Hypertension as a predictor of advanced colorectal cancer outcome and cetuximab treatment response.

Background: Adrenergic receptor stimulation is involved in the development of hypertension (htn) and has been implicated in cancer progression and dissemination of metastases in various tumours, including colon cancer. Adrenergic antagonists such as beta-blockers (bbs) demonstrate inhibition of invasion and migration in colon cancer cell lines and have been associated with decreased mortality in colorectal cancer (crc). We examined the association of baseline htn and bb use with overall (os) and progression-free survival (pfs) in patients with pretreated, chemotherapy refractory, metastatic crc (mcrc). We also examined baseline htn as a predictor of cetuximab efficacy. Methods: Using data from the Canadian Cancer Trials Group co.17 study [cetuximab vs. best supportive care (bsc)], we coded baseline htn and use of anti-htn medications, including bbs, for 572 patients. The chi-square test was used to assess the associations between those variables and baseline characteristics. Cox regression models were used for univariate and multivariate analyses of os and pfs by htn diagnosis and bb use. Results: Baseline htn, bb use, and anti-htn medication use were not found to be prognostic for improved os. Baseline htn and bb use were not significant predictors of cetuximab benefit. Conclusions: In chemorefractory mcrc, neither baseline htn nor bb use is a significant prognostic factor. Baseline htn and bb use are not predictive of cetuximab benefit. Further investigation to determine whether baseline htn or bb use have a similarly insignificant impact on prognosis in patients receiving earlier lines of treatment remains warranted.

Real-life treatment of metastatic colorectal cancer with regorafenib: a single-centre review.

BACKGROUND: Various tyrosine kinase signalling pathways affect the development and progression of colorectal cancer (crc). In clinical trials, regorafenib has been associated with a survival benefit in metastatic crc (mcrc). We assessed the safety and efficacy of regorafenib in real-world patients. METHODS: In a retrospective review of patients with mcrc treated with regorafenib at our institution from 2013 to 2015, patient demographics, treatment, and survival data were collected. Progression-free survival (pfs) and overall survival (os) were estimated using the Kaplan-Meier method. RESULTS: In total, 48 patients were offered regorafenib, and 35 (73%) started treatment. Of the patients who started regorafenib, 57% were men. Median age in the cohort was 61 years, and all patients had a performance status in the range 0-2. Time from diagnosis of mcrc to regorafenib treatment was more than 18 months in 71% of patients. Starting dose was 160 mg in 54% of the patients, 120 mg in 40%, and 80 mg in 6%. Dose reductions occurred in 34% of the patients, and interruptions, in 29%. Best response was progressive disease (60%) and stable disease (17%); response in the rest of the patients was unknown. The most common adverse events on regorafenib (any grade) were fatigue (57%), hyperbilirubinemia (43%), thrombocytopenia (37%), anorexia (31%), and hypertension (31%). The most common grade 3 or 4 adverse events were fatigue (29%), hypophosphatemia (17%), weight loss (11%), and hyperbilirubinemia (9%). Common reasons for discontinuing regorafenib included progressive disease (51%) and toxicity (26%). In patients treated with regorafenib, pfs was 2.4 months (95% confidence interval: 1.8 to 3.3 months) and os was 5.6 months (95% confidence interval: 3.7 to 8.9 months). No factors were associated with survival in univariate or multivariate analysis. CONCLUSIONS: In a real-world setting, regorafenib is associated with survival similar to that reported in the randomized controlled trials, but at the expense of toxicity leading to discontinuation in many patients. Future studies of regorafenib should focus on identifying the patients most likely to benefit and on minimizing toxicity.

Corrigendum: Eastern Canadian Gastrointestinal Cancer Consensus Conference 2014.

[This corrects the article DOI: 10.3747/co.22.2603.].

Palliative chemotherapy in advanced colorectal cancer patients 80 years of age and older.

