Antibiotics and Imiquimod for Cutaneous T-Cell Lymphoma in Veterans: A Patient Population with Agent Orange Exposure.

LESSONS LEARNED: Staphylococcus aureus infection in cutaneous T-cell lymphoma (CTCL) is thought to contribute to disease progression; thus, adjunctive treatment with antibiotics warrants further investigation. This trial of antibiotic therapy followed by imiquimod in early stage CTCL was not completed because of difficulties with patient accrual. BACKGROUND: Cutaneous T-cell lymphoma (CTCL), a form of non-Hodgkin lymphoma, is a heterogeneous group of malignancies of mature memory T lymphocytes. It has an annual age-adjusted incidence of 7.5 per million persons in the U.S. population [1]. The etiology of CTCL is unknown, but epidemiological studies have reported potential associations with environmental and occupational factors, including Agent Orange exposure in Vietnam Veterans [2]. Both topical and systemic therapies have been identified as effective in CTCL; the choice of treatment is dependent on disease stage, with the overall goal of improving symptoms given the chronic and recurrent nature of the disease. Several studies have suggested that CTCL is exacerbated by the presence of Staphylococcus aureus in the skin and can be ameliorated by treatment with antibiotics [3]. METHODS: Our study was designed to assess the effects of antibiotics and imiquimod on early stage CTCL. Patients between the ages of 30-89 years with stage I and II CTCL were eligible for enrollment. They could not be receiving concurrent therapy, and the study design included a 14-day washout period after discontinuation of CTCL therapy. The washout period was followed by doxycycline 100 mg p.o. b.i.d. for 14 days and then two packets (250 mg per packet) of imiquimod 5% cream topically to the most clinically active lesions 3 days a week (Monday, Wednesday, and Friday) for 28 days. Skin lesions were measured using the modified Severity Weighted Assessment Tool (mSWAT). RESULTS: Our study enrolled only two patients with early stage CTCL because of difficulty locating patients with active CTCL able to discontinue all therapy. The two enrolled patients completed all therapy. One patient had a complete response after imiquimod, whereas the other patient had stable disease. CONCLUSION: Antibiotics and imiquimod have reported activity as single agents in CTCL; we did not enroll enough patients to assess value in the sequence of antibiotic therapy followed by imiquimod.

Effectiveness of Complementary and Integrative Approaches in Promoting Engagement and Overall Wellness Toward Suicide Prevention in Veterans.

Objective: Suicide is a major public health problem, specifically among U.S. veterans, who do not consistently engage in mental health services, often citing stigma as a barrier. Complementary and Integrative Health (CIH) interventions are promising alternatives in promoting patient engagement and further, they may play a critical role in transitioning people into mental health care. Toward this goal, the Resilience and Wellness Center (RWC) was developed to break through the stigma barrier by addressing risk factors of suicide through multimodal CIH interventions via cohort design, promoting social connectedness and accountability among participants. Design: This is a program evaluation study at a large urban VA medical center, where assessments were evaluated from pre- to post-program completion to determine the effectiveness of an intensive multimodal CIH 4-week group outpatient intervention for suicide prevention. Outcome measures: Primary outcomes measured included group connectedness, severity of depression and hopelessness symptoms, suicidal ideation, sleep quality, and diet. Secondary outcomes included measures of post-traumatic stress disorder (PTSD), generalized anxiety severity stress/coping skills, pain, and fatigue. Results: The RWC showed high participant engagement, with an 84%-95% attendance engagement rate depending on suicide risk history. Data from 15 cohorts (N = 126) demonstrate favorable outcomes associated with participation in this comprehensive program, as evidenced by a reduction in suicidal ideation, depression, and hopelessness, but not sleep quality and diet. In addition, in a subset of veterans with a history of suicidal ideation or attempt, significant improvements were noted in pain, PTSD/anxiety symptoms, and stress coping measures. Conclusions: The RWC shows that an intensive complement of CIH interventions is associated with a significant improvement with high veteran engagement. Findings from this program evaluation study can be used to aid health care systems and their providers in determining whether or not to utilize such multimodal CIH integrated interventions as an effective treatment for at-risk populations as a part of suicide prevention efforts.

