Surgical delivery of drug releasing poly(lactic-co-glycolic acid)/poly(ethylene glycol) paste with in vivo effects against glioblastoma

Introduction

The median survival of patients with glioblastoma multiforme (astrocytoma grade 4) remains less than 18 months despite radical surgery, radiotherapy and systemic chemotherapy. Surgical implantation of chemotherapy eluting wafers into the resection cavity has been shown to improve length of survival but the current licensed therapy has several drawbacks. This paper investigates in vivo efficacy of a novel drug eluting paste in glioblastoma.

Methods

Poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) self-sintering paste was loaded with the chemotherapeutic agent etoposide and delivered surgically into partially resected tumours in a flank murine glioblastoma xenograft model.

Results

Surgical delivery of the paste was successful and practical, with no toxicity or surgical morbidity to the animals. The paste was retained in the tumour cavity, and preliminary results suggest a useful antitumour and antiangiogenic effect, particularly at higher doses. Bioluminescent imaging was not affected significantly by the presence of the paste in the tumour.

Conclusions

Chemotherapy loaded PLGA/PEG paste seems to be a promising technology capable of delivering active drugs into partially resected tumours. The preliminary results of this study suggest efficacy with no toxicity and will lead to larger scale efficacy studies in orthotopic glioblastoma models.     

The cellular basis for lack of antibody response to hepatitis B vaccine in humans

We had previously obtained evidence that among normal subjects the humoral antibody response to hepatitis B surface antigen (HBsAg) was bimodally distributed with about 14% of subjects producing less than 1,000 estimated radioimmunoassay RIA units. From the study of major histocompatibility complex (MHC) markers in the very poor responders who produced less than 36 estimated RIA units of antibody, it appeared that there was an excess of homozygotes for two extended haplotypes [HLA-B8, SC01, DR3] and [HLA-B44, FC31, DR7]. This finding suggested that a poor response was inherited as a recessive trait requiring nonresponse genes for HBsAg on both MHC haplotypes and was strengthened by finding a much lower antibody response among prospectively immunized homozygotes for [HLA-B8, SC01, DR3] compared with heterozygotes. In the present study, we have analyzed the cellular basis for nonresponse to this antigen by examining antigen-specific proliferation of T cells from responders and nonresponders in the presence and absence of autologous CD8+ (suppressor) cells. Peripheral blood cells from nonresponders to HBsAg failed to undergo a proliferative response to recombinant HBsAg in vitro, whereas cells from responders proliferated vigorously. This failure of cells from nonresponders to proliferate was not reversed in cell mixtures containing CD4+ and antigen-presenting cells devoid of CD8+ cells. There was no difference between responders and nonresponders with respect to the number of circulating T cells or their subsets, or the proliferative response to mitogens such as pokeweed or phytohemagglutinin or another antigen, tetanus toxoid. Our results indicate that our HBsAg nonresponding subjects have a very specific failure in antigen presentation or the stimulation of T helper cells, or both. Our evidence is against specific immune suppression as the basis for their nonresponsiveness. The failure of antigen presentation or T cell help is consistent with recessive inheritance of nonresponsiveness and suggests that response is dominantly inherited.     

Dashboard (in the) Knee

We present the case of a 19-year-old individual presenting to an orthopaedic outpatient clinic several months following a dashboard knee injury during a road traffic accident with intermittent mechanical symptoms. Despite unremarkable examination findings and normal magnetic resonance imaging, the patient was identified subsequently as having an intra-articular plastic foreign body consistent with a piece of dashboard on arthroscopic knee assessment, the retrieval of which resulted in a complete resolution of symptoms.     

Extended major histocompatibility complex haplotypes in type I diabetes mellitus.

We have studied major histocompatibility complex markers in Caucasian patients with type I diabetes mellitus and their families. The frequencies of extended haplotypes that were composed of specific HLA-B, HLA-DR, BF, C2, C4A, and C4B allelic combinations, which occurred more commonly than expected, were compared on random diabetic and normal chromosomes in the study families. We demonstrated that all of the previously recognized increases in HLA-B8, B18, B15, DR3, and perhaps DR4 could be ascribed to the increase among diabetic haplotypes of a few extended haplotypes: [HLA B8, DR3, SC01, GLO2]; [HLA-B18, DR3, F1C30]; [HLA-B15, DR4, SC33]; and [HLA-BW38, DR4, SC21]. In fact, HLA-DR3 on nonextended haplotypes was "protective", with a relative risk considerably less than 1.0. There was a paucity or absence among diabetic patients of several extended haplotypes of normal chromosomes, notably [HLA-B7, DR2, SC31] and [HLA-BW44, DR4, SC30]. The extended haplotype [HLA-BW38, DR4, SC21] is found only in Ashkenazi Jewish patients, which suggests that extended haplotypes mark specific mutations that arise in defined ethnic groups. The data show that no known MHC allele, including HLA-DR3 and possibly HLA-DR4, is per se a marker for or itself a susceptibility gene for type I diabetes. Rather, extended haplotypes, with relatively fixed alleles, are either carriers or noncarriers of susceptibility genes for this disease. Thus, the increased frequency (association) or the decreased frequency (protection) of individual MHC alleles is largely explainable by these extended haplotypes.     

