Tumor microenvironments feature immune inhibitory mechanisms that prevent T cells from generating effective antitumor immune responses. Therapeutic interventions aimed at disrupting these inhibitory ...mechanisms have been shown to enhance antitumor immunity, but they lack direct cytotoxic effects. Here, we investigated the effect of cytotoxic cancer chemotherapeutics on immune inhibitory pathways. We observed that exposure to platinum-based chemotherapeutics markedly reduced expression of the T cell inhibitory molecule programmed death receptor-ligand 2 (PD-L2) on both human DCs and human tumor cells. Downregulation of PD-L2 resulted in enhanced antigen-specific proliferation and Th1 cytokine secretion as well as enhanced recognition of tumor cells by T cells. Further analysis revealed that STAT6 controlled downregulation of PD-L2. Consistent with these data, patients with STAT6-expressing head and neck cancer displayed enhanced recurrence-free survival upon treatment with cisplatin-based chemoradiation compared with patients with STAT6-negative tumors, demonstrating the clinical relevance of platinum-induced STAT6 modulation. We therefore conclude that platinum-based anticancer drugs can enhance the immunostimulatory potential of DCs and decrease the immunosuppressive capability of tumor cells. This dual action of platinum compounds may extend their therapeutic application in cancer patients and provides a rationale for their use in combination with immunostimulatory compounds.
Capecitabine, oxaliplatin, and bevacizumab are standard treatment for metastatic colorectal cancer. This trial tested whether adding cetuximab to this combination is beneficial. The addition of ...cetuximab resulted not only in shorter progression-free survival than standard treatment but also in a reduced quality of life.
This trial tested whether adding cetuximab to standard treatment for metastatic colorectal cancer is beneficial. The addition of cetuximab resulted not only in shorter progression-free survival than standard treatment but also in a reduced quality of life.
Fluoropyrimidines (e.g., fluorouracil and capecitabine), irinotecan, and oxaliplatin are the standard cytotoxic drugs used in treating metastatic colorectal cancer.
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The combination of capecitabine and oxaliplatin is similar to the combination of fluorouracil and capecitabine in efficacy and safety.
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Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF),
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combined with fluoropyrimidine-based chemotherapy is now the standard first-line treatment for metastatic colorectal cancer. Cetuximab, a chimeric IgG1 monoclonal antibody against epidermal growth factor receptor (EGFR), has efficacy as monotherapy and in combination with irinotecan in irinotecan-resistant patients.
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We prospectively evaluated the addition of cetuximab to capecitabine, . . .
Lymph node status is the strongest prognostic factor for survival in colorectal cancer. There are several guidelines concerning the minimum numbers of lymph nodes that need to be examined to make ...reliable staging possible, but there is no consensus in the available literature. In this study, we determine in patients with rectal cancer factors that relate to the number of lymph nodes found and the presence of lymph node metastasis. In addition, the number of examined lymph nodes was correlated with prognosis. A total of 1227 patients were selected from a multicenter prospective randomized trial investigating the value of neoadjuvant radiotherapy. The median number of examined lymph nodes in all patients was 7.0. The number of retrieved lymph nodes in patients with node metastasis was significantly higher than in node negative patients. After neoadjuvant radiotherapy fewer lymph nodes were retrieved (6.9 vs. 8.5; P<0.0001). Variations in lymph node yield between pathology laboratories and individual pathologists were striking. The following patient and tumor characteristics are associated with a significant lower lymph node retrieval: age over 60 years, overweight, small size, and low invasion depth of the tumor, poor differentiation grade, and absence of a lymphoid reaction. Node negative patients in whom seven or less lymph nodes were examined had a lower recurrence free interval than patients in whom at least 8 lymph nodes were examined (17.0% vs. 10.7%, P=0.016). We conclude that in pathology laboratories a median of at least 8 lymph nodes need to be examined in rectal cancer specimens, but that higher numbers are desirable and achievable in most cases, even after preoperative radiotherapy.
