Variation in 'fast-track' referrals for suspected cancer by patient characteristic and cancer diagnosis: evidence from 670 000 patients with cancers of 35 different sites.

BACKGROUND: In England, 'fast-track' (also known as 'two-week wait') general practitioner referrals for suspected cancer in symptomatic patients are used to shorten diagnostic intervals and are supported by clinical guidelines. However, the use of the fast-track pathway may vary for different patient groups. METHODS: We examined data from 669 220 patients with 35 cancers diagnosed in 2006-2010 following either fast-track or 'routine' primary-to-secondary care referrals using 'Routes to Diagnosis' data. We estimated the proportion of fast-track referrals by sociodemographic characteristic and cancer site and used logistic regression to estimate respective crude and adjusted odds ratios. We additionally explored whether sociodemographic associations varied by cancer. RESULTS: There were large variations in the odds of fast-track referral by cancer (P<0.001). Patients with testicular and breast cancer were most likely to have been diagnosed after a fast-track referral (adjusted odds ratios 2.73 and 2.35, respectively, using rectal cancer as reference); whereas patients with brain cancer and leukaemias least likely (adjusted odds ratios 0.05 and 0.09, respectively, for brain cancer and acute myeloid leukaemia). There were sex, age and deprivation differences in the odds of fast-track referral (P<0.013) that varied in their size and direction for patients with different cancers (P<0.001). For example, fast-track referrals were least likely in younger women with endometrial cancer and in older men with testicular cancer. CONCLUSIONS: Fast-track referrals are less likely for cancers characterised by nonspecific presenting symptoms and patients belonging to low cancer incidence demographic groups. Interventions beyond clinical guidelines for 'alarm' symptoms are needed to improve diagnostic timeliness.

Pre-referral general practitioner consultations and subsequent experience of cancer care: evidence from the English Cancer Patient Experience Survey.

Prolonged diagnostic intervals may negatively affect the patient experience of subsequent cancer care, but evidence about this assertion is sparse. We analysed data from 73 462 respondents to two English Cancer Patient Experience Surveys to examine whether patients with three or more (3+) pre-referral consultations were more likely to report negative experiences of subsequent care compared with patients with one or two consultations in respect of 12 a priori selected survey questions. For each of 12 experience items, logistic regression models were used, adjusting for prior consultation category, cancer site, socio-demographic case-mix and response tendency (to capture potential variation in critical response tendencies between individuals). There was strong evidence (P < 0.01 for all) that patients with 3+ pre-referral consultations reported worse care experience for 10/12 questions, with adjusted odds ratios compared with patients with 1-2 consultations ranging from 1.10 (95% confidence intervals 1.03-1.17) to 1.68 (1.60-1.77), or between +1.8% and +10.6% greater percentage reporting a negative experience. Associations were stronger for processes involving primary as opposed to hospital care; and for evaluation than report items. Considering 1, 2, 3-4 and '5+' pre-referral consultations separately a 'dose-response' relationship was apparent. We conclude that there is a negative association between multiple pre-diagnostic consultations with a general practitioner and the experience of subsequent cancer care.

Multifunctional CD4⁺ T cells in patients with American cutaneous leishmaniasis.

Leishmaniasis is a group of important parasitic diseases affecting millions worldwide. To understand more clearly the quality of T helper type 1 (Th1) response stimulated after Leishmania infection, we applied a multiparametric flow cytometry protocol to evaluate multifunctional T cells induced by crude antigen extracts obtained from promastigotes of Leishmania braziliensis (LbAg) and Leishmania amazonensis (LaAg) in peripheral blood mononuclear cells from healed cutaneous leishmaniasis patients. Although no significant difference was detected in the percentage of total interferon (IFN)-γ-producing CD4(+) T cells induced by both antigens, multiparametric flow cytometry analysis revealed clear differences in the quality of Th1 responses. LbAg induced an important proportion of multifunctional CD4(+) T cells (28% of the total Th1 response evaluated), whereas LaAg induced predominantly single-positive cells (68%), and 57% of those were IFN-γ single-positives. Multifunctional CD4(+) T cells showed the highest mean fluorescence intensity (MFI) for the three Th1 cytokines assessed and MFIs for IFN-γ and interleukin-2 from those cells stimulated with LbAg were significantly higher than those obtained after LaAg stimulation. These major differences observed in the generation of multifunctional CD4(+) T cells suggest that the quality of the Th1 response induced by L. amazonensis antigens can be involved in the mechanisms responsible for the high susceptibility observed in L. amazonensis-infected individuals. Ultimately, our results call attention to the importance of studying a Th1 response regarding its quality, not just its magnitude, and indicate that this kind of evaluation might help understanding of the complex and diverse immunopathogenesis of American tegumentary leishmaniasis.

