Cabozantinib as the causative agent of high-grade fever in a patient with a background of metastatic clear cell renal cell carcinoma: a case report.

BACKGROUND: Fever, as an adverse event, is well documented in a wide array of drugs including multiple tyrosine kinase inhibitors however, it is not a previously well described consequence of the novel multi-targeted tyrosine kinase inhibitor, cabozantinib. CASE PRESENTATION: In this paper we document the first detailed review of high-grade fevers in a 54 year old male (Caucasian) with a background of metastatic clear cell renal cell carcinoma recently commenced on cabozantinib. After detailed investigation, we exclude infection and other common causes of fever as the causative agent and further, definitively resolve the recurrent fever by ceasing cabozantinib and starting a short course of oral corticosteroids. CONCLUSIONS: We have demonstrated that cabozantinib should always be considered in the aetiology of high-grade fever in relevant patients. Further, we demonstrate that temporary cessation of cabozantinib and a course of short-term steroids can induce resolution of fever and allow for recommencement of cabozantinib safely thereafter.

Online self-test identifies women at high familial breast cancer risk in population-based breast cancer screening without inducing anxiety or distress.

INTRODUCTION: Identifying high familial breast cancer (FBC) risk improves detection of yet unknown BRCA1/2-mutation carriers, for whom BC risk is both highly likely and potentially preventable. We assessed whether a new online self-test could identify women at high FBC risk in population-based BC screening without inducing anxiety or distress. METHODS: After their visit for screening mammography, women were invited by email to take an online self-test for identifying highly increased FBC risk-based on Dutch guidelines. Exclusion criteria were previously diagnosed as increased FBC risk or a personal history of BC. Anxiety (State-Trait Anxiety Inventory Dutch Version), distress (Hospital Anxiety Depression Scale) and BC risk perception were assessed using questionnaires, which were completed immediately before and after taking the online self-test and 2 weeks later. RESULTS: Of the 562 women invited by email, 406 (72%) completed the online self-test while 304 also completed questionnaires (response rate 54%). After exclusion criteria, 287 (51%) were included for data analysis. Median age was 56 years (range 50-74). A high or moderate FBC risk was identified in 12 (4%) and three (1%) women, respectively. After completion of the online self-test, anxiety and BC risk perception were decreased while distress scores remained unchanged. Levels were below clinical relevance. Most women (85%) would recommend the self-test; few (3%) would not. CONCLUSION: The online self-test identified previously unknown women at high FBC risk (4%), who may carry a BRCA1/2-mutation, without inducing anxiety or distress. We therefore recommend offering this self-test to women who attend population-based screening mammography for the first time.

Lifestyle Risk Factors for Breast Cancer in BRCA1/2-Mutation Carriers Around Childbearing Age.

BRCA1/2-mutation carriers are at high risk of breast cancer (BC) and ovarian cancer. Physical inactivity, overweight (body mass index ≥25, BMI), smoking, and alcohol consumption are jointly responsible for about 1 in 4 postmenopausal BC cases in the general population. Limited evidence suggests physical activity also increases BC risk in BRCA1/2-mutation carriers. Women who have children often reduce physical activity and have weight gain, which increases BC risk. We assessed aforementioned lifestyle factors in a cohort of 268 BRCA1/2-mutation carriers around childbearing age (born between 1968 and 1983, median age 33 years, range 21-44). Furthermore, we evaluated the effect of having children on physical inactivity and overweight. Carriers were asked about lifestyle 4-6 weeks after genetic diagnosis at the Familial Cancer Clinic Nijmegen. Physical inactivity was defined as sports activity fewer than once a week. Carriers were categorized according to the age of their youngest child (no children, age 0-3 years and ≥4 years). In total, 48% of carriers were physically inactive, 41% were overweight, 27% smoked, and 70% consumed alcohol (3% ≥8 beverages/week). Physical inactivity was 4-5 times more likely in carriers with children. Overweight was not associated with having children. Carriers with children are a subgroup that may specifically benefit from lifestyle support to reduce BC risk.

