Burn injuries in US service members: 2001-2018.

INTRODUCTION: Burns are an important cause of battlefield injury, accounting for 5-20% of the combat injury burden. To date, no report has examined the full range of burns, from mild to severe, resulting from post-9/11 conflicts. The present study leverages the Expeditionary Medical Encounter Database (EMED), a Navy-maintained health database describing all service member medical encounters occurring during deployment, to capture, quantify and characterize burn-injured service members and the injuries they sustained while deployed in support of post-9/11 operations. METHODS: The EMED was queried for all surviving service members with at least one burn injury, identified using injury-specific Abbreviated Injury Scale codes. Demographic and additional injury information were also obtained from the EMED. RESULTS: From 2001 through 2018, 2507 deployed service members sustained 5551 burns. Blasts accounted for 82% of injuries, largely attributed to the use of improvised explosive devices. Concurrent injury was common, with 30% sustaining a traumatic brain injury and 10% sustaining inhalation injury. Most burns were small, with 92% involving< 20% TBSA; 85% of burns involved< 10% TBSA. The head and the hands were the most commonly affected areas, accounting for 48% of all burns, with 80% of service members sustaining at least one burn to these areas. CONCLUSION: The majority of burns tend to be small in size, with the head and hands most commonly affected. As these areas are often left uncovered by the uniform, prevention measures, particularly improvement in and increased usage of personal protective gear, may help reduce these injuries and their consequences.

Relationship Between Tinnitus and Hearing Outcomes Among US Military Personnel After Blast Injury.

OBJECTIVES: To examine the association between tinnitus and hearing outcomes among US military personnel after blast injury, including any hearing loss, low-frequency hearing loss, high-frequency hearing loss, early warning shift, and significant threshold shift. DESIGN: In this retrospective study, the Blast-Related Auditory Injury Database was queried for male military service members who had audiometric data 2 years before and after blast injury between 2004 and 2012 with no history of hearing loss or tinnitus before injury (n = 1693). Tinnitus was defined by diagnostic codes in electronic health records. Multivariable logistic regression examined the association between tinnitus and hearing outcomes, while adjusting for covariates. RESULTS: Overall, 14.2% (n = 241) of the study sample was diagnosed with tinnitus within 2 years after blast injury. The proportions of all examined hearing outcomes were higher among service members with tinnitus than those without ( p < 0.001). In multivariable analysis, service members with tinnitus had higher adjusted odds of any hearing loss (odds ratio [OR] = 1.72, 95% confidence interval [CI] = 1.20-2.47), low-frequency hearing loss (OR = 2.77, 95% CI = 1.80-4.26), high-frequency hearing loss (OR = 2.15, 95% CI = 1.47-3.16), early warning shift (OR = 1.83, 95% CI = 1.36-2.45), and significant threshold shift (OR = 2.15, 95% CI = 1.60-2.89) compared with service members without tinnitus. CONCLUSIONS: The findings of this study demonstrate that tinnitus diagnosed within 2 years after blast injury is associated with the examined hearing outcomes in US military personnel. Service members with blast injury who subsequently experience tinnitus should receive routine audiometric hearing conservation testing and be carefully examined for poor hearing outcomes by an audiologist.

The relationship between self-reported physical functioning, mental health, and quality of life in Service members after combat-related lower extremity amputation.

PURPOSE: Service members with amputations experience numerous challenges, yet few studies have examined patient-reported outcomes, including physical functional status, mental-health screening status, and quality of life (QOL) or the relationship between these outcomes. MATERIALS AND METHODS: Service members with combat-related lower extremity amputations (N = 82) and participants in the Wounded Warrior Recovery Project were included. Patient-reported outcomes of physical functional status, posttraumatic stress disorder (PTSD), depression screening status, and QOL were compared, while accounting for amputation level. Linear regression assessed relationships between physical functional status and QOL, as well as mental-health screening status. RESULTS: Higher physical functioning scores were associated with better QOL, and lower physical functioning scores were associated with screening positive for PTSD or depression. When stratified by mental-health screening, a significant relationship was observed between mean physical functioning scores and amputation level with a negative PTSD or depression screen only. Additionally, those with bilateral amputation reported lower physical functioning. CONCLUSIONS: Physical functioning was associated with patient-reported outcomes, including QOL and mental-health screening. Screening positive for PTSD or depression was associated with worsened self-reported physical function and may outweigh the impact of amputation severity on physical functioning. Successful rehabilitation requires the integration of physical and mental health domains in order to achieve optimal functioning.Implications for rehabilitationThe current study shows that physical functioning in participants with combat-related amputation is related to the amputation level, quality of life, and mental-health symptom screening.Good mental health is crucial to optimal functioning, as presence of adverse mental-health symptoms may exacerbate physical functional limitations among those with combat-related amputations.Assessing variables related to adverse mental-health symptoms and ultimate physical functioning outcomes is critical for clinicians to optimize rehabilitative strategies and outcomes.

