Efficacy of cytoreductive surgery for metastatic upper tract urothelial carcinoma: a Surveillance, Epidemiology and End Results (SEER) study of 508 patients.

Background: Cisplatin-based combination chemotherapy alone is currently considered the standard of care for patients with metastatic upper tract urothelial carcinoma (mUTUC). However, less research has been done on the efficacy of other combinations. In this study, we explored the role of cytoreductive surgery in patients with mUTUC receiving different types of systemic therapy. Methods: Data from 9,436 anonymized records were abstracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2008-2018. Of these, 508 individuals received systemic therapy subsequent to being diagnosed with mUTUC. These patients had all been treated with systemic therapies such as chemotherapy and/or radiotherapy. Patients were stratified into either a non-surgical or surgical group based on cytoreductive surgery status before systemic therapeutics commenced. Kaplan-Meier curves were used to compare overall survival (OS) and cancer-specific survival (CSS). Cox's proportional hazard models were then used to analyze prognostic factors related to OS and CSS. Results: Of the 508 cases, 36.8% (n=187) had received cytoreductive surgery with systemic treatments. The remaining 63.2% (n=321) received either chemotherapy and/or radiotherapy alone. Kaplan-Meier curves showed that 11.6% had 3-year OS [95% confidential interval (CI): 7.1-17.3] for cytoreductive surgery with systemic treatment and 4.9% (95% CI: 2.7-8.0) for systemic treatment alone (P=0.001). The 3-year CSS was 14.9% for cytoreductive surgery plus systemic treatment (95% CI: 9.4-21.7%) and 6.0% (95% CI: 3.4-9.8%) for systemic treatments alone (P=0.003). Under multivariate regression analysis, primary ureter site OS had a hazard ratio (HR) of 0.74 (95% CI: 0.58-0.95, P=0.02) and a CSS HR of 0.72 (95% CI: 0.56-0.94, P=0.01). The cytoreductive surgery OS HR was 0.79 (95% CI: 0.65-0.95, P=0.02) and the CSS HR was 0.75 (95% CI: 0.61-0.92, P=0.006). Additionally, chemotherapy had an OS HR of 0.46 (95% CI: 0.33-0.0.65, P<0.001) and a CSS HR of 0.44 (95% CI: 0.31-0.63, P<0.001). Bones and liver metastases were also indicative of poorer prognosis. Validation was conducted through subgroup analysis which suggested cytoreductive surgery was effective only for patients who received chemotherapy or combined chemo-radiotherapy but not for radiotherapy alone. Conclusions: Cytoreductive surgery provided significantly increased OS and CSS for mUTUC patients who received chemotherapy or combined chemo-radiotherapy in this study. In addition, the primary tumor and metastatic sites were shown to be related to improved patient survival although this was a small and relatively homogeneous cohort of study, sample therefore, further research is required.

Association of health-related quality of life with urinary tract infection among kidney stone formers.

Kidney stones and infections significantly affect patients' health-related quality of life (HRQOL); however, the relationship between urinary tract infections (UTIs) and HRQOL in patients with kidney stones remains unclear. This study aimed to investigate the relationship using the validated Chinese version of the Wisconsin Stone Quality of Life questionnaire (C-WISQOL). We prospectively recruited 307 patients with kidney stones to complete the C-WISQOL before and after stone removal. The participants were diagnosed with UTI based on the presence of pyuria or bacteriuria with or without clinical symptoms. The psychometric properties of the C-WISQOL were statistically analyzed. Multivariate linear regression was used to predict the risk factors for impaired HRQOL in patients with stones and UTIs. The questionnaire is a reliable and robust tool for evaluating HRQOL in Chinese-speaking patients with urolithiasis. The UTI and kidney stone co-occurrence was significantly associated with female sex, diabetes mellitus, more previous stone events, higher antibiotic usage, positive stone- or UTI-related symptoms, and postoperative residual stones. The preoperative C-WISQOL scores and improvement in the HRQOL after stone removal in patients clinically diagnosed with UTI were significantly inferior to those in patients without UTI. The regression analyses showed that worse HRQOL was predicted by more previous stone events and positive stone- or UTI-related symptoms. In contrast, the presence of diabetes mellitus and postoperative residual stone fragments predicted a lower improvement in the HRQOL. These findings underscore UTI's harmful impact on perioperative HRQOL in patients with kidney stones and could help strategies benefit those patients.

HIV-1 binding to CD4 on CD4+CD25+ regulatory T cells enhances their suppressive function and induces them to home to, and accumulate in, peripheral and mucosal lymphoid tissues: an additional mechanism of immunosuppression.