Atypical mucocutaneous leishmaniasis caused by Leishmania braziliensis in an acquired immunodeficiency syndrome patient: T-cell responses and remission of lesions associated with antigen immunotherapy.

An atypical case of acquired immunodeficiency syndrome-associated mucocutaneous lesions due to Leishmania braziliensis is described. Many vacuolated macrophages laden with amastigote forms of the parasite were found in the lesions. Leishmanin skin test and serology for leishmaniasis were both negative. The patient was resistant to therapy with conventional drugs (antimonial and amphotericin B). Interestingly, remission of lesions was achieved after an alternative combined therapy of antimonial associated with immunotherapy (whole promastigote antigens). Peripheral blood mononuclear cells were separated and stimulated in vitro with Leishmania antigens to test the lymphoproliferative responses (LPR). Before the combined immunochemotherapy, the LPR to leishmanial antigens was negligible (stimulation index - SI=1.4). After the first course of combined therapy it became positive (SI=4.17). The antigen responding cells were predominantly T-cells (47.5%) most of them with CD8+ phenotype (33%). Very low CD4+ cells (2.2%) percentages were detected. The increased T-cell responsiveness to leishmanial antigens after combined therapy was accompanied by interferon-g (IFN-g) production as observed in the cell culture supernatants. In this patient, healing of the leishmaniasis lesions was associated with the induction of a specific T-cell immune response, characterized by the production of IFN-g and the predominance of the CD8+ phenotype among the Leishmania-reactive T-cells.

T-cell responsiveness of American cutaneous leishmaniasis patients to purified Leishmania pifanoi amastigote antigens and Leishmania braziliensis promastigote antigens: immunologic patterns associated with cure.

Patients suffering from American cutaneous leishmaniasis were studied before therapy (active lesion) and at the end of therapy (cured patients). Assays of lymphocyte proliferative responses of peripheral blood mononuclear cells induced in vitro by Leishmania braziliensis promastigote antigens (Lb) or by three proteins (A-2/P-2, P-4, and P-8) derived from Leishmania pifanoi amastigotes were performed. Antigen-stimulated cells were harvested for CD4 and CD8 phenotype analysis and the levels of gamma interferon (IFN-gamma), interleukin 2 (IL-2) and interleukin 4 (IL-4) produced were also determined. Results show two different patterns of Lb-induced T cell responses: (a) predominance of responding CD4+ cells and mixed type 1 and type 2 cytokine production (IFN-gamma, IL-2, and IL-4) during the active disease, (b) similar proportions of responding CD4+ and CD8+ cells and type 1 cytokine production (presence of IFN-gamma and IL-2 and very low IL-4) at the end of therapy (healed lesions). Thus, this last pattern is probably associated with a beneficial T cell response. The A-2/P-2 amastigote cysteine proteinase provided only marginal (s.i. approximately or = 2.5) T cell stimulation in 25% of patients studied; in contrast, the L. pifanoi P-4 and P-8 amastigote antigens induced significant stimulation (s.i. approximately or = 5) in approximately 50% of the patients. In comparison to Lb-stimulated cultures, lower proliferative responses of T lymphocytes to P-4 or P-8 were observed. However, the P-4- or P-8-stimulated cultures had similar percentages of reactive CD4+ and CD8+ cells, as well as type 1 cytokines (presence of IFN-gamma and IL-2, and low levels or absence of IL-4) in the supernatants both before and at the end of therapy. The consistent induction of apparently beneficial T cell responses by the P-4 and P-8 amastigote glycoproteins points to the possibility that these molecules be considered as candidates for future defined vaccines against leishmaniasis.

Tumor necrosis factor-alpha in human american tegumentary leishmaniasis.