Abstract Background Next to KRAS mutation status, additional predictive markers are needed for the response to cetuximab in patients with metastatic colorectal cancer (mCRC). Previous studies ...indicated that germline polymorphisms in specific genes may predict efficacy and toxicity of cetuximab in mCRC patients. Methods Germline DNA was isolated from 246 KRAS wild-type mCRC patients who were treated in the phase III CAIRO2 study with chemotherapy and bevacizumab alone or with the addition of cetuximab. Associations of epidermal growth factor ( EGF ) 61A > G, EGF receptor ( EGFR ) CA14–22 , cyclin D1 ( CCND1 ) 932G > A, fragment-C gamma receptor ( FCGR ) 2A 535A > G and FCGR3A 818A > C polymorphisms with progression-free survival (PFS) and cetuximab-related skin toxicity were studied. Results In cetuximab-treated patients, the FCGR3A 818C-allele was associated with decreased PFS compared with the FCGR3A 818AA genotype (median PFS, 8.2 95%CI, 6.7–10.3 versus 12.8 95%CI, 10.3–14.7 months, respectively; HR, 1.57 95%CI, 1.06–2.34; P = .025). The EGFR ⩾ 20 genotype was associated with decreased PFS compared with the EGFR < 20 genotype (median PFS, 7.6 95%CI, 6.7–10.0 versus 12.4 95%CI, 10.3–13.4 months, respectively; HR, 1.58 95%CI, 1.06–2.35; P = .024). The FCGR3A and EGFR polymorphisms were not associated with PFS in patients treated without cetuximab. None of the polymorphisms were associated with the incidence of grades 2–3 skin toxicity. Conclusion EGFR and FCGR3A germline polymorphisms are associated with PFS in KRAS wild-type mCRC patients treated with cetuximab, bevacizumab and chemotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Toll-like receptor (TLR) 2 and TLR4 play a pivotal role in recognition of Candida albicans. We demonstrate that TLR2(-/-) mice are more resistant to disseminated Candida infection, and this is ...associated with increased chemotaxis and enhanced candidacidal capacity of TLR2(-/-) macrophages. Although production of the proinflammatory cytokines TNF, IL-1alpha, and IL-1beta is normal, IL-10 release is severely impaired in the TLR2(-/-) mice. This is accompanied by a 50% decrease in the CD4+CD25+ regulatory T (Treg) cell population in TLR2(-/-) mice. In vitro studies confirmed that enhanced survival of Treg cells was induced by TLR2 agonists. The deleterious role of Treg cells on the innate immune response during disseminated candidiasis was underscored by the improved resistance to this infection after depletion of Treg cells. In conclusion, C. albicans induces immunosuppression through TLR2-derived signals that mediate increased IL-10 production and survival of Treg cells. This represents a novel mechanism in the pathogenesis of fungal infections.
Abstract Background Over the past decades, significant progress has been achieved in the cytotoxic treatment of colorectal cancer (CRC) by the use of fluoropyrimidines, irinotecan and oxaliplatin. ...However, as not all patients do respond to chemotherapy, there is a need for predictive and prognostic factors in order to optimise the treatment for individual patients. Although many potential molecular markers have been studied, none of these have been implemented in the standard of care for colorectal cancer patients. Method We performed a review of the data on the prognostic and/or predictive value of molecular markers for cytotoxic drugs in CRC. The following markers were included: dihydropyrimidine dehydrogenase, orotate phosphoribosyl transferase, thymidine phosphorylase, thymidylate synthase, mismatch repair deficiency, topoisomerase 1, excision cross-complementing gene and carboxylesterases. Results With the exception of mismatch repair deficiency, these molecular markers showed divergent and inconsistent results on their prognostic and/or predictive value. This underscores the complexity of the role of these markers. Conclusions We conclude that further retrospective testing of these markers is unlikely to add clinically useful results. More definite results may only be expected when these markers are included in the design of prospective randomised studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
BackgroundInterleukin (IL)–1α and IL-1β are protective proinflammatory cytokines involved in host defense against Candida albicans. It is, however, unknown whether they provide protection through ...similar mechanisms. We investigated the effect of endogenous IL-1α and IL-1β on disseminated C. albicans infection MethodsMice deficient in the genes encoding IL-1α (IL-1α−/−), IL-1β (IL-1β−/−), or both molecules (IL-1α−/−β−/−) were used. Survival and C. albicans outgrowth in the kidneys was assessed after intravenous injection of C. albicans ResultsBoth mortality and C. albicans outgrowth in the kidneys were significantly increased in IL-1α−/− and IL-1β−/− mice, compared with those in control mice, with the IL-1α−/−β−/− mice being most susceptible to disseminated candidiasis. The host defense mechanisms triggered by IL-1α and IL-1β differed from one another. IL-1β−/− mice showed decreased recruitment of granulocytes in response to an intraperitoneal C. albicans challenge, and generation of superoxide production was diminished in IL-1β−/− granulocytes. IL-1α−/− mice had a reduced capacity to damage C. albicans pseudohyphae. Protective type 1 responses were deficient in both IL-1α−/− and IL-1β−/− mice, as assessed by production of interferon-γ by splenocytes in response to heat-killed C. albicans ConclusionAlthough IL-1α and IL-1β have differential effects on the various arms of host defense, both cytokines are essential for mounting a protective host response against invasive C. albicans infection
