Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression

The integrin antagonist cilengitide has been explored as an adjunct with anti-angiogenic properties to standard of care temozolomide chemoradiotherapy (TMZ/RT → TMZ) in newly diagnosed glioblastoma. Preclinical data as well as anecdotal clinical observations indicate that anti-angiogenic treatment may result in altered patterns of tumor progression. Using a standardized approach, we analyzed patterns of progression on MRI in 21 patients enrolled onto a phase 2 trial of cilengitide added to TMZ/RT → TMZ in newly diagnosed glioblastoma. Thirty patients from the experimental treatment arm of the EORTC/NCIC pivotal TMZ trial served as a reference. MRIcro software was used to map location and extent of initial preoperative and recurrent tumors on MRI of both groups into the same stereotaxic space which were then analyzed using an automated tool of image analysis. Clinical and outcome data of the cilengitide-treated patients were similar to those of the EORTC/NCIC trial except for a higher proportion of patients with a methylated O(6)-methylguanyl-DNA-methyltransferase gene promoter. Analysis of recurrence pattern revealed neither a difference in the size of the recurrent tumor nor in the distance of the recurrences from the preoperative tumor location between groups. Overall frequencies of distant recurrences were 20 % in the reference group and 19 % (4/21 patients) in the cilengitide group. Compared with TMZ/RT → TMZ alone, the addition of cilengitide does not alter patterns of progression. This analysis does not support concerns that integrin antagonism by cilengitide may induce a more aggressive phenotype at progression, but also provides no evidence for an anti-invasive activity of cilengitide in patients with newly diagnosed glioblastoma.

Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019)

BACKGROUND Prostate cancer (PCa) is the second most common disease among men worldwide. It is important to know survival outcomes and prognostic factors for this disease. Recruitment for the largest therapeutic randomised controlled trial in PCa-the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial (STAMPEDE)-includes men with newly diagnosed metastatic PCa who are commencing long-term androgen deprivation therapy (ADT); the control arm provides valuable data for a prospective cohort. OBJECTIVE Describe survival outcomes, along with current treatment standards and factors associated with prognosis, to inform future trial design in this patient group. DESIGN, SETTING, AND PARTICIPANTS STAMPEDE trial control arm comprising men newly diagnosed with M1 disease who were recruited between October 2005 and January 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Overall survival (OS) and failure-free survival (FFS) were reported by primary disease characteristics using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (CIs) were derived from multivariate Cox models. RESULTS AND LIMITATIONS A cohort of 917 men with newly diagnosed M1 disease was recruited to the control arm in the specified interval. Median follow-up was 20 mo. Median age at randomisation was 66 yr (interquartile range [IQR]: 61-71), and median prostate-specific antigen level was 112 ng/ml (IQR: 34-373). Most men (n=574; 62%) had bone-only metastases, whereas 237 (26%) had both bone and soft tissue metastases; soft tissue metastasis was found mainly in distant lymph nodes. There were 238 deaths, 202 (85%) from PCa. Median FFS was 11 mo; 2-yr FFS was 29% (95% CI, 25-33). Median OS was 42 mo; 2-yr OS was 72% (95% CI, 68-76). Survival time was influenced by performance status, age, Gleason score, and metastases distribution. Median survival after FFS event was 22 mo. Trial eligibility criteria meant men were younger and fitter than general PCa population. CONCLUSIONS Survival remains disappointing in men presenting with M1 disease who are started on only long-term ADT, despite active treatments being available at first failure of ADT. Importantly, men with M1 disease now spend the majority of their remaining life in a state of castration-resistant relapse. PATIENT SUMMARY Results from this control arm cohort found survival is relatively short and highly influenced by patient age, fitness, and where prostate cancer has spread in the body.

Preclinical atherosclerosis and inflammation in 61-year-old men with newly diagnosed diabetes and established diabetes.