The establishment and persistence of many chronic infections have been demonstrated to depend on restraint of the vigor of the anti-microbial immune responses by CD4+CD25+ regulatory T (Treg) cells. In HIV-infected individuals, Treg cells suppress both HIV-specific and general CD4+ and CD8+ T cell responses. Increases of CD4+CD25+ Treg cell function during viral infections might be mediated by host-derived pro-inflammatory molecules or directly by viral infection or binding. We examined the effect HIV has upon binding to CD4+CD25+ Treg cells by exposing human purified CD4+CD25+ T cells from healthy donors to HIV-1 in vitro and assessing their Treg-associated functional marker profile and suppressive activities. We found that HIV-1 binding increased their suppressor activities by 2- to 5-fold, which was accompanied by enhanced expression of Treg-associated functional markers sCTLA-4, glucocorticoid-induced tumor necrosis factor receptor and FoxP3. Moreover, HIV-1 binding extended the survival of CD4+CD25+ Treg cells and up-regulated the expression of homing receptors CD62L and integrin alpha4beta7, which in turn would result in Treg cells migrating more rapidly to the peripheral lymph nodes and mucosal lymphoid tissues where anti-HIV immune responses are occurring. Importantly, CD4+CD25+ Treg cells exposed to HIV were not susceptible to homing-induced apoptosis like are other resting CD4+ cells following HIV-1 binding. We show that CD4+CD25+ Treg cells respond directly to HIV-1 itself through HIV gp120 interactions with CD4 molecules. Collectively, our findings explain a mechanism that contributes to the abnormal accumulation of intensified Treg cells in lymphoid and mucosal tissues in HIV patients, resulting in impairment of immune responses which would greatly help HIV persistence.

Apoptosis induced in HIV-1-exposed, resting CD4+ T cells subsequent to signaling through homing receptors is Fas/Fas ligand-mediated.

The hallmark of HIV-1 disease is the gradual disappearance of CD4+ T cells from the blood. The mechanism of this depletion, however, is still unclear. Evidence suggests that lymphocytes die in lymph nodes, not in blood, and that uninfected bystander cells are the predominant cells dying. Our and others' previous studies showed that the lymph node homing receptor, CD62 ligand (CD62L), and Fas are up-regulated on resting CD4+ T cells after HIV-1 binding and that these cells home to lymph nodes at an enhanced rate. During the homing process, signals are induced through various homing receptors, which in turn, induced many of the cells to undergo apoptosis after they entered the lymph nodes. The purpose of this study was to determine how the homing process induces apoptosis in HIV-1-exposed, resting CD4+ T cells. We found that signaling through CD62L up-regulated FasL. This resulted in apoptosis of only HIV-1-presignaled, resting CD4+ T cells, not normal CD4+ T cells. This homing receptor-induced apoptosis could be blocked by anti-FasL antibodies or soluble Fas, demonstrating that the Fas-FasL interaction caused the apoptotic event.

A novel in vitro system to generate and study latently HIV-infected long-lived normal CD4+ T-lymphocytes.

Studies of mechanisms of HIV-latency and its reactivation in long-lived resting CD4+ T-lymphocytes in patients have been limited due to the very low frequency of these cells ( approximately 1-10 cells per 10(6) CD4+ T-cells). To circumvent this obstacle, an in vitro culture system for post-activation long-term survival of normal CD4+ T-cells in a quiescent (non-cycling) state was developed and used to generate latently infected, long-lived quiescent CD4+ T-cells from HIV-infected, activated normal CD4+ T-lymphocytes. This yielded a frequency of approximately 5x10(4) latently infected cells per 10(6) cells in culture, which is approximately 10(3)- to 10(4)-fold higher than that available from patients. Moreover, 5-10% of long-term surviving non-cycling T-cells were found to make infectious HIV continuously at low levels, showing that HIV production from infected T-cells does not require full cellular activation. This model system should facilitate studies of long-lived, latently infected and persistently HIV-producing quiescent normal CD4+ T-lymphocytes.

HIV-1 induces IL-10 production in human monocytes via a CD4-independent pathway.