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Groenen P J T A, Blokx W A M, Diepenbroek C, Burgers L, Visinoni F, Wesseling P & van Krieken J H J M (2011) Histopathology59, 1–7
Preparing pathology for personalized medicine: possibilities for ...improvement of the pre‐analytical phase
With the introduction of new biological agents for cancer treatment enabling ‘personalized medicine’, treatment decisions based on the molecular features of the tumour are more common. Consequently, tissue evaluation in tumour pathology is becoming increasingly based on a combination of classical morphological and molecular analysis. The results of diagnostic tests rely not only on the quality of the method used but, to a large extent, also on the quality of specimens, which is dependent on the pre‐analytical procedures and storage. With the introduction of predictive immunohistochemical and molecular tests in clinical pathology, improvement and standardization of pre‐analytical procedures has become crucial. The aim of this review is to increase awareness with regard to tissue handling and for standardization of the pre‐analytical phase of a diagnostic process. In addition, several processing steps in tissue handling that need to be improved in order to obtain the quality needed for modern molecular medicine will be discussed. Optimal, standardized procedures are crucial if a high standard of test results is to be achieved, which is what each patient deserves.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The KRAS mutation status predicts the outcome of treatment with epidermal growth factor receptor targeted agents, and therefore the testing for KRAS mutations has become an important diagnostic ...procedure. To optimize the quality of this test, we compared the results of the two most commonly used KRAS mutation tests, cycle sequencing and a real‐time PCR‐based assay, in DNA extracted from formalin‐fixed paraffin‐embedded (FFPE) colorectal cancer samples of 511 patients. The results were interpreted in the context of the tumour cell percentage and the assay parameters. In 510 samples KRAS mutation status assessment was successful. A KRAS mutation was detected in 201 tumours (39.4%). Sequencing and the real‐time PCR‐based assay generated the same result in 486 samples (95.3%). The sequencing result was considered false positive in one (0.2%) and false negative in nine samples (1.8%). The assay result was considered false positive in six (1.2%) and false negative in seven samples (1.4%). Explanations for discrepant test results were a higher sensitivity of the assay in samples with a low tumour cell percentage, occurrence of mutations that are not covered by the assay and δ Ct values approximating the cut‐off value of the assay. In conclusion, both sequencing and the real‐time PCR‐based assay are reliable tests for KRAS mutation analysis in FFPE colorectal cancer samples, with a sensitivity of 95.5% (95% confidence interval CI 91.7–97.9%) and 96.5% (95% CI 93.0–98.6%), respectively. The real‐time PCR based assay is the method of choice in samples with a tumour cell percentage below 30%.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Follicular lymphoma (FL) is a disease characterized by a long clinical course marked by frequent relapses that vary in clinical aggressiveness over time. Therefore, the main dilemma at each relapse ...is the choice for the most effective treatment for optimal disease control and failure-free survival while at the same time avoiding overtreatment and harmful side effects. The selection for more aggressive treatment is currently based on histologic grading and clinical criteria; however, in up to 30% of all cases these methods prove to be insufficient. Using supervised classification on a training set of paired samples from patients who experienced either an indolent or aggressive disease course, a gene expression profile of 81 genes was established that could, with an accuracy of 100%, distinguish low-grade from high-grade disease. This profile accurately classified 93% of the FL samples in an independent validation set. Most important, in a third series of FL cases where histologic grading was ambiguous, precluding meaningful morphologic guidance, the 81-gene profile shows a classification accuracy of 94%. The FL stratification profile is a more reliable marker of clinical behavior than the currently used histologic grading and clinical criteria and may provide an important alternative to guide the choice of therapy in patients with FL both at presentation and at relapse. (Blood. 2005;105:301-307)
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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