OBJECTIVE The aim of this study was to investigate the occurrence of subclinical atherosclerosis and underlying mechanisms in men with newly diagnosed diabetes and established diabetes compared with healthy control subjects. RESEARCH DESIGN AND METHODS In a population-based study of 61-year-old Caucasian men (n = 271) with established diabetes (n = 50) and newly diagnosed diabetes (n = 24) and healthy control subjects (n = 197), standard risk factors and highly sensitive (hs) C-reactive protein (CRP) were measured. Ultrasound measurements of intima-media thickness (IMT) were performed bilaterally in the common carotid artery, and a composite measure was calculated from common carotid and carotid bulb IMT (composite IMT). The plaque status was assessed. RESULTS Composite IMT and carotid plaque size increased gradually among the healthy control subjects, newly diagnosed diabetic patients, and established diabetic patients (P for trend < or =0.001, respectively). CRP was higher in newly and established diabetes (NS between diabetes groups) compared with healthy control subjects (P < 0.001). Total cholesterol levels were lower in newly diagnosed diabetes (5.51 +/- 1.13 mmol/l, P < 0.05) and established diabetes (5.45 +/- 1.15 mmol/l, P < 0.01) compared with those of healthy control subjects (5.77 +/- 1.03 mmol/l). In men with diabetes (n = 74), diabetes onset status (newly diagnosed versus established), waist-to-hip ratio (WHR), and serum triglycerides, but not CRP, explained 16% of the variance in composite IMT. CONCLUSIONS This is the first study to show increased preclinical atherosclerotic changes (IMT and plaque size) and increased inflammation (hs-CRP) in men with newly diagnosed diabetes as well as in patients with established diabetes compared with healthy control subjects. WHR, diabetes onset status (newly diagnosed versus established), and triglycerides, but not CRP, were independent correlates of carotid artery IMT in men with diabetes.

Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment.

Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.Leukemia advance online publication, 20 November 2015; doi:10.1038/leu.2015.281.

Decreasing Proportion of Recent Infections among Newly Diagnosed HIV-1 Cases in Switzerland, 2008 to 2013 Based on Line-Immunoassay-Based Algorithms.

BACKGROUND: HIV surveillance requires monitoring of new HIV diagnoses and differentiation of incident and older infections. In 2008, Switzerland implemented a system for monitoring incident HIV infections based on the results of a line immunoassay (Inno-Lia) mandatorily conducted for HIV confirmation and type differentiation (HIV-1, HIV-2) of all newly diagnosed patients. Based on this system, we assessed the proportion of incident HIV infection among newly diagnosed cases in Switzerland during 2008-2013. METHODS AND RESULTS: Inno-Lia antibody reaction patterns recorded in anonymous HIV notifications to the federal health authority were classified by 10 published algorithms into incident (up to 12 months) or older infections. Utilizing these data, annual incident infection estimates were obtained in two ways, (i) based on the diagnostic performance of the algorithms and utilizing the relationship 'incident = true incident + false incident', (ii) based on the window-periods of the algorithms and utilizing the relationship 'Prevalence = Incidence x Duration'. From 2008-2013, 3'851 HIV notifications were received. Adult HIV-1 infections amounted to 3'809 cases, and 3'636 of them (95.5%) contained Inno-Lia data. Incident infection totals calculated were similar for the performance- and window-based methods, amounting on average to 1'755 (95% confidence interval, 1588-1923) and 1'790 cases (95% CI, 1679-1900), respectively. More than half of these were among men who had sex with men. Both methods showed a continuous decline of annual incident infections 2008-2013, totaling -59.5% and -50.2%, respectively. The decline of incident infections continued even in 2012, when a 15% increase in HIV notifications had been observed. This increase was entirely due to older infections. Overall declines 2008-2013 were of similar extent among the major transmission groups. CONCLUSIONS: Inno-Lia based incident HIV-1 infection surveillance proved useful and reliable. It represents a free, additional public health benefit of the use of this relatively costly test for HIV confirmation and type differentiation.

Understanding causes of hospitalization and access to care among newly diagnosed HIV patients in Houston, TX