In HIV-infected patients, increased levels of IL-10, mainly produced by virally infected monocytes, were reported to be associated with impaired cell-mediated immune responses. In this study, we investigated how HIV-1 induces IL-10 production in human monocytes. We found that CD14(+) monocytes infected by either HIV-1(213) (X4) or HIV-1(BaL) (R5) produced IL-10, IL-6, tumor necrosis factor-alpha (TNF-alpha), and to a lesser extent, IFN-gamma. However, the capacity of HIV-1 to induce these cytokines was not dependent on virus replication since UV-inactivated HIV-1 induced similar levels of these cytokines. In addition, soluble HIV-1 gp160 could induce CD14(+) monocytes to produce IL-10 but at lower levels. Cross-linking CD4 molecules (XLCD4) with anti-CD4 mAbs and goat anti-mouse IgG (GAM) resulted in high levels of IL-6, TNF-alpha and IFN-gamma but no IL-10 production by CD14(+) monocytes. Interestingly, neither anti-CD4 mAbs nor recombinant soluble CD4 (sCD4) receptor could block IL-10 secretion induced by HIV-1(213), HIV-1(BaL) or HIV-1 gp160 in CD14(+) monocytes, whereas anti-CD4 mAb or sCD4 almost completely blocked the secretion of the other cytokines. Furthermore, HIV-1(213) could induce IL-10 mRNA expression in CD14(+) monocytes while XLCD4 by anti-CD4 mAb and GAM failed to do so. As with IL-10 protein levels, HIV-1(213)-induced IL-10 mRNA expression in CD14(+) monocytes could not be inhibited by anti-CD4 mAb or sCD4. Taken together, HIV-1 binding to CD14(+) monocytes can induce CD4-independent IL-10 production at both mRNA and protein levels. This finding suggests that HIV induces the immunosuppressive IL-10 production in monocytes and is not dependent on CD4 molecules and that interference with HIV entry through CD4 molecules may have no impact on counteracting the effects of IL-10 during HIV infection.

CD4+CD25+ regulatory T cells restrain pathogenic responses during Leishmania amazonensis infection.

Although activation of CD4(+) T cells mediates pathogenesis in Leishmania amazonensis (La)-infected mice, these susceptible mice do not develop a polarized Th2 response, suggesting a unique mechanism of disease susceptibility. To understand how Th cell activities are regulated, we examined the frequency and phenotypes of regulatory T (Treg) cells. At 1-3 wk of infection, relatively high percentages of CD4(+)CD25(+)CD86(+) T cells, as well as high levels of FoxP3, TGF-beta1, and IL-10RI transcripts, were detected in the skin and draining lymph nodes, indicating local accumulation of Treg cells. Lesion-derived, IL-10-producing CD4(+)CD25(+) cells effectively suppressed proliferation and cytokine (IL-2 and IFN-gamma) production of CD4(+)CD25(-) effector cells. Adoptive transfer of lesion-derived CD4(+)CD25(+) cells to syngeneic, naive C57BL/6 mice before infection significantly reduced disease development. To further validate the beneficial role of Treg cells in La infection, we adoptively transferred CD25(+) T cell-depleted splenocytes (derived from naive mice) into RAG1(-/-) mice. This transfer rendered RAG1(-/-) mice more susceptible to La infection than the mice receiving control splenocytes. The beneficial effect of Treg cells was transitory and correlated with decreased activation of IFN-gamma-producing effector T cells. This study uncovers an intriguing role of Treg cells in restraining pathogenic responses during nonhealing Leishmania infection and emphasizes a balance between Treg and Th1-like effector cells in determining the outcome of New World cutaneous leishmaniasis.

Enhanced replication of Leishmania amazonensis amastigotes in gamma interferon-stimulated murine macrophages: implications for the pathogenesis of cutaneous leishmaniasis.

During Leishmania major infection in mice, gamma interferon (IFN-gamma) plays an essential role in controlling parasite growth and disease progression. In studies designed to ascertain the role of IFN-gamma in Leishmania amazonensis infection, we were surprised to find that IFN-gamma could promote L. amazonensis amastigote replication in macrophages (Mphis), although it activated Mphis to kill promastigotes. The replication-promoting effect of IFN-gamma on amastigotes was independent of the source and genetic background of Mphis, was apparently not affected by surface opsonization of amastigotes, was not mediated by interleukin-10 or transforming growth factor beta, and was observed at different temperatures. Consistent with the different fates of promastigotes and amastigotes in IFN-gamma-stimulated Mphis, L. amazonensis-specific Th1 transfer helped recipient mice control L. amazonensis infection established by promastigotes but not L. amazonensis infection established by amastigotes. On the other hand, IFN-gamma could stimulate Mphis to limit amastigote replication when it was coupled with lipopolysaccharides but not when it was coupled with tumor necrosis factor alpha. Thus, IFN-gamma may play a bidirectional role at the level of parasite-Mphi interactions; when it is optimally coupled with other factors, it has a protective effect against infection, and in the absence of such synergy it promotes amastigote growth. These results reveal a quite unexpected aspect of the L. amazonensis parasite and have important implications for understanding the pathogenesis of the disease and for developing vaccines and immunotherapies.