BACKGROUND: Colorectal cancer (crc) has a median diagnostic age of 68 years. Despite significant progress in chemotherapy (ctx) options, few data on outcomes or toxicity from ctx in patients 80 years of age and older are available. We investigated ctx in such patients with metastatic crc (mcrc), hypothesizing high rates of hospitalization and toxicity. METHODS: A retrospective chart review identified patients 80 years of age and older with mcrc who initiated ctx between 2005-2010 at our institution. Patient demographics and ctx data were collected. Endpoints included rates of hospitalization, ctx discontinuation because of toxicity, and overall survival. RESULTS: In 60 patients, ctx was initiated on 88 occasions. Median age in the cohort was 83 years; 52% were men; 72% lived with family; 53% had a modified Charlson comorbidity index of 2 or greater; and 31% were taking 6 or more prescription medications at baseline. At baseline, 33% of the patients were anemic (hemoglobin < 100 g/L), 36% had leukocytosis (white blood cells > 11×10(9)/L), and 48% had renal impairment (estimated glomerular filtration rate < 60 mL/min/1.73 m(2)). In 53%, ctx was given as first-line treatment. The initial ctx dose was adjusted in 67%, and capecitabine was the most common chemotherapeutic agent (45%). In 19 instances (22%), the patient was hospitalized during or within 30 days of ctx; in 26 instances (30%), the ctx was discontinued because of toxicity, and in 48 instances (55%), the patient required at least 1 dose reduction, omission, or delay. Median overall survival was 17.8 months (95% confidence interval: 14.3 to 20.8 months). CONCLUSIONS: In the population 80 years of age and older, ctx for mcrc is feasible; however, most recipients will require dose adjustments, and a significant proportion will be hospitalized or stop ctx because of toxicity. Prospective research incorporating geriatric assessment tools is required to better select these older patients for ctx.

Eastern Canadian Gastrointestinal Cancer Consensus Conference 2014.

The annual Eastern Canadian Colorectal Cancer Consensus Conference was held in Montreal, Quebec, 23-25 October 2014. Expert radiation, medical, and surgical oncologists and pathologists involved in the management of patients with gastrointestinal malignancies participated in presentations and discussions resulting in consensus statements on such hot topics as management of neuroendocrine tumours, advanced and metastatic pancreatic cancer, and metastatic colorectal cancer.

Posterior atlantoaxial dislocation without associated fracture.

We report on a 38-year-old man with post-traumatic posterior displacement of the atlas with respect to the axis without any associated fracture or neurological deficit caused by the displacement. Radiographs, computed tomography (CT) and magnetic resonance imaging (MRI) revealed posterior displacement of the atlas with the odontoid peg lying anterior and to the right of the anterior arch of the atlas.

Antigen-driven lymphocyte recruitment to the lung is diminished in the absence of urokinase-type plasminogen activator (uPA) receptor, but is independent of uPA.

The requirement for urokinase plasminogen activator (uPA) and uPA receptor (uPAR) in T lymphocyte migration is unknown. uPA(-/-) mice have fewer pulmonary lymphocytes in response to certain infections, but its unknown whether this is due to diminished recruitment. Primed, recipient mice were IT inoculated with Ag. Three days later, fluorescently labeled lymphoblasts from background-matched control wild-type (WT), uPA(-/-), or uPAR(-/-) donor mice were injected i.v., and their recruitment was determined. Approximately twice the number of uPA(-/-) compared with WT lymphoblasts were recruited to the lungs of WT recipients. This difference was eliminated when uPA(-/-) and WT lymphoblasts were injected into uPA(-/-) recipients. Thus, the reduced number of lung lymphocytes in infected uPA(-/-) mice is not due to reduced recruitment. However, uPAR is critically involved in recruitment. Markedly fewer uPAR(-/-) compared with WT lymphoblasts were recruited to the lung. These findings suggest that uPAR may be a novel target for immune modulation in T lymphocyte-mediated disorders.

Prevalence of coronary artery disease in patients with symptomatic peripheral vascular disease.

BACKGROUND: Prevalence of coronary artery disease has been reported to be quite high in patients with peripheral vascular disease in western literature. Therefore, it is important to study the coronary anatomy in patients with symptomatic peripheral vascular disease. METHODS AND RESULTS: Fifty-three patients presenting with symptoms of peripheral vascular disease underwent peripheral angiography in our institute during the last 2 years. The total number of vessels involved in these patients was 117. Fifteen patients had involvement of the upper limb vessels, 46 patients had involvement of the lower limb vessels and 6 patients had involvement of the carotid/vertebral arteries. Coronary arteriography was done in all the patients. Only 8 (15%) patients were found to have coronary artery disease with involvement of 11 arteries. Eighty-four (72%) peripheral vessels out of the 117 vessels involved showed total occlusion, whereas only 2 (18%) coronary arteries out of 11 vessels involved showed total occlusion. CONCLUSIONS: This study shows that the majority of patients with symptomatic peripheral vascular disease have normal coronaries, the extent of their involvement being low despite severe peripheral vascular disease.