More than a quarter of patients with HIV in the United States are diagnosed in hospital settings most often with advanced HIV related conditions.(1) There has been little research done on the causes of hospitalization when the patients are first diagnosed with HIV. The aim of this study was to determine if the patients are hospitalized due to an HIV related cause or due to some other co-morbidity. Reduced access to care could be one possible reason why patients are diagnosed late in the course of the disease. This study compared the access to care of patients diagnosed with HIV in hospital and outpatient setting. The data used for the study was a part of the ongoing study “Attitudes and Beliefs and Steps of HIV Care”. The participants in the study were newly diagnosed with HIV and recruited from both inpatient and outpatient settings. The primary and the secondary diagnoses from hospital discharge reports were extracted and a primary reason for hospitalization was ascertained. These were classified as HIV-related, other infectious causes, non–infectious causes, other systemic causes, and miscellaneous causes. Access to care was determined by a score based on responses to a set of questions derived from the HIV Cost and Services Utilization Study (HCSUS) on a 6 point scale. The mean score of the hospitalized patients and mean score of the patients diagnosed in an outpatient setting was compared. We used multiple linear regressions to compare mean differences in the two groups after adjusting for age, sex, race, household income educational level and health insurance at the time of diagnosis. There were 185 participants in the study, including 78 who were diagnosed in hospital settings and 107 who were diagnosed in outpatient settings. We found that HIV-related conditions were the leading cause of hospitalization, accounting for 60% of admissions, followed by non-infectious causes (20%) and then other infectious causes (17%). The inpatient diagnosed group did not have greater perceived access-to-care as compared to the outpatient group. Regression analysis demonstrated a statistically significant improvement in access-to-care with advancing education level (p=0.04) and with better health insurance (p=0.004). HIV-related causes account for many hospitalizations when patients are first diagnosed with HIV. Many of these HIV-related hospitalizations could have been prevented if patients were diagnosed early and linked to medical care. Programs to increase HIV awareness need to be an integral part of activities aimed at control of spread of HIV in the community. Routine testing for HIV infection to promote early HIV diagnosis can prevent significant morbidity and mortality.^

Incidence of breast cancer in first-degree female relatives of men with newly diagnosed prostate cancer

Prostate cancer is the most common incident cancer and the second leading cause of death in men in the United States. Although numerous attempts have been made to identify risk factors associated with prostate cancer, the results have been inconsistent and conflicting. The only established risk factors are age and ethnicity. A positive family history of prostate cancer has also been shown to increase the risk two- to three-fold among close relatives.^ There are several similarities between breast and prostate cancer that make the relationship between the two of interest. (1) Histologically, both cancers are predominantly adenocarcinomas, (2) both organs have a sexual and/or reproductive role, (3) both cancers occur in hormone-responsive tissue, (4) therapy often consists of hormonal manipulation, (5) worldwide distribution patterns of prostate and breast cancer are positively correlated.^ A family history study was conducted to evaluate the aggregation of prostate cancer and co-aggregation of breast cancer in 149 patients referred to The University of Texas, M.D. Anderson Cancer Center with newly diagnosed prostate cancer. All patients were white, less than 75 years of age at diagnosis and permanent residents of the United States. Through a personal interview with the proband, family histories were collected on 1,128 first-degree relatives. Cancer diagnoses were verified through medical records or death certificate. Standardized incidence ratios were calculated using a computer program by Monson incorporating data from Connecticut Tumor Registry.^ In this study, familial aggregation of prostate cancer was verified only among the brothers, not among fathers. Although a statistically significant excess of breast cancer was not found, the increased point estimates in mothers, sisters and daughters are consistent with a co-aggregation hypothesis. Rather surprising was the finding of a seven-fold increased risk of prostate cancer and a three-fold increased risk of breast cancer among siblings in the presence of a maternal history of any cancer. Larger family history studies including high risk (African-Americans) and lower-risk groups (Hispanics) and incorporating molecular genetic evaluations should be conducted to determine if genetic differences play a role in the differential incidence rates across ethnic groups. ^

Expansion of a recurrent V beta 5.3+ T-cell population in newly diagnosed and untreated HLA-DR2 multiple sclerosis patients.

We have used a PCR-based technology to study the V beta 5 and V beta 17 repertoire of T-cell populations in HLA-DR2 multiple sclerosis (MS) patients. We have found that the five MS DR2 patients studied present, at the moment of diagnosis and prior to any treatment, a marked expansion of a CD4+ T-cell population bearing V beta 5-J beta 1.4 beta chains. The sequences of the complementarity-determining region 3 of the expanded T cells are highly homologous. One shares structural features with that of the T cells infiltrating the central nervous system and of myelin basic protein-reactive T cells found in HLA-DR2 MS patients. An homologous sequence was not detectable in MS patients expressing DR alleles other than DR2. However, it is detectable but not expanded in healthy DR2 individuals. The possible mechanisms leading to its in vivo proliferation at the onset of MS are discussed.