Very high uptake of risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers: A single-center experience.

OBJECTIVE: Risk-reducing salpingo-oophorectomy (RRSO) is the only effective surgical strategy to reduce the increased risk of epithelial ovarian cancer in BRCA1/2 mutation carriers. Given the long-term health consequences of premature surgical menopause, we need insight in uptake and timing of RRSO to guide us in improving healthcare. METHODS: A single-center retrospective cohort study of BRCA1/2 mutation carriers diagnosed and counseled at the multidisciplinary Family Cancer Clinic of the Radboud university medical center in Nijmegen, The Netherlands, between 1999 and 2014. Descriptive statistics were used to analyze uptake and timing of RRSO. RESULTS: Data of 580 BRCA1/2 were analyzed. The uptake of RRSO among mutation carriers who are currently above the upper limit of the recommended age for RRSO, is 98.5% and 97.5% for BRCA1 and BRCA2 mutation carriers, respectively. The vast majority undergoes RRSO ≤40 (BRCA1) or ≤45 (BRCA2) years of age, provided that mutation status is known by that age: 90.8% and 97.3% of BRCA1 and BRCA2 mutation carriers, respectively. CONCLUSIONS: The uptake of RRSO among BRCA1/2 mutation carriers who were counseled at our Family Cancer Clinic is extremely high. High uptake might be largely attributed to the directive and uniform way of counseling by professionals at our Family Cancer Clinic. Given the fact that RRSO is often undergone at premenopausal age in our population, future research should focus on minimizing long-term health consequences of premature surgical menopause either by optimization of hormone replacement therapy or by investigating alternative strategies to RRSO.

Young age and a positive family history of colorectal cancer are complementary selection criteria for the identification of Lynch syndrome.

Families at high risk for Lynch syndrome can effectively be recognised by microsatellite instability (MSI) testing. The aim of the present study is to compare the effectiveness of a MSI test for the identification of Lynch syndrome in patients selected by a pathologist mainly based on young age at diagnosis (MSI-testing-indicated-by-a-Pathologist; MIPA), with that of patients selected by a clinical geneticist mainly based on family history (MSI-testing-indicated-by-Family-History; MIFH). Patients with a Lynch syndrome associated tumour were selected using MIPA (n=362) or MIFH (n=887). Germline DNA mutation testing was performed in 171 out of 215 patients (80%) with a MSI positive tumour. MSI was tested positive in 20% of the MIPA-group group compared to 16% in the MIFH-group (P=0.291). In 91 of 171 patients with MSI positive tumours tested for germline mutations were identified as Lynch syndrome patients: 42% in the MIPA-group and 56% in the MIFH-group (P=0.066). Colorectal cancer (CRC) or endometrial cancer (EC) presenting at an age below 50 years would have led to the diagnosis of Lynch syndrome in 89% of these families (CRC below 50 years: 88% and EC below 50 years: 12%). Families detected by MIPA were characterised more often by extracolonic Lynch syndrome associated malignancies, especially EC (P<0.001). Our results indicate that recognition of Lynch syndrome by CRC or EC below 50 years is as effective as a positive family history. Families from patients selected by individual criteria more often harbour extracolonic Lynch syndrome associated malignancies.

Bone reaction adjacent to microplasma-sprayed calcium phosphate-coated oral implants subjected to an occlusal load, an experimental study in the dog.