Successful post-cardiopulmonary resuscitation urokinase therapy for massive perioperative pulmonary embolism - a case report.

We report a case of hip arthroplasty done under epidural and general anaesthesia. The patient had two episodes of acute massive pulmonary embolism perioperatively. He received cardiopulmonary resuscitation for the cardiovascular collapse that ensued and was administered a single dose of urokinase inspite of having relative (major) contraindications to the same.

Effects of cytokine gene therapy on particulate-induced inflammation in the murine air pouch.

Retroviral vectors encoding the human IL-1 antagonist (IL-1Ra) gene and the human tumor necrosis factor soluble receptor (sTNF-R) gene were investigated using an in vivo model of the inflammatory response to orthopedic wear debris. Air pouches established in BALB/c mice were injected with polymethylmethacrylate (PMMA) particles to provoke an inflammatory reaction, and infected with retroviral vectors expressing IL-1Ra, sTNF-R or a LacZ marker gene. Pouch membranes and fluids were harvested after 48 or 72 hours for analyses. Positive PCR reactions for Neo genes were observed specifically in DNA extracted from the membrane of retroviral-infected pouches. ELISA assays revealed the presence of human IL-1 Ra in pouch fluid from DFG-IRAP-Neo transduced mice, but not control animals. Histological evaluation indicated that the IL-1Ra gene transfer was associated with markedly decreased inflammation in the model, with resolution of the edematous phase of the reaction, decreased pouch fluid accumulation, and lowered macrophage influx. The data suggest that the air pouch model represents a useful tool to evaluate gene therapy, and demonstrate that IL-1Ra gene therapy may be an appropriate therapeutic approach to inflammation.

Urokinase receptor-deficient mice have impaired neutrophil recruitment in response to pulmonary Pseudomonas aeruginosa infection.

Leukocytes express both urokinase-type plasminogen activator (uPA) and the urokinase receptor (uPAR, CD87). Evidence in vitro has implicated uPAR as a modulator of beta2 integrin function, particularly CR3 (CD11b/CD18, Mac-1). Pseudomonas aeruginosa infection has been demonstrated to recruit neutrophils to the pulmonary parenchyma by a beta2 integrin-dependent mechanism. We demonstrate that mice deficient in uPAR (uPAR-/-) have profoundly diminished neutrophil recruitment in response to P. aeruginosa pneumonia compared with wild-type (WT) mice. The requirement for uPAR in neutrophil recruitment is independent of the serine protease uPA, as neutrophil recruitment in uPA-/- mice is indistinguishable from recruitment in WT mice. uPAR-/- mice have impaired clearance of P. aeruginosa compared with WT mice, as demonstrated by CFU and comparative histology. WT mice have diminished neutrophil recruitment to the lung when an anti-CD11b mAb is given before inoculation with the pathogen, while recruitment of uPAR-/- neutrophils is unaffected. We conclude that uPAR is required for the recruitment of neutrophils to the lung in response to P. aeruginosa pneumonia and that this requirement is independent of uPA. Further, we show that uPAR and CR3 act by a common mechanism during neutrophil recruitment to the lung in response to P. aeruginosa. This is the first report of a requirement for uPAR during cellular recruitment in vivo against a clinically relevant pathogen.

Giant spinal arachnoid cysts: computed tomography, magnetic resonance imaging and magnetic resonance myelography correlation.

Two cases of giant spinal arachnoid cysts, one of them being symptomatic, are discussed, along with their CT, MRI and MR myelography findings.

Serial plasma fibronectin levels in pre-eclamptic and normotensive women.

OBJECTIVE: Endothelial cell damage has been put forward as an underlying factor for development of pre-eclampsia. This study was carried out to see if fibronectin, which is a marker of endothelial damage, could be used as a marker of pre-eclampsia. METHODS: A longitudinal study was conducted on 100 normotensive primigravidae registered before 20 weeks of gestation. These subjects were followed until delivery and three blood samples were collected, first at registration, i.e. before 20 weeks, second around 28 weeks and third at 36 weeks or later till delivery. Fibronectin levels were assayed by ELISA and women observed for any signs of pre-eclampsia. RESULTS: Fourteen subjects developed pre-eclampsia. Fibronectin levels were observed to rise as pregnancy advanced but the rise was significantly higher in subjects who developed pre-eclampsia. The fibronectin levels were also significantly higher in these 14 subjects even in the first sample, i.e. before 20 weeks of gestation when compared with normotensive subjects (P < 0.01). CONCLUSIONS: Fibronectin levels could be used as an early valuable biomarker for the development of pre-eclampsia.