A Focus on Non-Amputation Combat Extremity Injury: 2001-2018.

INTRODUCTION: Extremity injuries have comprised the majority of battlefield injuries in modern U.S. conflicts since World War II. Most reports have focused on serious injuries only and, to date, no reports have described the full extent of combat extremity injuries, from mild to severe, resulting from post-9/11 conflicts. This study aims to identify and characterize the full spectrum of non-amputation combat-related extremity injury and extend the findings of previous reports. METHODS: The Expeditionary Medical Encounter Database was queried for all extremity injured service members (SMs) deployed in support of post-9/11 conflicts through July 2018. Only injuries incurred during combat operations were included in this report. Major amputations were excluded as well as SMs killed in action or who died of wounds. Extremity injuries were categorized by body region, nature of injury, and severity. Demographics and injury event characteristics are also presented. RESULTS: A total of 17,629 SMs sustained 42,740 extremity injuries during 18,004 separate injury events. The highest number of SMs were injured in 2004 (n = 3,553), 2007 (n = 2,244), and 2011 (n = 2,023). Injured SMs were mostly young (78% under 30 years), male (97%), junior- to mid-level enlisted (89%), in the Army (69%) or Marine Corps (28%), active duty (84%), serving as infantry and gun crew (59%), and injured in support of Operation Iraqi Freedom (60%). Blast weaponry was responsible for 75% of extremity injuries. Injuries were similarly distributed between the lower (52%) and upper (48%) extremities. The most common sites of lower extremity injury were the lower leg/ankle complex (40%) and thigh (26%). The most common upper extremities sites were the shoulder and upper arms (37%), and the hand, wrist, and fingers (33%). Nearly half (48%) of all extremity injuries were open wounds (48%), followed by fractures (20%) and contusions/superficial injuries (16%). SMs sustained an average of 2.4 extremity injuries per event and 56% of injuries were considered mild, with a median Injury Severity Score (ISS) of 3. CONCLUSION: This study is the first publication to capture, review, and characterize the full range, from mild to severe, of non-amputation combat-related extremity injuries resulting from post-9/11 conflicts. The high prevalence of extremity injury, particularly in such a young population, and associated short- and long-term health outcomes, will impact military health care systems for decades to come.

Low back pain, mental health symptoms, and quality of life among injured service members.

OBJECTIVE: Pain is a significant public health issue that may be particularly problematic among injured service members who are at high risk of chronic physical and mental health conditions. The goals of this study were to describe the prevalence and types of low back pain (acute vs. recurrent) among service members injured while on combat deployments, and to examine the differences in posttraumatic stress disorder (PTSD) and depression prevalence and severity, as well as quality of life, for individuals with low back pain compared with those without. METHOD: Baseline assessment data from a subset of participants (n = 4,397) in the Wounded Warrior Recovery Project, a large, longitudinal examination of patient-reported outcomes, were used in conjunction with Department of Defense medical records data. RESULTS: Almost half of participants had acute or recurrent low back pain diagnoses, and the majority of individuals had no diagnosis of low back pain prior to their deployment-related injury. Individuals with low back pain, particularly recurrent, screened positive for PTSD and depression at higher rates, reported more severe symptoms of these disorders, and demonstrated poorer quality of life than those without. CONCLUSIONS: Low back pain was a prevalent issue among service members with deployment-related injury and was associated with worsened mental health outcomes and quality of life. Health care providers and researchers in multiple disciplines should consider the complex relationships between pain and mental health in order to further optimize treatment and outcomes. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Clinical audiometric patterns of hearing loss following blast-related injury in U.S. military personnel.

