Exposure to Agent Orange is associated with increased recurrence after surgical treatment of stage I non-small cell lung cancer.

OBJECTIVE: Approximately 3 million Americans served in the armed forces during the Vietnam War. Veterans have a higher incidence rate of lung cancer compared with the general population, which may be related to exposures sustained during service. Agent Orange, one of the tactical herbicides used by the armed forces as a means of destroying crops and clearing vegetation, has been linked to the development of several cancers including non-small cell lung cancer. However, traditional risk models of lung cancer survival and recurrence often do not include such exposures. We aimed to examine the relationship between Agent Orange exposure and overall survival and disease recurrence for surgically treated stage I non-small cell lung cancer. METHODS: We performed a retrospective cohort study using a uniquely compiled dataset of US Veterans with pathologic I non-small cell lung cancer. We included adult patients who served in the Vietnam War and underwent surgical resection between 2010 and 2016. Our 2 comparison groups included those with identified Agent Orange exposure and those who were unexposed. We used multivariable Cox proportional hazards and Fine and Gray competing risk analyses to examine overall survival and disease recurrence for patients with pathologic stage I disease, respectively. RESULTS: A total of 3958 Vietnam Veterans with pathologic stage I disease were identified (994 who had Agent Orange exposure and 2964 who were unexposed). Those who had Agent Orange exposure were more likely to be male, to be White, and to live a further distance from their treatment facility (P < .05). Tumor size distribution, grade, and histology were similar between cohorts. Multivariable Cox proportional hazards modeling identified similar overall survival between cohorts (Agent Orange exposure hazard ratio, 0.97; 95% CI, 0.86-1.09). Patients who had Agent Orange exposure had a 19% increased risk of disease recurrence (hazard ratio, 1.19; 95% CI, 1.02-1.40). CONCLUSIONS: Veterans with known Agent Orange exposure who undergo surgical treatment for stage I non-small cell lung cancer have an approximately 20% increased risk of disease recurrence compared with their nonexposed counterparts. Agent Orange exposure should be taken into consideration when determining treatment and surveillance regimens for Veteran patients.

Association between imaging surveillance frequency and outcomes following surgical treatment of early-stage lung cancer.

BACKGROUND: Recent studies have suggested that more frequent postoperative surveillance imaging via computed tomography following lung cancer resection may not improve outcomes. We sought to validate these findings using a uniquely compiled dataset from the Veterans Health Administration, the largest integrated health-care system in the United States. METHODS: We performed a retrospective cohort study of veterans with pathologic stage I non-small cell lung cancer receiving surgery (2006-2016). We assessed the relationship between surveillance frequency (chest computed tomography scans within 2 years after surgery) and recurrence-free survival and overall survival. RESULTS: Among 6171 patients, 3047 (49.4%) and 3124 (50.6%) underwent low-frequency (<2 scans per year; every 6-12 months) and high-frequency (≥2 scans per year; every 3-6 months) surveillance, respectively. Factors associated with high-frequency surveillance included being a former smoker (vs current; adjusted odds ratio [aOR] = 1.18, 95% confidence interval [CI] = 1.05 to 1.33), receiving a wedge resection (vs lobectomy; aOR = 1.21, 95% CI = 1.05 to 1.39), and having follow-up with an oncologist (aOR = 1.58, 95% CI = 1.42 to 1.77), whereas African American race was associated with low-frequency surveillance (vs White race; aOR = 0.64, 95% CI = 0.54 to 0.75). With a median (interquartile range) follow-up of 7.3 (3.4-12.5) years, recurrence was detected in 1360 (22.0%) patients. High-frequency surveillance was not associated with longer recurrence-free survival (adjusted hazard ratio = 0.93, 95% CI = 0.83 to 1.04, P = .22) or overall survival (adjusted hazard ratio = 1.04, 95% CI = 0.96 to 1.12, P = .35). CONCLUSIONS: We found that high-frequency surveillance does not improve outcomes in surgically treated stage I non-small cell lung cancer. Future lung cancer treatment guidelines should consider less frequent surveillance imaging in patients with stage I disease.

A real-world study of pneumonitis in non-small cell lung cancer patients receiving durvalumab following concurrent chemoradiation.