Experimental acute hematogenous osteomyelitis in mice. I. Histopathological and immunological findings.

This study investigated immunological responses to Staphylococcus aureus bone infection. Because considerable immunological information is available on the mouse, a murine model of acute hematogenous osteomyelitis was established. Osteomyelitis was created in the proximal tibia of C3H/HeJ mice by a tibial epiphyseal fracture followed by intravenous bacterial inoculation with Staphylococcus aureus (strain LS-1). Swelling and warmth of the limb was found, and following limb exposure, abscess formation was evident in the proximal tibia. Histological examination revealed distortion primarily at the hypertrophic zone of the physis and polymorphonuclear leukocyte infiltration throughout the damaged area of the proximal tibia. Local infection was demonstrated at the fracture site, evidenced by the recovery of Staphylococcus aureus following microbiological analysis of tissue specimens. Polymerase chain reaction was utilized to detect 16S ribosomal prokaryotic nucleic acid to demonstrate that the diagnosis of osteomyelitis could be established in the absence of conventional microbiological techniques. The infected mice had an increase of circulating large leukocytes (granulocytes) and an elevation of total serum immunoglobulin. Flow cytometry revealed significant increases in splenic B lymphocytes and in lymph-node CD4+ T lymphocytes. These results indicate that an experimental model of acute hematogenous osteomyelitis that closely resembles the pathology of the disease in humans may be consistently induced in mice. Furthermore, marked immunological changes may be observed in response to the Staphylococcus aureus bone infection.

Experimental acute hematogenous osteomyelitis in mice. II. Influence of Staphylococcus aureus infection on T-cell immunity.

A murine model of acute hematogenous osteomyelitis was used to study the immune response following Staphylococcus aureus infection and to examine the hypothesis that the bacteria may modify T-cell responses due to the production of bacterial enterotoxins with mitogenic or superantigenic activity. Lymph-node T cell-receptor expression was assessed with use of flow cytometry and reverse transcription-polymerase chain reaction techniques, and increased apoptosis (programmed cell death) in T-cell subsets was monitored. The expression and levels of circulating cytokines and T-cell cytokines within tissues surrounding the damaged area of the proximal tibia were also investigated. Analysis of T-cell receptors in experimental osteomyelitis revealed two distinct patterns of T-cell evolution during the disease. Certain T-cell subsets (Vbeta2, Vbeta3, Vbeta9, and Vbeta10) were activated and expanded during the first 24 hours after infection; they reached maximum levels 6 days after infection, followed by a return to pre-infection levels. In contrast, other T-cell subsets (Vbeta11, Vbeta12, Vbeta13, Vbeta14, and Vbeta16) contracted during the first 24 hours after infection, followed by expansion to a maximum level 9 days after infection. Activation and proliferation of T-cell subsets (notably Vbeta14 T cells) was followed by apoptosis, suggesting that staphylococcal bone infection caused superantigenic-like effects on the mouse immune system. Analysis of cytokine responses in local tissue revealed that the T-cell cytokines interleukin-2 and interferon-gamma showed a late and relatively short activation pattern compared with the inflammatory cytokines interleukin-1, interleukin-6, and tumor necrosis factor-alpha. The results suggest that Staphylococcus aureus bone infection may undermine the antibacterial immune response through downregulation of T-cell immunity and immune-cytokine production, which could increase the severity of the systemic infection and local osseous destruction that occur with acute hematogenous osteomyelitis.

The use of hybrid lenses in management of the irregular cornea.

The use of SoftPerm hybrid lenses was investigated as part of a 10 year retrospective audit of keratoconus in the Contact Lens Service at Nottingham University Hospital which serves a population of approximately one million. During this period, nine patients (14 eyes) were fitted with SoftPerm a lenses for keratoconus. Two further patients (two eyes) were included with a diagnosis of irregular astigmatism and one patient (one eye) was fitted post-corneal graft. Seven patients were regarded as successful hybrid lens wearers and five were regarded as unsuccessful wearers. Of the unsuccessful cases, one patient managed satisfactorily using a rigid gas permeable corneal on the unaffected eye, two patients subsequently had successful corneal grafts, one patient continued with restricted rigid gas permeable lens wear and one patient defaulted.