BACKGROUND: A new microplasma spraying equipment (MSE) to deposit calcium phosphate (CaP) ceramic coatings onto titanium substrates has been developed. With this system, it is possible to spray fine particles and to apply textured hydroxylapatite coatings onto titanium surfaces. Moreover, due to the low heat power of the microplasma jet, overheating of the powder particles as well as excessive local overheating of the substrate are diminished. Furthermore, because of the small laminar plasma jet, it is possible to achieve high spray efficiency in the case of spraying for dental implants. Also, the low level of noise (25-50 dB) and hardly any dust makes it possible to operate MSE under conditions of normal workrooms. OBJECTIVE: The aim was to investigate, in a mandibular dog model, the effect of functional load on soft-tissue adaptation as well as crestal bone-level changes around titanium implants provided with newly developed microplasma-sprayed CaP coatings. MATERIAL AND METHODS: For histomorphometrical evaluation, 56 screw-type titanium implants were inserted into the mandibles of seven adult Beagle dogs. The implants were either acid etched without an additional coating, coated with a conventionally plasma-sprayed CaP ceramic (PS), coated with a microplasma-sprayed CaP ceramic (MPS) or with a microplasma-sprayed coating at only the apical part (aMPS). To assess the effect of occlusal loading, a split-mouth design was used. Six weeks after implantation, the implants in one half of the mandible of each dog were functionally loaded whereas the contra lateral implants served as control. One year after loading, the animals were sacrificed. Soft-tissue dimension as well as marginal bone level were histologically assessed. RESULTS: Histometric analysis of undecalcified histologic sections included the evaluation of the sulcus depth, the dimension of the junctional epithelium and the connective tissue as well as the first bone-to-implant contact. For MPS-surfaced implants, functional loading was associated with--compared with the non-loaded state--unchanged soft-tissue dimension. Furthermore, the soft-tissue dimension did not differ from the dimensions around non-coated, PS and aMPS implants. Moreover, the first bone-to-implant contact was not significantly altered by functional loading and comparable non-coated, PS and aMPS implants. CONCLUSION: Within the limits of the experiment, we conclude that, in comparison, functional loading does not affect the marginal soft-tissue response to MPS CaP-coated implants. However, in comparison, functional loading might affect marginal bone response to MPS CaP-coated implants.

Loaded microplasma-sprayed CaP-coated implants in vivo.

Microplasma spray equipment to deposit calcium phosphate ceramic (CaP) coatings has been developed. Fifty-six titanium implants were inserted into the mandibles of 7 adult beagle dogs. The implants were either acid-etched (NC), conventionally plasma-sprayed (PS), micro-plasma-sprayed (MPS), or micro-plasma-sprayed (aMPS) only at the apical part. After 6 weeks, implants in one half of the mandible were subjected to load. Fifty-two weeks thereafter, the animals were killed. Regardless of load, bone healing was comparable for all surfaces tested. It was concluded that loading of MPS CaP-coated implants evokes a favorable bone response, and that the bone response does not differ from that of PS CaP-coated implants. However, functional loading of PS as well as MPS CaP-coated implants might be associated with increased crestal bone maintenance as compared with non-coated implants.

Bone reaction adjacent to microplasma-sprayed CaP-coated oral implants subjected to occlusal load, an experimental study in the dog. Part I: short-term results.

BACKGROUND: A new microplasma spraying equipment (MSE) to deposit calcium phosphate ceramic (CaP) coatings onto titanium substrates has been developed. With this system, it is possible to spray fine particles and to apply textured hydroxylapatite coatings onto titanium surfaces. Moreover, due to the low heat power of the microplasma jet, overheating of the powder particles as well as excessive local overheating of the substrate is diminished. Furthermore, because of the small laminar plasma jet, it is possible to achieve high spray efficiency in the case of spraying for dental implants. Also, the low level of noise (25-50 dB) and hardly any dust makes it possible to operate MSE under conditions of normal workrooms. OBJECTIVE: The aim was to investigate, in a mandibular dog model, bone biological properties and the occlusal loading effects of titanium implants provided with newly developed microplasma-sprayed CaP coatings. MATERIAL AND METHODS: For histomorphometrical evaluation, 48 screw-type titanium implants were inserted into the mandibles of six adult beagle dogs. The implants were either acid etched without additional coating, coated with a conventionally plasma-sprayed CaP ceramic, coated with a microplasma-sprayed CaP ceramic or with a microplasma-sprayed coating at the apical part only. To assess the effect of occlusal loading, a split-mouth design was used. Six weeks after implantation, the implants in one half of the mandible of each dog were functionally loaded, while the contra lateral implants served as control. Six weeks after loading, the animals were sacrificed and bone-to-implant contact as well as the amount of bone around the implants were assessed. RESULTS: Irrespective of surface and functional load, no statistically significant differences (P>0.05) were found either for bone-to-implant contact or for the amount of bone between the various implant surfaces. On the other hand, functional loading of the non-coated implants was associated with a tendency towards crestal bone loss. CONCLUSION: Within the limits of the experiment, we conclude that functional loading of MPS CaP coatings induces a favorable bone response, and furthermore, that the bone response, irrespective of the loading condition, does not differ from conventional plasma-sprayed CaP coatings.