The VA and Non-VA Experience of Tracking Good Care.

The VA Mission Act of 2018 allows for choice of health care for 9 million veterans in their community, but deciding where the best care is requires transparency. Recent reports questioning the transparency of reporting health care outcomes in the Department of Veterans Affairs (VA), the largest US health care organization, pointed to flaws in how VA tracks and improves performance, and posed questions about the validity and transparency of using popular hospital ratings systems to define good care. To explore this further, the authors examined 3 widely referenced public health care ranking models - U.S. News America's Best Hospitals, Truven Health Analytics, and Hospital Compare - and the VA model. Upon examination, the authors find that metrics used across the 4 models are neither comparable nor transparent. Between 6%-46% reporting deficiencies were found in reporting of hospital metrics in non-VA hospitals, which reduces transparency for the public. In contrast, VA reporting is 100%. Comparing VA health care and Hospital Compare quality outcomes showed similar or better outcomes for VA for the same metrics of quality and for comparable health care costs. VA inpatient satisfaction falls significantly short of the private sector, but no individual VA outcome measure was found to contribute significantly to inpatient satisfaction. However, overall inpatient satisfaction increased over time with higher global hospital ranking in both VA and non-VA health care. Encouraging use of uniform rating models and reporting of metrics from all hospitals would improve transparency of current health care reporting to the consumer.

A novel approach to assess real-world efficacy of cancer therapy in metastatic prostate cancer. Analysis of national data on Veterans treated with abiraterone and enzalutamide.

BACKGROUND: With 1.3 million new cases in 2018 worldwide, prostate cancer remains a challenge. Development of novel therapies targeting the androgen pathway followed recognition of the continued importance of androgens in castrate-resistant prostate cancer. To assess abiraterone and enzalutamide efficacy we analyzed data from US Veterans Administration Medical Centers (VAMCs). METHODS: We used a novel method independent of assessment intervals and ideal for real-world analysis to estimate rates of tumor growth (g) and regression (d). FINDINGS: Using the VA Informatics and Computing Infrastructure, we collected data from 5,116 Veterans with castrate-resistant prostate cancer prescribed abiraterone, enzalutamide or both. We estimated values for g and d and demonstrated a correlation of g with overall survival (P < .0001). Abiraterone and enzalutamide slowed growth rates across age groups and across the entire VAMC system, although less so in Veterans previously treated with a taxane and those with Gleason grade group 5 tumors. Abiraterone and enzalutamide efficacy in first-line were comparable although abiraterone in first-line slowed growth rates significantly more in African Americans than in Caucasians; enzalutamide was a better salvage therapy. When abiraterone was first-line and g was low, switching to enzalutamide was associated with a faster g in 67%. INTERPRETATION: In the real-world g can be estimated using a novel analysis method indifferent to assessment intervals that correlates highly with OS. While we show excellent real-world outcomes with abiraterone and enzalutamide, 2 effective and tolerable therapies, our results in VAMCs suggest enzalutamide should follow abiraterone. Changing therapies may be detrimental and consideration should be given to continue monitoring of growth rates over time. Funding Support from the Prostate Cancer Foundation and the Blavatnik Family Foundation.

Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma.

It has been proposed that CD4 T-cell responses to Staphylococcus aureus (SA) can inadvertently enhance neoplastic progression in models of skin cancer and cutaneous T-cell lymphoma (CTCL). In this prospective study, we explored the effect of transient antibiotic treatment on tumor cells and disease activity in 8 patients with advanced-stage CTCL. All patients experienced significant decrease in clinical symptoms in response to aggressive, transient antibiotic treatment. In some patients, clinical improvements lasted for more than 8 months. In 6 of 8 patients, a malignant T-cell clone could be identified in lesional skin, and a significant decrease in the fraction of malignant T cells was observed following antibiotics but an otherwise unchanged treatment regimen. Immunohistochemistry, global messenger RNA expression, and cell-signaling pathway analysis indicated that transient aggressive antibiotic therapy was associated with decreased expression of interleukin-2 high-affinity receptors (CD25), STAT3 signaling, and cell proliferation in lesional skin. In conclusion, this study provides novel evidence suggesting that aggressive antibiotic treatment inhibits malignant T cells in lesional skin. Thus, we provide a novel rationale for treatment of SA in advanced CTCL.