Background: Locally advanced non-small cell lung cancer (LA-NSCLC) treated with the programmed death-ligand 1 inhibitor durvalumab has been associated with significant rates of pneumonitis, which has led to higher rates of discontinuation of therapy in real-world populations. Thus far there has been no consensus in the literature on the impact of pneumonitis on survival. Methods: This is a retrospective cohort study of veterans receiving durvalumab between 12/5/2017 and 4/15/2020. Participants were identified using VINCI data services. Patients were followed through 9/14/2021. Development of clinical pneumonitis was assessed through review of documentation and graded using CTCAE 4.0 criteria. Univariate logistic regression analysis evaluated for associations between body mass index (BMI), age, race, co-morbidity index, chemotherapy regimen, chronic obstructive pulmonary disease (COPD) severity, and development of clinical pneumonitis. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier methods. Cox proportional hazards models were utilized to evaluate the association between risk of death at 1 and 2 years and candidate predictor variables. Results: A total of 284 patients were included in this study. Sixty-one patients developed clinically significant pneumonitis, 7 patients developed grade 5 pneumonitis (death from pneumonitis). The median OS in patients that developed pneumonitis was 27.8 vs. 36.9 months in patients that did not develop pneumonitis (P=0.22). BMI was found to be a clinical predictor of pneumonitis (P=0.04). COPD severity, race, age at durvalumab start date, chemotherapy regimen, and Romano comorbidity index were not significant predictors of pneumonitis. Cox proportional hazards analysis failed to demonstrate an association between the development of pneumonitis and risk of death in this population. Conclusions: The incidence of clinically significant pneumonitis is higher than noted in the PACIFIC trial in this cohort, however this high rate of pneumonitis does not have an impact on OS or PFS. Obesity was found to be a significant predictor of pneumonitis in this patient population.

Advancing age and the risk of bleomycin pulmonary toxicity in a largely older cohort of patients with newly diagnosed Hodgkin Lymphoma.

OBJECTIVES: In patients with Hodgkin Lymphoma (HL), the relationship between increasing age and bleomycin pulmonary toxicity (BPT) remains unclear. This study explores associations between age and BPT in a real-world cohort of largely older patients with HL. MATERIAL AND METHODS: This study retrospectively evaluated a nationwide patient cohort of United States Veterans diagnosed with HL in VA medical centers between October 1, 2002 and December 31, 2013 (follow up through April 15, 2016). The primary outcome was the development BPT, defined as: ambient air oxygen saturations <92% with pulmonary infiltrates on chest radiograph and no other etiologies OR clinician documentation of BPT. Multivariable logistic regression was used to evaluate variables associated with development of BPT. Cox proportional hazards analysis was performed to evaluate the risk of death up-to 5-years from diagnosis. RESULTS: Overall, 847 patients received chemotherapy and 739 of these patients received bleomycin. Sixty-six patients (9.3%) developed BPT. The incidence of BPT per age category: 0.03 (9/262), 0.07 (13/188), 0.13 (23/171), and 0.24 (21/88) for age categories: ≤ 49, 50-59, 60-69 and ≥ 70 years. Odds of BPT steadily increased with advancing age (compared to patients age ≤ 49 years) with odds ratios of 1.65 (95% CI 0.68-4.03), 3.24 (1.43-7.34), 6.01(2.52-7.34) for age categories 50-59, 60-69 and ≥ 70 years, respectively. The was no association between bleomycin and risk of death up-to 5-years [HR: 0.87; 95% CI (0.61-1.23)]. CONCLUSION: This study demonstrates a direct relationship between age >60 years and odds of developing clinically significant BPT.

Metformin Use and Pancreatic Cancer Survival among Non-Hispanic White and African American U.S. Veterans with Diabetes Mellitus.