Bone-supportive behavior of microplasma-sprayed CaP-coated implants: mechanical and histological outcome in the goat.

BACKGROUND: New microplasma spray (MPS) equipment to deposit calcium phosphate (CaP) ceramic coatings onto titanium substrates has been developed. With this apparatus, it is possible to spray fine particles, as well as to apply textured hydroxylapatite coatings onto titanium surfaces. Moreover, due to the low heat power of the microplasma jet, overheating of the powder particles as well as excessive local overheating of the substrate is reduced. Furthermore, because of the small laminar plasma jet, it is possible to achieve high spray efficiency in the case of spraying of dental implants. Additionally, the low level of noise (25-50 dB) and hardly any dust makes it possible to operate the MSE under normal workroom conditions. OBJECTIVE: The aim of this study was to examine the biological properties of different MPS - CaP coatings on titanium implants when inserted into the femoral condyle of goats. MATERIAL AND METHODS: For histomorphometrical evaluation as well as mechanical testing, 48 screw-type titanium implants were inserted into the femoral condyles of 12 goats each. The implants were either coated with a conventionally plasma-sprayed CaP ceramic, MPS CaP ceramic, or acid-etched without an additional CaP coating. Six and 12 weeks after implantation, the animals were sacrificed and bone-to-implant contact, amount of bone, as well as mechanical bone fixation were evaluated. RESULTS: For bone-to-implant contact no statistically significant difference was found between the different CaP coatings. However, statistically significant differences were found between non-coated, acid-etched titanium implants and CaP-coated implants after 6 and 12 weeks of healing. The bone values were not statistically significantly different between the different CaP coatings at 6 and 12 weeks. Furthermore, CaP ceramic-coated implants showed statistically significantly higher torque values compared with the non-coated implants after 6 and at 12 weeks of healing. No significant differences existed between the various types of CaP coatings. CONCLUSION: On the basis of our observations, we conclude that conventionally plasma-sprayed CaP ceramic-coated implants, as well as MPS-coated implants have a comparable effect on adjacent bone response.

In primary breast cancer the mitotic activity yields similar prognostic information as the histological grade: a study with long-term follow-up.

We evaluated with long-term follow-up, the prognostic value of the mitotic activity index (MAI) and the volume corrected mitotic index (M/V-index) compared with that of the histological grade in breast cancer patients not treated with adjuvant systemic therapy. Of 739 consecutive patients living in the city of Nijmegen, the Netherlands, 477 patients with primary unilateral breast cancer were not treated with adjuvant systemic therapy and eligible for the study. In multivariate survival analyses the MAI and M/V-index showed similar hazard ratios (HRs) compared to HRs of histological grade for overall survival (OS) (HR: 1.45, 1.48, and grade II versus grade I (GII/GI) 1.34, grade III versus grade I (GIII/GI) 1.53, respectively) and for breast cancer specific survival (BCSS) (HR: 1.27, 1.57, and (GII/GI) 1.57 (GIII/GI) 2.32, respectively). Other independent prognostic variables for OS and BCSS were age at diagnosis, tumour size, and number of positive lymph nodes. In the present study with long term follow-up, we compared the prognostic value of mitotic activity with that of histological grade and found no advantage for the mitotic activity in predicting either BCSS or OS and concluded that histological grade and the mitotic activity were equally informative in predicting patient outcome. As histological grade is a well established and widely used prognosticator we do not have arguments to replace the histological grade by the mitotic indices MAI or M/V-index.

