recently, has pursued this interest by use of such materials as templates for new lead discovery. Through the expertise and facilities in its Natural Products Discovery Department, Glaxo extracts relatively small quantities of plant material (typically 200-250 g dry weight) and cultures microorganisms from environmental samples (typically 10-50 g). Extracts and fermentation broths are screened in order to detect bioactive principles (BPs). If the potency, selectivity and specificity of the BP is acceptable, isolation, purification and structural elucidation follows. It is most unlikely, in our experience, that the BP itself will become a drug; it is much more likely that we shall need to initiate a medicinal chemistry synthesis program in order to try to produce a molecule that has both the essential biological and desirable chemical properties to become a drug development candidate. This synthetic process is often a long one and our confidence that such a process is worth undertaking is greatly improved if the BP is novel. An essential component of any medicinal chemistry strategy is that it allows us to obtain secure intellectual property rights through patents. Acquisition of product claim protection, the strongest form of patent protection, is of great importance. Safety testing and clinical development of the candidate drug can take 7-10 years, and often more, during which patent protection is constantly eroding. Recognizing that acquisition of Natural Products Source Materials is an issue of growing concern, Glaxo Research and Development Ltd. (GRD), in the early part of 1992, implemented a policy for plant supply. This policy was subsequently modified to embrace source materials such as environmental, soil and marine samples from which fungi, micro- and microorganisms may be obtained. As a direct consequence of this policy, Natural Product Source Materials supply agreements are only concluded with national and international organizations who possess the expertise to identify and collect the samples. It is equally important that our suppliers have the authority, which must be provided to GRD in writing, to collect such materials and to provide them to GRD for extraction and screening purposes. Such materials must be from sustainable and accessible sources. We will not seek to collect any endangered species. Though ethnomedical information can be helpful, it is not essential. Plants must be taxonomically classified. We reimburse the supplying institute for their efforts and their expertise, and recognize an obligation to offer a royalty to the institute in the event that drug discovery, with subsequent commercialization, owes its origin, however indirectly, to a material that it provided. In discussions with the institute, we insist that "a fair proportion' (>40%) of that royalty be used for the direct benefit of the people in the collection source area. In this context, GRD recognizes the importance of local training and education.

A genetic marker of high TNF-alpha production in heart transplant recipients.

The cytokine TNF-alpha has been implicated in the pathogenesis of both acute and chronic transplant rejection. Levels of the cytokine are known to vary in a normal population, leading to speculation that high responders may be at greater risk of rejection. Particular TNF region polymorphic markers have been associated with increased TNF-alpha levels and a biallelic polymorphism has been identified at position -308 of the TNF-alpha promoter that may contribute significantly to the interindividual variation in healthy persons. We describe here a new association between a polymorphic locus in the TNF gene region and increased production of TNF-alpha in heart transplant recipients. We studied two microsatellite markers that flank the TNFA gene, as well as a biallelic polymorphism at position -308 of the TNFA promoter, and found that the microsatellite allele TNFd3 was significantly associated with the capacity of leukocytes to produce TNF-alpha in vitro. No association was demonstrated for the promoter region polymorphism. Patients were receiving cyclosporine (CsA) and prednisolone (pred) at the time of sampling, which are known to interrupt 5' regulation of TNFA transcription in T cells and macrophages and may therefore negate the influence of the -308 polymorphism. Because of this we suggest that TNFd3 may be a marker for a 3' repressor region polymorphism that is of importance in immunosuppressed individuals.

Treatment of postoperative wound infections following spinal fusion with instrumentation.

Postoperative wound infections following spinal fusion with instrumentation often present diagnostic and therapeutic difficulties. This article reviews 34 such infections. An infection rate of 3.7% was noted. Depending on various clinical indicators, treatment strategies included short-course antibiotics, prolonged intravenous antibiotics, or intravenous antibiotics followed by suppressive antibiotics and eventual hardware removal. To eradicate these infections, removal of instrumentation is often required; this option, however, may result in an unstable spine. Treatment algorithms were developed for treatment of postoperative spinal surgical site infections and to minimize the possibility of spine instability. All patients were cured of their infections.

The use of ketorolac in lumbar spine surgery: a cost-benefit analysis.

The use of ketorolac was studied in patients undergoing lumbar laminectomy and those receiving lumbar fusion with or without instrumentation. Laminectomy patients in the ketorolac group used significantly less narcotic analgesic than did those in the narcotic treatment group. Ketorolac patients in both surgical categories experienced better pain control than narcotic group patients did. Laminectomy ketorolac patients experienced less sedation than did those in the narcotic group, and a similar trend was noted for fusion patients. A significant improvement in postoperative ambulation was demonstrated in the fusion ketorolac group. Postoperative total drug costs were significantly greater in both ketorolac treatment groups. A one-half day decrease in hospitalization was noted for laminectomy ketorolac patients. The overall annual financial impact of the use of ketorolac in lumbar spine patients is a net savings of $211,095.

Effects of food deprivation on cocaine base smoking in rhesus monkeys.

Studies have shown that both food deprivation and response cost have important influences on the magnitude of self-administration of a wide variety of psychoactive drugs. In an attempt to extend these findings to the smoked route of drug self-administration, the effects of food allotment and fixed-ratio (FR) value were evaluated in four male rhesus monkeys trained to smoke cocaine base. In the first phase of the experiment, monkeys were trained to self-administer experiment, monkeys were trained to self-administer smoked cocaine base under a chained progressive-ratio (PR), fixed-ratio (FR) schedule during daily experimental sessions. Monkeys were required to make 20 lever-press responses and then five inhalations on a smoking spout to obtain the first smoke delivery. The lever ratio than increased to 60, 140, 300, 620, 1260, 2540, and 4940 for each successive smoke delivery. The initial lever ratio value was reset to 20 at the beginning of each daily session. The body weights of three monkeys were determined under free-feeding conditions. Monkeys were then restricted to 100 g food and, when body weights had stabilized, the daily food allotment was increased to 150 g, approximately 210 g, or greater than 400 g (satiation). As the daily food allotment and body weight increased, the mean number of smoke deliveries decreased in two of three monkeys. In the second phase of the experiment, three monkeys were maintained under either food-satiated or food-restricted conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Panic disorder: a personal and nursing perspective.

Fortunately, the symptoms of PD and agoraphobia now can be managed effectively with medication or with a combination of medication and behavioral treatments. It is certain that these new treatments will give many patients who were once disabled by this disorder the chance to lead normal lives.