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine produced by activated macrophages and other cells. In order to verify whether the serum levels of TNF-alpha in American tegumentary leishmaniasis patients are associated with the process of cure or aggravation of the disease, 41 patients were studied: 26 cases of cutaneous leishmaniasis (CL) and 15 of mucocutaneous leishmaniasis (MCL). During active disease the serum levels of TNF-alpha of MCL patients were significantly higher than those of CL patients and control subjects (healthy individuals and cutaneous lesions from other etiologies). The MCL patients had serum titers of TNF-alpha significantly lower at the end of antimonial therapy than before therapy. After a six-month follow-up, the MCL patients had serum levels of TNF-alpha similar to those observed at the end of the therapy as well as to those of CL patients and control subjects. No significant variation in the serum levels of TNF-alpha was observed in CL patients throughout the study period (before, at the end of therapy and after a six-month follow-up). The possible relationship between the high TNF-alpha serum levels and severity of the disease is discussed.

Effect of in vivo depletion of CD4+ T cells on experimental infection of susceptible BALB/c mice with Leishmania amazonensis.

The role played by CD4+ T lymphocytes in susceptible BALB/c mice infected with Leishmania amazonensis was investigated. Depletion of CD4+ T cells was achieved in experimentally infected mice by means of treatment with anti-CD4 monoclonal antibody (mAb), resulting in significant reductions in the size of lesions and in mortality when compared with control animals. Moreover, the parasite load in the depleted mice, as quantified by limiting dilution analysis, was about 10-times lower than in the control groups. In addition, the incidence of metastases in the depleted mice was significantly reduced, and their appearance delayed as compared to the control animals. These effects correlated with a selective depletion of CD4+ T cells in the spleens of the mAb-treated mice, suggesting a role for CD4+ T cells in the aggravation of L. amazonensis infection in BALB/c mice.

Synergy between activated Leishmania major-specific CD4+ T lymphocytes and bone-marrow-derived cells in the exacerbation of murine cutaneous leishmaniasis.

Mechanisms of exacerbation of murine cutaneous leishmaniasis mediated by Leishmania major-specific CD4+ T lymphocytes were studied. Using a limiting dilution assay for the quantification of Leishmania parasites, the infected tissues (footpad) of lethally irradiated mice were found to contain tenfold less parasites at four days of infection than the footpads of infected unirradiated animals. Injection of bone marrow cells depleted of T cells into irradiated mice at the site of infection led to an increase in parasite numbers to levels equivalent to those seen in unirradiated mice. After injection of either L. major-specific CD4+ T cells, previously shown to exacerbate cutaneous leishmaniasis, into the infected footpad or the intravenous (i.v.) injection of bone marrow cells depleted of T cells, the numbers of parasites in lesions of irradiated mice never reached the values found in unirradiated control mice. In contrast, the concomitant transfer of CD4+ T-cell populations in situ and bone marrow cells depleted of T cells intravenously led to an increase in parasite loads in irradiated mice up to levels comparable to those of the unirradiated mice. This suggested that recruitment of myelomonocytic cells at the site of the lesions plays a role in the exacerbation of murine cutaneous leishmaniasis mediated by these CD4+ T lymphocytes. Finally, a similar effect was observed with T cells specific for an antigen unrelated to Leishmania, provided that this antigen was added to the L. major infecting inoculum.

Human american cutaneous leishmaniasis (Leishmania b. braziliensis) in Brazil: lymphoproliferative responses and influence of therapy.

The host defence to Leishmania parasites is believed to depend on cell-mediated immune responses. Three groups of inhabitants from an endemic area in Rio de Janeiro were studied: Group I consisted of 28 patients with cutaneous lesions, Group II of 28 healthy persons (without ulcers) but with positive Montenegro skin tests (MST) and Group III of 29 healthy persons with negative MST. The peripheral blood lymphocyte proliferative responses induced by leishmanial-antigens (Leishmania b. braziliensis lymphoproliferative response) as well as by Concanavalin A (Con A-lymphoproliferative response), both measured by 3H-thymidine incorporation were tested in each group. The results showed that: The Leishmania b. braziliensis lymphoproliferative response (L.b.b.-LPR) in healthy persons with positive MST (Group II) was higher than in patients prior to therapy (Group I); A significantly higher L.b.b.-LPR was found in patients and healthy persons with positive MST as compared to Group III (negative MST); The L.b.b.-LPR of Group I (patients) increased during antimonial therapy--this might possibly be related to the destruction of parasites; The levels of L.b.b.-LPR after therapy became similar to the ones before therapy; All individuals from the three groups had a positive Con A-lymphoproliferative response (Con A-LPR); All patients who had a histopathological picture of granulomatous reaction also had a positive L.b.b.-LPR; A poor response to antimonial therapy observed in six patients was associated with a low L.b.b.-LPR.