Educational-support groups for BRCA mutation carriers satisfy need for information but do not affect emotional distress.

INTRODUCTION: Due to high cancer risks, women carrying a BRCA 1/2 mutation face a complex choice between breast and ovarian cancer surveillance and prophylactic surgery. The aim of this study is to evaluate educational-support groups, which are offered to facilitate mutual support between BRCA mutation carriers and to provide adequate information. METHODS: Female BRCA mutation carriers were approached by a social worker after genetic test disclosure and offered participation in educational-support groups. Data regarding emotional well-being, breast cancer risk knowledge and perception, cancer risk management behaviour and family communication were collected both before (T1) and after group participation (T2). RESULTS: Of the 34 participants, mean levels of negative mood states at T1 were significantly higher compared to those of a norm group (depression p < 0.001, anger p < 0.001, fatigue p = 0.04, tension p = 0.03) and remained high at T2. Self-perceived breast cancer risk and frequency of cancer thoughts were high both at T1 and T2. Breast cancer risk knowledge was accurate both at T1 and T2; women either followed current surveillance advices or obtained prophylactic surgery. Communication with the family of origin was significantly reduced at T2 compared to T1 (p = 0.02). At T2, all women indicated that group participation highly met their needs of BRCA-related information to support their decision-making processes regarding cancer surveillance or prophylactic surgery. CONCLUSION: After following an educational support group female BRCA mutation carriers were able to make cancer risk management decisions but still reported high levels of emotional distress while family communication appeared diminished.

Vascular endothelial growth factor levels do not predict efficacy of systemic adjuvant treatment as assessed in 1127 breast cancer patients.

The vascular endothelial growth factor (VEGF) is a mediator of angiogenesis and has proven to be of prognostic value in patients with primary breast cancer. In this study we investigated whether VEGF is of predictive value with regard to the efficacy of adjuvant systemic therapy in primary invasive breast cancer. In 1127 tumors of patients with invasive breast cancer the cytosolic levels of VEGF were measured using a quantitative enzyme-linked immunosorbent assay. These patients were followed for a median follow-up time of 59 months (range 2-268 months) after primary surgery. Correlations with well-known prognostic factors, and univariate and multivariate survival analyses were performed. The VEGF levels showed a positive correlation with age, menopausal status and tumor size. In addition, VEGF levels were inversely correlated with estrogen and progesterone receptor levels. A high VEGF level predicted an early relapse in the univariate relapse-free survival (RFS) analysis for all patients (P=0.010), but not in the multivariate analysis. Furthermore, there were no statistically significant interactions between the levels of VEGF and the use of adjuvant endocrine therapy or chemotherapy in the RFS analysis. We conclude that tumor levels of VEGF do not predict the efficacy of adjuvant endocrine therapy or chemotherapy in patients with primary breast cancer.

Carbonic anhydrase-9 expression levels and prognosis in human breast cancer: association with treatment outcome.

Here, we set out to assess CA9 expression levels by real-time quantitative RT-PCR in breast cancer tissue samples obtained from 253 patients, and correlated those with relapse-free (RFS) survival. The median follow-up time was 75 months (range 2-168 months). CA9 expression was mainly found in high-grade, steroid receptor negative cancer tissues. CA9 levels were not significantly associated with RFS (P=0.926, hazard ratio (HR)=0.99, 95% CI=0.80-1.22) in the total cohort of 253 patients. In multivariate analysis with other clinicopathological factors, CA9 (P=0.018, HR=0.77, 95% CI=0.62-0.96), the interaction of adjuvant chemotherapy with CA9 (P=0.009, HR=1.31, 95% CI=1.07-1.61) and the interaction of adjuvant endocrine therapy with CA9 (P<0.001, HR=1.41, 95% CI=1.20-1.66) all contributed significantly to the final model. These results indicate that patients with low CA9 levels benefit more from adjuvant treatment than do patients with high levels. Thus, the determination of CA9 levels could aid in the selection of patients who will not benefit from adjuvant therapy, and whose prognosis will more likely improve with other treatment modalities.