Telenephrology: Providing Healthcare to Remotely Located Patients with Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) patients who live far (>30 miles) from their nephrologist experience lower rates of clinic visit adherence, limited access to treatment, and higher rates of hospitalization and mortality than patients who live in close proximity to their nephrologist. Strategies to minimize disparities between urban and remotely located CKD patients are needed. The purpose of this study was to determine whether adherence to clinic visits and clinical outcomes in the remote management of CKD via telenephrology is comparable to in-person conventional care. METHODS: Renal clinic adherence and composite outcomes of death, end-stage renal disease (ESRD), or doubling of serum creatinine (Cr) were measured in geographically remote Hudson Valley VA Medical Center (HVVAMC) CKD patients enrolled in telenephrology (n = 112) and CKD patients enrolled in the Bronx VAMC renal clinic (n = 116). RESULTS: Prior to implementing the telenephrology service, 53.1% of scheduled visits of rural HVVAMC patients to the Bronx VAMC renal clinic were either cancelled or were "no-shows." This was reduced by nearly half (28.5%) after instituting telenephrology (p < 0.001). Moreover, the frequency of attending appointments was greater in the telenephrology (71.9%) vs. in-person Bronx VA cohort (61.0%). The incidence of the composite outcome of death, ESRD, or doubling of Cr was similar between both groups (p = 0.96) over 2 years of follow-up. CONCLUSIONS: Remote CKD care delivered through telenephrology improves renal clinic visit adherence while delivering comparable renal outcomes. Application of this technology is a promising method to provide access to care to rural CKD patients and to minimize the disparity between urban/rural patients.

Malignant inflammation in cutaneous T-cell lymphoma-a hostile takeover.

Cutaneous T-cell lymphomas (CTCL) are characterized by the presence of chronically inflamed skin lesions containing malignant T cells. Early disease presents as limited skin patches or plaques and exhibits an indolent behavior. For many patients, the disease never progresses beyond this stage, but in approximately one third of patients, the disease becomes progressive, and the skin lesions start to expand and evolve. Eventually, overt tumors develop and the malignant T cells may disseminate to the blood, lymph nodes, bone marrow, and visceral organs, often with a fatal outcome. The transition from early indolent to progressive and advanced disease is accompanied by a significant shift in the nature of the tumor-associated inflammation. This shift does not appear to be an epiphenomenon but rather a critical step in disease progression. Emerging evidence supports that the malignant T cells take control of the inflammatory environment, suppressing cellular immunity and anti-tumor responses while promoting a chronic inflammatory milieu that fuels their own expansion. Here, we review the inflammatory changes associated with disease progression in CTCL and point to their wider relevance in other cancer contexts. We further define the term "malignant inflammation" as a pro-tumorigenic inflammatory environment orchestrated by the tumor cells and discuss some of the mechanisms driving the development of malignant inflammation in CTCL.

Preliminary outcomes of laparoscopic sleeve gastrectomy in a Veterans Affairs medical center.

BACKGROUND: Preliminary results of a new bariatric surgery program in a VA Medical Center using laparoscopic sleeve gastrectomy (LSG). METHODS: Prospective review of the first 50 patients who underwent LSG. Percentage change in body mass index (BMI), comorbidities, serum glucose, glycosylated hemoglobin (HbA1c), lipid profiles, and medications were recorded. RESULTS: Mean age was 52 years. Average BMI was 46 kg/m(2). There were no mortalities or staple line leaks. The percentage excess BMI loss was 47% and 54% at 6 and 12 months, respectively. After 6 months, fasting glucose level decreased from 127 to 93 mg/dL, and mean glycosylated hemoglobin decreased from 6.8% to 5.7%. At 1-year follow-up evaluation, serum cholesterol decreased from 182 to 168 mg/dL, mean triglycerides from 179 to 93 mg/dL, low-density lipoprotein from 110 to 94 mg/dL, and high-density lipoprotein increased from 42 to 50 mg/dL. CONCLUSIONS: Laparoscopic sleeve gastrectomy is safe and effective for morbidly obese VA patients and resulted in significant discontinuation of medication for hypertension, diabetes and hyperlipidemia.