Objective: To identify clinical audiometric patterns of hearing loss following blast-related injury (BRI) in US military personnel.Design: Retrospective cohort study.Study sample: A total of 1186 male Navy and Marine Corps service members with normal hearing thresholds on pre-injury audiograms who had post-injury audiograms in the Blast-Related Auditory Injury Database.Results: Low- and high-frequency pure-tone averages (PTAs) were significantly higher in those with BRI than non-blast-related injury (NBRI) for both ears (p < 0.001 for all comparisons). Overall, 172 (15%) service members met criteria for post-injury hearing loss and were categorised into PTA or single-frequency hearing loss subgroups. PTA hearing loss was more common in the BRI group (50% vs. 33%, p < 0.036), whereas single-frequency hearing loss was more common in the NBRI group. Most hearing loss was mild to moderate in degree, and three distinct audiometric patterns emerged (i.e. flat, sloping and rising). A flat pattern was the most prevalent configuration among those with PTA hearing loss, especially bilateral loss. Single-frequency hearing loss was mostly unilateral and high frequency.Conclusions: In this study, BRI produced hearing loss across test frequencies, generating more clinically actionable post-injury audiograms than NBRI. We found that post-injury audiometric patterns of hearing loss among military personnel may vary.

Prominent Injury Types in Vehicle Underbody Blast.

BACKGROUND: To fully understand the injury mechanisms during an underbody blast (UBB) event with military vehicles and develop new testing standards specific to military vehicles, one must understand the injuries sustained by the occupants. METHODS: Injury data from Service Members (SM) involved in UBB theater events that occurred from 2010 to 2014 were analyzed. Analysis included the investigation of prominent skeletal and visceral torso injuries. Results were categorized by killed-in-action (n = 132 SM) and wounded-in-action (n = 1,887 SM). RESULTS: Over 90% (553/606 SM) of casualties in UBB events with Abbreviated Injury Scale (AIS) 2+ injury sustained at least one skeletal fracture, when excluding concussion. The most frequent skeletal injuries from UBB were foot fractures (13% of injuries) for wounded-in-action and tibia/fibula fractures (10% of injuries) for killed-in-action. Only 1% (11/1037 SM) of all casualties with AIS 2+ injuries had visceral torso injuries without also sustaining skeletal fractures. In these few casualties, the coded injuries were likely due to trauma from a loading path other than direct UBB loading. CONCLUSION: Skeletal fractures are the most frequent AIS 2+ injury resulting from UBB events. Visceral torso injuries are infrequent in individuals that survive and they generally occur in conjunction with skeletal injuries.

Self-reported Functional Status in US Service Members After Combat-Related Amputation.

The objective of this study was to describe the functional status of US service members after combat-related amputation. This was a cross-sectional analysis of data from a subsample of the Wounded Warrior Recovery Project, an ongoing, web-based, longitudinal examination of patient-reported outcomes of injured service members. The study sample included 82 Wounded Warrior Recovery Project participants with a combat-related lower extremity amputation who reported using a prosthetic device and completed the Orthotics and Prosthetics Users' Survey Lower Extremity Functional Status, which measures self-reported functional status in participants with a prosthetic device. Basic activities, such as walking indoors, getting on and off the toilet, and getting up from a chair, were reported by the majority of participants as "very easy/easy," whereas higher-level activities, such as climbing stairs, walking long distances, or running, were more often reported as "slightly difficult/very difficult" or "cannot do this activity." Functional status varied significantly by amputation site (unilateral below knee, unilateral above knee, or bilateral; P = 0.004), with significantly better function reported in those with unilateral below knee than bilateral amputation (P < 0.05). These findings highlight deficits in the functional status of US service members with combat-related amputation. Self-reported functional status of daily activities may help target important activities for patient-centered goals.

Association of Specific Lower Extremity Injuries With Delayed Amputation.

INTRODUCTION: Despite medical interventions to preserve viability and functionality of injured limb(s) among combat-injured service members, delayed amputations may occur. The goal of this study was to determine whether specific lower extremity (LE) injuries were associated with delayed amputations. METHODS: The Expeditionary Medical Encounter Database was queried for combat-related LE injuries between 2003 and 2015. The Abbreviated Injury Scale (AIS) was used to categorize LE injuries by severity. Injury episodes with a maximum LE AIS of 1 or amputation on the day of injury were excluded. The final sample included 2,996 service members with at least one LE injury with an AIS ≥2. The frequencies of specific LE fractures and nerve and vessel injuries were determined. Logistic regression with paired independent variables was performed to examine the impact of multiple LE injuries on the odds of delayed amputation. RESULTS: Delayed LE amputation was identified in 308 (10.3%) service members in the sample. The delayed and no amputation groups did not differ in age and service branch. The majority of injury episodes were blast-related and with an Injury Severity Score ≥9. The most frequent fractures were tibia (34.4%) and fibula (29.3%), but the highest rates of delayed amputation were in those with navicular (36.2%), talus (30.0%), or calcaneus (28.1%) fractures. Odds of amputation were highest among service members with the calcaneus fracture and LE nerve injury (odds ratio [OR]: 41.74; 95% confidence interval [CI], 14.70, 118.55; p < 0.001), calcaneal fracture and LE vessel injury (OR: 17.99; 95% CI: 10.53, 30.74; p < 0.001), and calcaneus and tibia fractures (OR: 15.12; 95% CI: 9.54, 23.96; p < 0.001) combinations. CONCLUSIONS: Odds of delayed amputation increased substantially with specific injury combinations. These findings may guide clinical decision-making in the acute care period.