DNA immunization with the gene encoding P4 nuclease of Leishmania amazonensis protects mice against cutaneous Leishmaniasis.

Infection with the protozoan parasite Leishmania amazonensis can cause diverse clinical forms of leishmaniasis. Immunization with purified P4 nuclease protein has been shown to elicit a protective response in mice challenged with L. amazonensis and L. pifanoi. To explore the potential of a DNA-based vaccine, we tested the L. amazonensis gene encoding P4 nuclease as well as adjuvant constructs encoding murine interleukin-12 (IL-12) and L. amazonensis HSP70. Susceptible BALB/c mice were immunized with the DNA encoding P4 alone, P4/IL-12, or P4/HSP70 prior to challenge with L. amazonensis promastigotes. Mice given P4/IL-12 exhibited no lesion development and had a 3- to 4-log reduction in tissue parasite burdens compared to controls. This protection corresponded to significant increases in gamma interferon and tumor necrosis factor alpha production and a reduction in parasite-specific immunoglobulin G1, suggesting an enhancement in Th1 responses. Moreover, we immunized mice with the L. amazonensis vaccines to determine if this vaccine regimen could provide cross-protection against a genetically diverse species, L. major. While the P4/HSP70 vaccine led to self-healing lesions, the P4/IL-12 vaccine provided negligible protection against L. major infection. This is the first report of successful use of a DNA vaccine to induce protection against L. amazonensis infection. Additionally, our results indicate that different vaccine combinations, including DNA encoding P4, HSP70, or IL-12, can provide significant protection against both Old World and New World cutaneous leishmaniasis.

Impaired expression of inflammatory cytokines and chemokines at early stages of infection with Leishmania amazonensis.

Infection of mice with Leishmania major results in disease progression or resolution, largely depending on the genetic backgrounds of the mouse strains. Infection with Leishmania amazonensis, on the other hand, causes progressive cutaneous lesions in most inbred strains of mice. We hypothesized that deficient activation of early immune responses contributes to the pathogenesis in L. amazonensis-infected mice. To distinguish early molecular events that determine the outcome of Leishmania infections, we examined cytokine gene expression in C57BL/6 mice infected with either L. amazonensis or L. major (a healing model). After 2 to 4 weeks, L. amazonensis-infected mice had significantly delayed and depressed expression of inflammatory cytokines (interleukin-12 [IL-12], gamma interferon, IL-1 alpha, IL-1 beta), CC chemokines (CC chemokine ligand 3 [CCL3]/macrophage inflammatory protein 1 alpha [MIP-1 alpha], CCL4/MIP-1 beta, CCL5/RANTES, MIP-2), and chemokine receptors (CCR1, CCR2, CCR5) in foot tissues and draining lymph nodes compared to the expression in L. major-infected controls. These findings correlated with defective T-cell responsiveness to parasite stimulation in vivo and in vitro. Adoptive transfer of L. amazonensis-specific Th1 cells prior to infection overcame the immune defects of the animals, leading to complete control of the disease. Studies with gene knockout mice suggested that IL-10, but not IL-4, contributed partially to compromised immunity in L. amazonensis-infected hosts. The data suggest that there is impairment in multiple immune functions at early stages of infection with L. amazonensis parasites and provide a compelling rationale to explore immune augmentation as an intervention in American cutaneous leishmaniasis.

Analysis of T helper cell responses during infection with Leishmania amazonensis.

Most inbred strains of mice are susceptible to Leishmania amazonensis infection and develop progressive cutaneous lesions. However, the role of Th subsets in the disease and the molecular basis of pathogenesis are unclear. To address this issue, we examined the frequency of cytokine-producing CD4+ T cells and the profile of alphabeta T cell receptor (TCR) usage in infected BALB/c mice. At different infection stages, CD4+ cells of draining lymph nodes contained comparable frequencies of Th1 and Th2 cells, produced comparable levels of interleukin-4 (IL-4) and interferon-gamma in vitro, and showed no significant bias in aalphabetaTCR usage. However, T cells became highly polarized to a Th2 phenotype (IL-4+, IL-10+) within a few cycles of in vitro restimulation. These Th2 cells preferentially expressed Valpha2, Vbeta4, or Vbeta8.1/8.2, and significantly exacerbated disease in cell-transferred mice. Thus, unlike a Th2-dominant phenotype seen in L. major infection, a mixed Th1/Th2 response can be maintained in L. amazonensis-infected mice via an as-yet-unidentified mechanism.