BACKGROUND: The effect of metformin use on survival among patients with pancreatic ductal adenocarcinoma (PDAC) is controversial. Furthermore, there are no data on African American patients. To address these, we analyzed data from the United States Veterans Health Administration (VHA). METHODS: A population-based retrospective cohort study evaluating overall survival among 3,811 patients with PDAC with preexisting diabetes mellitus, diagnosed with PDAC within the VHA between 1998 and 2013. We calculated HRs and 95% confidence intervals (CI) using multivariable adjusted time-varying Cox proportional hazards regression to control for immortal time bias and confounders. RESULTS: Metformin use was not associated with overall survival in the complete analyses (HR = 1.05; 95% CI, 0.92-1.14; P = 0.28). However, among patients who were metformin naïve at the time of PDAC diagnosis (N = 1,158), metformin use was associated with improved overall survival in non-Hispanic white patients (HR = 0.78; 95% CI, 0.61-0.99; P = 0.04), but not African American patients (HR = 1.20; 95% CI, 0.75-1.93; P = 0.45). The survival benefit among non-Hispanic whites was limited to patients with metastatic disease (HR = 0.67; 95% CI, 0.44-1.01; P = 0.06). Among African American patients with metastatic disease, HR was 1.30 (95% CI, 0.77-2.53; P = 0.28). There was a suggestion of heterogeneity by race in patients with metastatic disease (P heterogeneity = 0.05). CONCLUSIONS: We observed no associations between metformin use and survival in patients with PDAC, but there appears to be a survival benefit among non-Hispanic white patients who were metformin naïve at the time of PDAC diagnosis. IMPACT: If confirmed in other studies, our findings suggest that metformin as an adjunctive treatment for PDAC may not improve survival among African American patients.

Post-MGUS Diagnosis Serum Monoclonal-Protein Velocity and the Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma.

BACKGROUND: Multiple myeloma is a common hematologic malignancy consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). Little is known about postdiagnosis clinical predictors of progression of MGUS to multiple myeloma to guide MGUS management. This study aimed to investigate whether the rate of rise in serum monoclonal protein concentration during the year after MGUS diagnosis-M-protein velocity-predicts progression of MGUS to multiple myeloma. METHODS: Data from the U.S. Veterans Health Administration system were used. A retrospective cohort of patients with MGUS who progressed to multiple myeloma were matched on age at MGUS diagnosis and race in a 1:4 ratio to the patients with MGUS using incidence density sampling. Kaplan-Meier curves were plotted. Univariable and multivariable conditional logistic regression analyses were fitted from the matched risk sets. RESULTS: A total of 128 cases and 490 matched controls were included. The case group contained a higher percentage of patients with M-protein velocity >0.1 g/dL/year than the control group (44.5% vs. 28.2%, P <0.0001). M-protein velocity of >0.1 g/dL during the year following MGUS diagnosis was positively associated with progression of MGUS to multiple myeloma (multivariable-adjusted odds ratio = 2.15; 95% confidence interval, 1.37-3.35). CONCLUSIONS: Patients with a positive M-protein velocity during the year after MGUS diagnosis may be considered for more frequent monitoring for early detection and timely treatment of multiple myeloma. Future prevention studies could target these patients for intervention evaluation. IMPACT: Our results suggest a new clinical predictor of progression to multiple myeloma following MGUS diagnosis, which has potential to identify high-risk patients for management and prevention.

Treatment of Advanced Prostate Cancer.

Advanced prostate cancer is a heterogenous disease with multiple treatment options. Patients with advanced disease are stratified based evidence of metastasis and sensitivity to hormone therapy. Men with hormone sensitive disease are treated with androgen deprivation therapy and possibly chemotherapy. The treatment options for men with castrate resistant disease are rapidly evolving with multiple recently approved treatment options. Determining the proper sequence and combination of these therapies remains a work in progress.

Obesity and the Transformation of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma: A Population-Based Cohort Study.

Background: Multiple myeloma (MM) is one of the most common hematologic malignancies in the United States and is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). This study investigates the role of obesity in the progression of MGUS to MM. Methods: A retrospective identified cohort of patients in the US Veterans Health Administration database diagnosed with MGUS between October 1, 1999, and December 31, 2009, was followed through August 6, 2013. Patient-level clinical data were reviewed to verify MM diagnosis, if any. Survival analyses utilizing interval-censored data were used to investigate the risk of progression of MGUS to MM. Statistical tests were two-sided. Results: The analytic cohort consisted of 7878 MGUS patients with a median follow-up of 68 months. Within the cohort, 39.8% were overweight and 33.8% were obese; 64.1% were of white race. During follow-up, 329 MGUS patients (4.2%) progressed to MM: 72 (3.5%) normal-weight patients (median follow-up = 61.9 months), 144 (4.6%) overweight patients (median follow-up = 69.1 months), and 113 (4.3%) obese patients (median follow-up = 70.6 months). In the multivariable analysis, overweight (hazard ratio [HR] = 1.55, 95% confidence interval [CI] = 1.16 to 2.06) and obesity (HR = 1.98, 95% CI = 1.47 to 2.68) were associated with an increased risk of transformation of MGUS to MM. Moreover, black race was associated with a higher risk of MM (HR = 1.98, 95% CI = 1.55 to 2.54). Conclusions: Obesity and black race are risk factors for transformation of MGUS to MM. Future clinical trials should examine whether weight loss is a way to prevent the progression to MM in MGUS patients.

