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.

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.

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.

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.