Preliminary study of hearing protection and non-impact, blast-induced concussion in US military personnel.

PRIMARY OBJECTIVE: To examine the relationship between hearing protection and non-impact, blast-induced concussion in US military personnel. RESEARCH DESIGN: Retrospective cohort study. METHODS AND PROCEDURES: A total of 501 US service members from the Expeditionary Medical Encounter Database with hearing protection status reported either 'worn' or 'not worn' were eligible for analysis. Clinical records were reviewed for concussion diagnoses. Univariate and multiple logistic regressions were performed. MAIN OUTCOMES AND RESULTS: Overall, 270 (53.9%) service members sustained non-impact, blast-induced concussion and 231 (46.1%) sustained other blast injuries. Only 39.6% (107 of 270) of service members with concussion wore hearing protection at the point of injury compared with 61.0% (141 of 231) of those with other injuries (p < 0.001). After adjusting for covariates, service members wearing hearing protection had significantly lower odds of concussion compared with those not wearing hearing protection (odds ratio = 0.42, 95% confidence interval = 0.29-0.62). CONCLUSIONS: To our knowledge, this preliminary study is the first to demonstrate that hearing protection is associated with lower odds of non-impact, blast-induced concussion. The benefits of using hearing protection in terms of force readiness could be significant since many service members wounded in recent conflicts were diagnosed with concussion.

Health-related quality of life among US military personnel injured in combat: findings from the Wounded Warrior Recovery Project.

PURPOSE: Little is known about the long-term, health-related quality of life (HRQOL) of those wounded in combat during Operations Enduring Freedom, Iraqi Freedom, and New Dawn. The present study described the overall HRQOL for a large group of US service members experiencing mild-to-severe combat-related injuries, and assessed the unique contribution of demographics, service- and injury-related characteristics, and mental health factors on long-term HRQOL. METHOD: The Wounded Warrior Recovery Project examines patient-reported outcomes in a cohort of US military personnel wounded in combat. Participants were identified from the Expeditionary Medical Encounter Database, a US Navy-maintained deployment health database, and invited to complete a web-based survey. At the time of this study, 3245 service members consented and completed the survey. Hierarchical linear regression analyses were conducted to assess the unique contribution of each set of antecedents on HRQOL scores. RESULTS: HRQOL was uniquely associated with a number of demographics, and service- and injury-related characteristics. Nevertheless, screening positive for posttraumatic stress disorder (B = - .09; P < .001), depression (B = - .10; P < .001), or both as a set (B = - .19; P < .001) were the strongest predictors of lower long-term HRQOL. CONCLUSIONS: Postinjury HRQOL among service members wounded in combat was associated with service and injury experience, and demographic factors, but was most strongly linked with current mental health status. These findings underscore the significance of mental health issues long after injury. Further, findings reinforce that long-term mental health screening, services, and treatment are needed for those injured in combat.

Impact of Blast Injury on Hearing in a Screened Male Military Population.

Exposure to hazardous intensity levels of combat noise, such as blast, may compromise a person's ability to detect and recognize sounds and communicate effectively. There is little previous examination of the onset of hearing health outcomes following exposure to blast in representative samples of deployed US military personnel. Data from the prospective Blast-Related Auditory Injury Database were analyzed. We included only those participants with qualified hearing tests within a period of 12 months prior to, and following, injury (n = 1,574). After adjustment for relevant covariates and potential confounders, those who sustained a blast injury had significantly higher odds of postinjury hearing loss (odds ratio = 2.21; 95% confidence interval: 1.42, 3.44), low-frequency hearing loss (odds ratio = 1.95; 95% confidence interval: 1.01, 3.78), high-frequency hearing loss (odds ratio = 2.45; 95% confidence interval: 1.43, 4.20), and significant threshold shift compared with a group with non-blast-related injury. An estimated 49% of risk for hearing loss in these blast-injured, deployed military members could be attributed to the blast-related injury event. This study reinforced that it is imperative to identify at-risk populations for early intervention and prevention, as well as to consistently monitor the effects of blast injury on hearing outcomes.