Association between metformin use and progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans with diabetes mellitus: a population-based retrospective cohort study.

BACKGROUND: Multiple myeloma is one of the most common haematological malignancies in the USA and is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). We aimed to assess the association between metformin use and progression of MGUS to multiple myeloma. METHODS: We did a retrospective cohort study of patients registered in the US Veterans Health Administration database and diagnosed with MGUS between Oct 1, 1999, and Dec 31, 2009. We included patients (aged >18 years) with at least one International Classification of Diseases (9th revision) code for diabetes mellitus and one treatment for their diabetes before MGUS diagnosis. We reviewed patient-level clinical data to verify diagnoses and extract any available data for size of baseline M-protein and type of MGUS. We defined metformin users as patients with diabetes who were given metformin consistently for 4 years after their diabetes diagnosis and before multiple myeloma development, death, or censorship. Our primary outcome was time from MGUS diagnosis to multiple myeloma diagnosis. We used Kaplan-Meier curves and Cox models to analyse the association between metformin use and MGUS progression. FINDINGS: We obtained data for 3287 patients, of whom 2003 (61%) were included in the final analytical cohort. Median follow-up was 69 months (IQR 49­96). 463 (23%) participants were metformin users and 1540 (77%) participants were non-users. 13 (3%) metformin users progressed to multiple myeloma compared with 74 (5%) non-users. After adjustment, metformin use was associated with a reduced risk of progression to multiple myeloma (hazard ratio 0·47, 95% CI 0·25­0·87). INTERPRETATION: For patients with diabetes diagnosed with MGUS, metformin use for 4 years or longer was associated with a reduced risk of progression of MGUS to multiple myeloma. Prospective studies are needed to establish whether this association is causal and whether these results can be extrapolated to non-diabetic individuals. FUNDING: Barnes-Jewish Hospital Foundation, National Institutes of Health, Agency for Healthcare Research and Quality, American Cancer Society.

The role of atopy in corneal graft survival in keratoconus.

PURPOSE: To compare the prevalence of endothelial rejection episodes and the probability of graft survival after initial and repeat penetrating keratoplasty (PK) in patients with keratoconus with and without atopy. METHODS: A retrospective review was conducted of all patients receiving PK for keratoconus at the University of Texas Southwestern Medical Center at Dallas from 1988 to 2009. Inclusion criteria involved those with both an International Classification of Diseases-9 code for keratoconus and a Current Procedural Terminology code for PK based on a computer database search. Patients younger than 18 years were excluded. These records were then reviewed for a history of atopic disorders. The main outcome measures included the prevalence of endothelial rejection episodes and the probability of graft survival. The probability of corneal graft survival in patients with and without a history of atopy was compared using the Kaplan-Meier method. RESULTS: There were 168 grafts in 122 patients. There were 66 (39.2%) and 102 (60.8%) grafts with and without a history of atopy, respectively. Bilateral first grafts were required in 32 patients, 14 and 18 patients with and without a history of atopy, respectively. The atopic and nonatopic groups had no significant differences with respect to age, preexisting ocular conditions, concomitant surgical procedures, and length of follow-up. Men received first grafts significantly more frequently than women in the nonatopic group (P = 0.029); however, there was no sex difference in repeat grafts. There were no significant differences in the prevalence of endothelial rejection episodes after the first (P = 0.716), second (P > 0.999), and third or further grafts (P > 0.999). Graft survival between the atopic and nonatopic groups did not differ significantly in the first (P = 0.881), second (P = 0.752), or third or further graft (P = 0.157). Among first grafts in the atopic group, no statistically significant difference in survival existed among patients analyzed with different manifestations of atopy (P = 0.061). One episode of allograft endothelial rejection created a statistically significant difference in ultimate graft survival probability in both the atopic (P = 0.003) and nonatopic (P = 0.002) groups. CONCLUSIONS: Among patients with keratoconus receiving PK, there is no statistically significant difference in the prevalence of endothelial graft rejection episodes or probability of graft survival between patients with and without a clinical history of atopy.