The prognostic value of the mitotic activity index in patients with primary breast cancer who were not treated with adjuvant systemic therapy.

BACKGROUND: At the St Gallen meeting of 2001 it was agreed to select high-risk patients for adjuvant systemic therapy by lymph node status, tumor size, age, hormone receptor status, and histological grade. In The Netherlands it was chosen to use either the histological grade or the mitotic activity index (MAI). The aim of this study was to retrospectively evaluate the independent prognostic value of the MAI in primary breast cancer patients, who were not treated with adjuvant systemic therapy, on relapse-free survival (RFS) and overall survival (OS). PATIENTS AND METHODS: The data of 137 systemically untreated patients with primary breast cancer diagnosed between 1992 and 1996, of whom MAI was assessed, were retrospectively collected. The MAI was correlated to classical prognostic factors and we determined the prognostic value of the MAI, the histological grade and other prognostic factors. RESULTS: The median observation time was 4.2 years. The MAI showed a positive correlation to lymph node status (P < 0.001) and a negative correlation to age (P = 0.005), menopausal status (P < 0.001) and the ER and PgR status (r(s) = -0.390 [ER], r(s) = -0.440 [PgR], both P < 0.001). A high MAI (> or = 15) predicted a reduced RFS and OS in the Kaplan-Meier analysis (P = 0.0070 and P = 0.0017, respectively). Also in the multivariate analysis, the MAI showed to be an independent predictor of poor RFS (P = 0.035), in addition to lymph node status. However, the MAI did not predict for OS, in contrast to tumor size and lymph node status. CONCLUSION: The present study confirms that the MAI is an independent prognostic factor for RFS, but not for OS and may be useful for daily clinical practice.

High prevalence of premalignant lesions in prophylactically removed breasts from women at hereditary risk for breast cancer.

PURPOSE: Women with a hereditary predisposition for breast cancer have an extremely high risk of developing invasive breast carcinoma, and many women consider prophylactic mastectomy to avoid this risk. The use of prophylactic mastectomy is still debated. Identification of frequent premalignant lesions in mastectomy specimens would support the preventive concept of prophylactic mastectomy. PATIENTS AND METHODS: We performed a prospective study of breast specimens from 67 women at extremely high genetic risk of breast cancer, with or without previous breast cancer, who were undergoing prophylactic mastectomy (66% were carriers of a BRCA1 or BRCA2 mutation). Breast specimens were studied by radiographic and macroscopic examination of 5-mm tissue slices, with subsequent histology of suspicious lesions and random samples from each quadrant of the breast and the nipple area. RESULTS: In 57% of the women, one or more different types of high-risk histopathologic lesions were present: 37% atypical lobular hyperplasia, 39% atypical ductal hyperplasia, 25% lobular carcinoma-in-situ, and 15% ductal carcinoma-in-situ. A 4-mm invasive ductal carcinoma was found in one woman with ductal carcinoma-in-situ. None of these lesions was detected at palpation or mammography, which were performed before the mastectomy. The presence of high-risk lesions was independently related to age older than 40 years (odds ratio, 6.6; P =.01) and to bilateral oophorectomy before prophylactic mastectomy (odds ratio, 0.2; P = 0.02). CONCLUSION: Many women at high risk of hereditary breast cancer develop high-risk histopathologic lesions, especially after the age of 40 years. Surveillance does not detect such high-risk histopathologic lesions.

The prognostic value of vascular endothelial growth factor in 574 node-negative breast cancer patients who did not receive adjuvant systemic therapy.