Change in neoadjuvant chemotherapy could alter the prognosis of patients with pancreatic adenocarcinoma: A case report

BACKGROUNDNeoadjuvant treatment has become a standard of care for borderline or locally advanced pancreatic cancer and is increasingly considered even for up-front resectable disease. The aim of this article is to present the case of a 62-year-old patient with locally advanced pancreatic adenocarcinoma who was successfully treated with gemcitabine plus nab-paclitaxel after the failure of the first line treatment.CASE SUMMARYComputerized tomography scan and magnetic resonance imaging demonstrated a nodular lesion of ill-defined limits in the body of the pancreas, measuring approximately 4.2 cm × 2.7 cm, with an infiltrative aspect. The tumor had contact with the superior mesenteric vein, splenomesenteric junction and the proximal segment of the splenic artery, causing focal reduction of its lumens. Due to vascular involvement, neoadjuvant chemotherapy treatment with eight cycles of “folinic acid, 5-fluorouracil, irinotecan and oxaliplatine” (FOLFIRINOX) were performed. At the end of the cycles, surgery was performed, but the procedure was interrupted due to finding of lesions suspected of metastasis. Gemcitabine plus nab-paclitaxel was then successfully used for neoadjuvant treatment with subsequent R0 surgical resection.CONCLUSIONGemcitabine plus nab-paclitaxel may be effective as an alternative regimen when FOLFIRINOX fails as the first line of treatment, suggesting the need for further studies to identify which patients would benefit from each type of therapeutic approach.     

Detection of antibodies to Trypanosoma cruzi among blood donors in the southwestern and western United States. II. Evaluation of a supplemental enzyme immunoassay and radioimmunoprecipitation assay for confirmation of seroreactivity

BACKGROUND: Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is endemic to Latin America and may be transmitted in the United States via blood donated by infected immigrants. Blood- borne pathogens such as T. cruzi require supplemental testing for confirmation of seroreactivity. STUDY DESIGN AND METHODS: A study was undertaken to determine an optimal scheme for confirmation of seroreactivity in repeatedly reactive samples identified by the Chagas antibody enzyme immunoassay (EIA). The procedure for initial confirmation involves three purified antigens coated onto three separate polystyrene beads and uses an EIA format. If the sample is reactive with two of three or three of three antigens, it is confirmed as seroreactive. If none or one of three beads is reactive, the sample is indeterminate and subjected to a radioimmunoprecipitation assay (RIPA). The RIPA must demonstrate characteristic bands at 32, 34, and 90 kDa. RESULTS: When tested with sera from persons with potentially cross-reactive diseases (n = 39) or against a presumed negative population from southeast Wisconsin (n = 289), the confirmatory EIA had a specificity of 100 percent. Sensitivity was 100 percent (28/28) with xenodiagnosis-positive sera and 97.6 percent (80/82) with chagasic sera from Latin America. The RIPA showed a specificity of 100 percent in EIA- nonreactive samples (n = 100) and a sensitivity of 100 percent with both xenodiagnosis-positive (28/28) and chagasic (82/82) sera. CONCLUSION: The confirmatory EIA and the RIPA together provide a highly specific and sensitive means of confirming seroreactivity for antibodies to T. cruzi.     

Yersinia-related Arthritis in the United Kingdom. A Report of 12 Cases and review of the Literature

Reactive arthritis following infection with Yersinia is endemicin Scandanavian countries; the prevalence is low in the UK,however. We have reviewed the literature pertaining to Yersinia-relatedreactive arthritis in the UK and describe 12 patients who presentedover a 3-year period with an asymmetrical seronegative polyarthropathyand serological evidence of recent Yersinia infection. Fivepatients recalled having a diarrhoeal illness prior to the onsetof the arthropathy. None had a prior history of psoriasis, inflammatorybowel disease or ankylosing spondylitis. A history of urethraldischarge was elicited from one patient. Extra-articular manifestationswere seen in three patients (iritis in two, erythema nodosumin another). Four patients developed chronic joint disease afterperiods of 4, 6, 8, and 18 months, respectively. The prevalenceof Yersinia-related arthritis in the UK may be higher than previouslythought.