Efficacy of telavancin in the treatment of methicillin-resistant Staphylococcus aureus osteomyelitis: studies with a rabbit model.

OBJECTIVES: Staphylococcus aureus is the most common pathogen isolated in osteomyelitis. This study evaluated the efficacies of telavancin (an investigational, rapidly bactericidal lipoglycopeptide with a multifunctional mechanism of action against Gram-positive bacteria), vancomycin and linezolid in a rabbit methicillin-resistant S. aureus (MRSA) osteomyelitis model. METHODS: Localized osteomyelitis was induced in New Zealand White rabbits by percutaneous injection of 10(6) cfu of MRSA clinical isolate 168-1 into the intramedullary cavity. Two weeks post-infection, rabbits with radiographically confirmed, localized proximal tibial osteomyelitis were randomized into four groups (n = 15 per group): untreated controls; vancomycin 30 mg/kg subcutaneously every 12 h; linezolid 60 mg/kg orally every 8 h; and telavancin 30 mg/kg subcutaneously every 12 h. After 4 weeks of antibiotic treatment, animals were left untreated for 2 weeks. Rabbits were then euthanized and the tibias harvested. Bone matrix and marrow from each tibia were cultured and bacterial counts determined. RESULTS: For MRSA isolate 168-1, the MIC was 0.25 mg/L for telavancin, 0.5 mg/L for vancomycin and 0.5 mg/L for linezolid. Tibial cultures were positive for MRSA in 9 of 15 (60%) untreated controls, and 3 of 15 (20%) telavancin-treated, 3 of 15 (20%) vancomycin-treated and 4 of 14 (29%) linezolid-treated rabbits. CONCLUSIONS: Telavancin has comparable efficacy to vancomycin and linezolid in a rabbit model of MRSA osteomyelitis.

Reproduction in couples who are affected by human immunodeficiency virus: medical, ethical, and legal considerations.

There has been a transformation in the treatment of human immunodeficiency virus from the treatment of complications that define acquired immune deficiency syndrome to the maintenance of long-term health, with an expanding number of antiretroviral medications. Because human immunodeficiency virus infection now is considered to be a chronic disease, couples will be seen in greater numbers for preconception counseling. The ethical and legal implications, including the relevance of the Americans with Disability Act, are complex but support the assistance with reproduction of couples who are affected by human immunodeficiency virus in many instances. All couples who are affected by human immunodeficiency virus, whether fertile or infertile, who want to have genetically related offspring should be seen preconceptionally for counseling and testing. Intensive education involves a multidisciplinary approach to ensure that a couple is fully informed. Determination of whether to offer treatment should be based on the same criteria that are applied to couples who are affected by other chronic diseases. Medical treatment is dependent on the unique circumstances of each couple. In general, the affected partner(s) should be treated aggressively with antiretrovirals and then serum; if applicable, semen testing is required to document undetectable concentrations of human immunodeficiency virus (<50-100 copies/mL).

Gamete retrieval in terminal conditions: is it practical? What are the consequences?

There is an increasing interest in, and request for, gamete retrieval from recently deceased or near-dead subjects for the purpose of posthumous procreation. This usually arises in an emergency situation with little time for physicians to consider ethical ramifications. Advance planning is needed to help these physicians make thoughtful decisions. After considering the complexity of the issues involved, the Ethics Consult Service and the Ethics Committee at the University of Virginia requested that we develop a policy on gamete retrieval for subjects in terminal conditions, which would govern and guide involved providers should this process be requested. Our team consisted of members of the Ethics Consult Service and Ethics Committee, as well as personnel who might be intimately involved in the gamete retrieval process, including the director of the Human Gamete and Embryo Laboratory, a urologist, and a reproductive endocrinologist. In addition to reviewing the current literature describing the actual processes involved, we explored the ethical implications of gamete retrieval in these situations. A policy was developed and approved by the Ethics Committee at our institution, and is included in this article.