Pristane-induced arthritis in mice. V. Susceptibility to pristane-induced arthritis is determined by the genetic regulation of the T cell repertoire.

OBJECTIVE: Pristane-induced arthritis (PIA) is an experimental seropositive arthritis that is characterized by serologic and cellular immune abnormalities and is dependent on the presence of a competent CD4+ T cell population. We examined the regulation of PIA by genes of the major histocompatibility complex (MHC) and the Mls-1 loci to determine whether the selection of the T cells that infiltrate arthritic joints is a critical factor in disease susceptibility. METHODS: Genetic regulation of PIA was investigated using F1 hybrid and congenic strain analysis to determine the influence of MHC and Mls-1 genes. The T cell receptor Vbeta phenotypes of lymph node cells and T cells infiltrating arthritic joints were examined with 2-color flow cytometry and reverse transcription-polymerase chain reaction techniques. RESULTS: F1 hybrid offspring from 2 major PIA-susceptible strains (DBA/1 x BALB/c) were resistant to the induction of arthritis because of the interaction between genes of the MHC and the Mls-1 loci, which modified the T cell repertoire. This conclusion was supported by the observed resistance to PIA in BALB/ c-Mls-1a mice, where T cells expressing the Vbeta8.1 and Vbeta6 phenotypes were absent. The receptor phenotype of T cells infiltrating arthritic joints in DBA/1 mice was markedly skewed toward Vbeta8.1 and Vbeta6 compared with the population observed in lymph nodes from either PIA or normal control DBA/1 mice. CONCLUSION: The data support the hypothesis that PIA is a T cell-mediated disease. While pristane causes a polyclonal T cell expansion that gives rise to lymphadenopathy, the development of arthritis in susceptible strains of mice occurs due to the preservation of specific T cell subsets with the capacity to infiltrate synovial joints.

T cells infiltrating the skin of Tsk2 scleroderma-like mice exhibit T cell receptor bias.

The T cell repertoire expressed by Tsk2 mice, a novel experimental model of systemic sclerosis, was examined to determine whether cells infiltrating the areas of involved skin exhibit a T cell receptor (TCR) bias. Reverse transcription-polymerase chain reactions (RT-PCR) were conducted using RNA extracted from lymph nodes and skin from TSk2 mice and from normal mice, with an oligonucleotide primer library specific for the variable region of the TCR (beta) chain. RT-PCR signals were observed in all lymph node cell (LNC) samples from both Tsk2 mice and control mice, with eighteen of the twenty-one Vbeta types present. In contrast, cDNA extracted from areas of involved skin from Tsk2 mice exhibited a restricted pattern, with positive Vbeta signals corresponding to eight T cell subtypes (Vbeta1, 6, 8.1, 8.2, 10, 11, 16, and 18). Band strength analysis revealed that three Vbeta subtypes dominated within this restricted pattern (Vbeta8.1, 11, and 18). Moreover, this pattern of Vbeta bias was consistent among the four skin samples from different Tsk2 mice. These data suggest that a restricted T cell population participates in the inflammatory cell infiltrate of Tsk2 skin.

T cell receptor (V beta) bias in the response of rheumatoid arthritis synovial fluid T cells to connective tissue antigens.

T cell receptor (V beta) use in the response to type II collagen and cartilage proteoglycans was analysed in peripheral blood and synovial fluid T cells from RA patients. T cells from RA patients with an immune response to connective tissue antigens, and paired PB and SF samples were stimulated in vitro with type II collagen, high density aggrecan proteoglycans (PG), and the T cell mitogen concanavalin A. After short term culture, mRNA was extracted from cells and a reverse transcription-polymerase chain reaction was performed, using primers specific for eight TCR V beta determinants. Blood cells stimulated with ConA generated strong bands with virtually all the V beta primers tested, but the TCR (V beta) expression by SF T cells stimulated with mitogen was biased, suggesting a selection process during joint infiltration. The V beta phenotypes of cells responding to PG was restricted in individual RA patients, but the pattern of V beta use in the the RA population was not consistent. In contrast, the V beta phenotypes of SF cells responding to CII was highly biased in both individual patients and the RA population, with V beta 14, V beta 17, and V beta 8 phenotypes predominant. We conclude that the T cell response to connective tissue antigens is restricted compared with mitogen stimulation, with the highest degree of TCR bias seen in the response of SF T cells to stimulation with type II collagen.