Increased presence of cognitive impairment in hemodialysis patients in the absence of neurological events.

BACKGROUND/AIMS: Cognitive impairment (CI) is highly prevalent among hemodialysis (HD) patients and is associated with increased morbidity and mortality. The aim was to compare cognitive function in HD patients with no history of stroke or dementia and well-matched controls. Studies are required to determine the impact of HD and chronic kidney disease-specific risks on CI. METHODS: 76 outpatients (50 receiving outpatient HD and 26 with normal kidney function matched for age and comorbidity) underwent a cross-sectional observational study. HD patients were well dialyzed and had optimal hemoglobin levels. A battery of eight neuropsychological tests was used. Outcomes included assessment scores of neurocognitive testing and prevalence and subtype of CI. RESULTS: Compared to controls, HD subjects had significantly lower composite scores for each tested cognitive domain. In each domain except memory, the percentage of subjects with impairment was significantly higher in HD subjects than controls. Differences between the groups were independent of vascular and dementia risk factors. 82% of HD subjects met criteria for CI versus 50% of controls. Non-amnestic subtype of CI was more prevalent in both groups. CONCLUSION: Well-dialyzed HD patients with optimized hemoglobin levels and with no history of stroke or dementia performed significantly worse on multiple measures of cognition compared to controls. A higher prevalence of non-memory impairment may suggest an underlying vascular versus neurodegenerative mechanism. HD and chronic kidney disease-specific risk factors may contribute to early CI not readily detected by routine screening methods.

Homocysteine and cognitive function in very elderly nondemented subjects.

OBJECTIVES: To examine the association of homocysteine with cognitive functioning in very elderly community-dwelling individuals (80 years or older). METHODS: Two hundred twenty-eight nondemented community-dwelling individuals were assessed with a broad neuropsychological battery. Bloods were drawn to measure homocysteine, serum vitamin B12, and folate levels and APOE genotype. RESULTS: Higher homocysteine levels were associated with poorer executive-language functioning scores (r = -0.311). The association persisted when serum B12 and folate levels were controlled for (r = -0.308). Homocysteine levels were not associated with memory score (r = 0.120). CONCLUSIONS: In very elderly, nondemented community dwellers, high homocysteine levels are associated with poorer executive-language functioning but not with memory. This possible differential effect of homocysteine on cognitive functions suggests that it may affect only specific brain regions or mechanisms underlying healthy executive functioning.

Cognitive profile of chronic kidney disease and hemodialysis patients without dementia.

BACKGROUND/AIMS: The high risk and prevalence of dementia among patients with chronic kidney disease (CKD) and in those receiving hemodialysis (HD) may be preceded by mild cognitive impairment (MCI). We aimed to assess cognitive function in CKD and HD patients with no history of stroke or dementia, in order to identify and characterize early cognitive deficits. METHODS: 24 CKD and 27 HD male outpatients without history of cerebrovascular or neurodegenerative disease underwent comprehensive neuropsychological testing in an observational cross-sectional study. Test results were used to categorize patients into MCI subtypes. RESULTS: All subjects scored ≥28 on the Mini-Mental State Examination. The prevalence of executive function was at least 25% in both groups and memory impairment occurred in 13% of the HD patients and 15% of those with CKD. MCI occurred in 76% of the group and HD patients showed a higher prevalence of MCI compared to CKD patients (89 vs. 63%) with a preponderance (>70%) of cases across both groups classified as non-amnestic MCI. CONCLUSION: Predialysis CKD and HD patients have a high prevalence of MCI despite normal global cognitive function. MCI was more prevalent among the HD patients and deficits more frequently resulted in non-amnestic MCI.