The growth and metastasising capacity of solid tumours are dependent on angiogenesis. Vascular endothelial growth factor is a mediator of angiogenesis. In this study we investigated whether vascular endothelial growth factor is associated with the natural course of the disease in primary invasive breast cancer. In 574 tumours of patients with node-negative invasive breast cancer the cytosolic levels of vascular endothelial growth factor were measured using a quantitative enzyme-linked immunosorbent assay. These patients did not receive adjuvant systemic therapy and were followed for a median follow-up time of 61 months (range 2-155 months) after the primary diagnosis. Correlations with well-known prognostic factors, and univariate and multivariate survival analyses were performed. Vascular endothelial growth factor level was positively associated with age and tumour size (P=0.042 and P=0.029, respectively). In addition, vascular endothelial growth factor level was inversely, but weakly correlated with progesterone receptor levels (PgR) (r(s)=-0.090, P=0.035). A high vascular endothelial growth factor level (equal or above the median level of 0.53 ng mg(-1) protein) predicted a reduced relapse-free survival and overall survival in the univariate survival rate analysis (for both P=0.005). In the multivariate analysis as well, vascular endothelial growth factor showed to be an independent predictor of poor relapse-free survival and overall survival (P=0.045 and P=0.029, respectively), in addition to age, tumour size and PgR. The results show that cytosolic levels of vascular endothelial growth factor in tumour tissue samples are independently indicative of prognosis for patients with node-negative breast cancer who were not treated with adjuvant systemic therapy. This implies that vascular endothelial growth factor is related with the natural course of breast cancer progression.

Arrested differentiation, the self-renewing memory lymphocyte, and vaccination.

Vaccination for persistent viral or bacterial infections must program the immune system for a lifelong need to generate antigen-specific effector lymphocytes. How the immune system does this is not known, but recent studies have shown that a subset of B lymphocytes, the germinal center B cell, is capable of self-renewal because it expresses a transcriptional repressor, BCL6, that blocks terminal differentiation. If a similar mechanism for arresting differentiation exists for long-lived, antigen-selected lymphocytes, a stem cell-like capacity for self-renewal could be the basis for the continual generation of effector lymphocytes from the memory pool. Understanding how to regulate the terminal differentiation of lymphocytes will improve immunotherapeutic approaches for chronic infectious diseases and cancer.

Immunology of DNA vaccines: CpG motifs and antigen presentation.

DNA vaccines elicit high levels of specific cytotoxic T lymphocytes and antibody production in numerous animal models. However, the specific immunological events which lead to this effective immune response remain unclear. Presentation of DNA-encoded antigens is particularly intriguing as there is now evidence to suggest that this occurs via both endogenous intracellular and cross-presentation. Further, it has been observed that many plasmid DNA vectors used in DNA vaccination contain CpG motifs--sequences of bacterial DNA which induce pro-inflammatory cytokines in various cells--and which thus provide a novel adjuvant for injected antigens. In this review we will discuss the effects these bacterial DNA sequences have on cells of the immune system, the immune response generated after DNA vaccination and the mechanisms by which DNA-encoded antigens are likely to be presented.

Potential strategies utilised by papillomavirus to evade host immunity.

The co-evolution of papillomaviruses (PV) and their mammalian hosts has produced mechanisms by which PV might avoid specific and non-specific host immune responses. Low level expression of PV proteins in infected basal epithelial cells, together with an absence of inflammation and of virus-induced cell lysis, restricts the opportunity for effective PV protein presentation to immunocytes by dendritic cells. Additionally, PV early proteins, by a range of mechanisms, may restrict the efficacy of antigen presentation by these cells. Should an immune response be induced to PV antigens, resting keratinocytes (KC) appear resistant to interferon-gamma-enhanced mechanisms of cytotoxic T-lymphocyte (CTL)-mediated lysis, and expression of PV antigens by resting KC can tolerise PV-specific CTL. Thus, KC, in the absence of inflammation, may represent an immunologically privileged site for PV infection. Together, these mechanisms play a part in allowing persistence of PV-induced proliferative skin lesions for months to years, even in immunocompetent hosts.