Barriers and Facilitators to Treatment among Newly Diagnosed Hypertensive Patients in Nepal: a Qualitative Study

Thesis (Master's)--University of Washington, 2016-06

Sleep Patterns and Parents’ Experience in Caring for Young Children Newly Diagnosed with Juvenile Idiopathic Arthritis

Thesis (Ph.D.)--University of Washington, 2016-05

Interferon-α-2b and oral cytarabine ocfosfate for newly diagnosed chronic myeloid leukaemia

Background: Treatment with interferon and subcutaneous cytarabine produces superior cytogenetic responses in chronic myeloid leukaemia (CML) than treatment with interferon alone, but at the expense of greater toxicity. Cytarabine ocfosfate (YNK01) is an oral precursor of cytarabine that may overcome some of the inconvenience and toxicities associated with subcutaneous cytarabine administration. Patients and methods: We studied the efficacy and tolerability of combination therapy with interferon-alpha-2b and YNK01 in patients with newly diagnosed, untreated CML. Forty patients were treated with interferon-alpha-2b (5 MU/m(2)/day) plus monthly courses of YNK01 (600 mg/day for 10 days) for I year. Results: The 6-month complete haematological response rate was 63% and the 1-year major cytogenetic response rate was 30%, with 10% of cytogenetic responses being complete. With a median follow-up of 57 months, the estimated 5-year overall survival was 86% (95% confidence interval 70% to 94%). Treatment tolerability was poor, with toxicity leading to discontinuation of one or both drugs in 60% of cases. The median daily dose of interferon alpha-2b was 7.75 MU and the median dose of YNK01 was 600 mg/day for each 10-day treatment cycle. Conclusions: Interferon-alpha-2b and YNK01 produce cytogenetic responses comparable to those achieved with interferon-alpha-2b and parenteral cytarabine, although toxicity was excessive. Alternate dosing strategies may enhance the tolerability of YNK01.

Psychosocial impact of newly diagnosed advanced breast cancer

The purpose of this study was to delineate the key emotional concerns of women newly diagnosed with recurrent or metastatic breast cancer. Sixty-six women diagnosed with metastatic breast cancer within the previous 6 months, receiving treatment at the Medical Oncology Departments of two metropolitan teaching hospitals, completed measures of HADS, IES, CARES-SF and Memorial Symptom Assessment Scale, and participated in a semistructured interview. There were high levels of psychological morbidity, 56.7% of women younger than 55 years qualifying as 'cases' on the HADS, compared with 34.5% of women aged over 55 years. The total HADS score was significantly correlated with the Global and Physical Subscales of the MSAS and CARES. Women younger than 55 years had significantly higher levels of intrusive and avoidant symptoms than women over 55 years. Women also reported high numbers of physical symptoms. Key themes which emerged during the interviews were: difficulties in communicating with doctors, perceived delay in diagnosis, the emotional impact, concerns about the family, feelings about why the cancer developed, other life stress and trauma, and use of non-prescribed treatments. Copyright (c) 2004 John Wiley & Sons, Ltd.

First-line therapy with latanoprost 0.005% results in improved ocular circulation in newly diagnosed primary open-angle glaucoma patients: a prospective, 6-month, open-label study

Purpose To evaluate the effect of latanoprost 0.005% on the optic nerve head (ONH) and retinal circulation of newly diagnosed and previously untreated primary open-angle glaucoma (POAG) patients. Methods Twenty-two newly diagnosed and previously untreated POAG patients (mean age±SD: 68.38±11.92 years) were included in this longitudinal open-label study. Patients were treated with latanoprost 0.005% once a day. Intraocular pressure (IOP), systemic blood pressure (BP), mean ocular perfusion pressure (MOPP), and ocular perfusion parameters ‘volume’, ‘velocity’, and ‘flow’ measured at the optic nerve head (ONH) and retina by means of Heidelberg Retina Flowmeter system were evaluated during a 6-month follow-up period. Results Treatment with latanoprost 0.005% resulted in a significant decrease in IOP (P<0.0001) and increase in MOPP (P<0.0001). After correcting for changes in MOPP, the blood velocity measured at the ONH level was significantly higher after 6 months of treatment than at baseline (P=0.0310). In addition, blood volume and flow measured at the peripapillary retina level improved after 3 and 6 months of treatment (P=0.0170; P=0.0260, and P=0.0170; P=0.0240 respectively). Conclusion Previously untreated POAG patients exhibit reduced IOP, increased MOPP and improved ocular perfusion at the ONH and retina levels when treated with Latanoprost 0.005%. These effects could be beneficial for glaucoma patients suffering from ocular vascular dysregulation.