Cerebrovascular effects of hemodialysis in chronic kidney disease.

Patients with end-stage renal disease (ESRD) undergoing hemodialysis are known to suffer cognitive deficits and stroke of unknown etiology. It has been suspected that the treatment itself may contribute to the syndrome by unknown mechanisms, which we investigated in this study. End-stage renal disease patients on hemodialysis (n=19) or peritoneal dialysis (PD, n=5) were compared with 14 healthy controls. Subjects participated in magnetic resonance imaging (MRI) measurements of cerebral atrophy, cerebral blood flow (CBF) arterial spin labeled-MRI (ASL-MRI), quantitative Doppler blood flow through the internal carotid artery, and cerebral oxymetry. The Doppler and oxymetry procedures were also performed at the beginning and end of a single hemodialysis session. End-stage renal disease patients on hemodialysis showed significant cerebral atrophy, associated with longer hemodialysis duration and cognitive deficits, including focal bilateral lesions in the caudate nucleus and midbrain. Cerebral oxygenation was extremely low before dialysis (rSO(2) 41+/-13, compared with 70+/-2 in controls, P<0.02) and improved only slightly after dialysis. Carotid blood flow was also very low at the start of dialysis (115+/-28 mL/sec, versus 193+/-56 in controls, P<0.005) but normalized at the end of the session (181 mL/sec). The PD patients showed intermediate values, between the hemodialysis and controls. Notably, duration of hemodialysis treatment predicted global gray-matter volume (r=-0.74), change of blood flow during dialysis (r=-0.65), and baseline rSO(2) (r=-0.65). The findings suggest that ESRD patients on hemodialysis suffer low CBF during the interdialytic cycle. Coupled with low cerebral oxygenation levels and atherosclerosis, this may contribute significantly to the etiology of the observed cerebral atrophy, cognitive deficits, and high stroke prevalence.

Pneumonitis in human cytomegalovirus infection.

Human cytomegalovirus (HCMV) is a beta herpes virus with a double stranded DNA genome of 240kbp. The virus is prevalent and establishes a latent infection in most adults. HCMV is an opportunistic pathogen for patients with impaired cellular immunity. HCMV pneumonia is a common presentation of HCMV disease in immunocompromised patients. The incidence of HCMV pneumonitis can be as high as 90% in lung transplant recipients. This paper takes a fresh look at the challenging perspectives of molecular, immunologic, cellular, diagnostic, clinical, and therapeutic characteristics of HCMV infection as future targets for development of antiviral strategies.

Polyomavirus in human cancer development.

In animal studies, polyoma viruses have been found to be viral agents for oncogenesis and to produce a wide range of pathological lesions in experimental animals, including a variety of neoplastic tumors. The human polyoma viruses (JCV and BKV), along with their simian cousin (SV40), are ubiquitous viruses that are primarily associated with progressive multifocal leukoencephalolopathy (PML) and hemorrhagic cystitis, respectively, under specific conditions in immunocompromized individuals. Currently, polyoma viruses are now undergoing increasing scrutiny as possible causes for several human cancers. Evidence has been mounting recently that JCV, BKV as well as SV40 are potential oncogenic viruses in humans as well.

Induction of immunity against human cytomegalovirus.

Most healthy individuals have been exposed to human cytomegalovirus (HCMV) and harbor the virus in a dormant form. However, in situations of immune compromise, HCMV infection is associated with high mortality rates in recipients of bone marrow transplants and with significant morbidity in recipients of solid organ transplants. Conventional vaccination with attenuated HCMV or HCMV proteins fails to prime protective immune responses, presumably because the antigens fail to be presented effectively in vivo. Dendritic cells (DC) are professional antigen-presenting cells that can be genetically engineered to direct their ability to induce immune responses toward immunodominant HCMV antigens. DC are a distinct lineage of leukocytes whose function is most notable for their ability to form clusters with T cells and stimulate vigorous cytotoxic T lymphocyte responses. We hypothesize that in this capacity, DC engineered to express HCMV antigens are uniquely positioned to control immunity against HCMV.