Gender Differences in Posttraumatic Stress Disorder Among U.S. Navy Healthcare Personnel.

BACKGROUND: The role of women in the U.S. military has changed markedly over the course of 20th- and 21st-century conflicts. Although women frequently occupy healthcare positions in the military, little is known about gender differences in posttraumatic stress disorder (PTSD) within this occupational subgroup. MATERIALS AND METHODS: A total of 4275 (667 women and 3608 men) U.S. Navy healthcare personnel supporting military operations in Iraq and Afghanistan were identified from electronic deployment records. Data from Post-Deployment Health Assessments were abstracted to identify PTSD screen positives, and to adjust for self-reported combat exposure and other deployment experiences. RESULTS: The prevalence of PTSD screen positive in the sample was 8.2% (n = 351/4275). After adjusting for combat exposure, previous psychiatric history, and demographics, women had significantly higher odds of screening positive for PTSD than did men (odds ratio = 1.99, 95% confidence interval 1.34-2.96). Interactions between gender and combat exposure, and between gender and previous psychiatric history were not statistically significant. CONCLUSIONS: This is one of the first studies to examine gender differences in PTSD among military healthcare personnel. Future research should account for additional stressors, such as long work hours, disrupted sleep patterns, and number of casualties treated. As women are further integrated into military occupations that may lead to different exposures, knowledge of gender differences in the manifestation of PTSD is paramount for prevention and treatment purposes.

Development of a comprehensive Blast-Related Auditory Injury Database (BRAID).

The Department of Defense Hearing Conservation Program provides specific guidance for service components to prevent occupational hearing loss; however, it does not specifically contend with the unique noise exposures observed in the theater of war, such as blasts and explosions. In order to examine the effects of blast injury on hearing sensitivity, we developed a large database composed of demographic, audiometric, point of injury, and medical outcome data, with the primary aim of developing a long-standing and integrated capability for the surveillance, assessment, and investigation of blast-related hearing outcomes. Methods used to develop the dataset are described. Encompassing more than 16,500 Navy and Marine Corps personnel, the Blast-Related Auditory Injury Database (BRAID) includes individuals with a blast-related injury and nonblast control subjects. Using baseline and postdeployment hearing threshold data, a retrospective analysis of the cohort revealed that the rate of hearing loss for the injured servicemembers was 39%. The BRAID will be useful for studies that assess hearing patterns following deployment-related injury, such as blast exposures, that facilitate exploration of health outcomes and whether they are predictive of audiometric disposition and that help establish hearing loss prevention strategies and program policies for affected military commands and servicemembers.

Characterization and Comparison of Combat-Related Injuries in Women During OIF and OEF.

Although historically restricted from combat roles, women suffer from combat-related injuries, especially in recent conflicts where asymmetrical warfare erases distinctions between forward and rear operating areas. U.S. servicewomen who sustained combat-related injury in Operation Iraqi Freedom (OIF) or Operation Enduring Freedom (OEF) between January 2003 and May 2014 were identified from the Expeditionary Medical Encounter Database. Injuries were characterized using Abbreviated Injury Scale and International Classification of Diseases, 9th Revision codes. Of the 844 combat-related injury episodes in women, 51% (n = 433) were OIF injuries and 49% (n = 411) were OEF injuries. Blast events were responsible for 90% of injuries. The average Injury Severity Score was 3, with no statistical difference in means between OIF and OEF. Of significance were increased head injuries in OEF compared with OIF (80% vs. 48%; p < 0.001). Although the majority of combat-related injuries suffered by women were mild, some women suffered life-threatening injuries, and nearly 65% of the injury episodes resulted in more than one injury. More research is needed as the roles of women in the military continue to expand. Future studies will investigate quality of life outcomes and gender differences in combat-related injuries.

Dwell time and psychological screening outcomes among military service members with multiple combat deployments.

Recent studies have found that longer dwell times, or the period of time between deployments, may be protective against combat-related psychological outcomes. The purpose of this study was to examine the association between dwell time and psychological morbidity, while accounting for combat exposure. U.S. Marines with two combat deployments between 2005 and 2008 were identified from electronic deployment records. Those who screened positive for post-traumatic stress disorder and depression, and who were referred for mental health services were identified from the Post-Deployment Health Assessment. For the final study sample of 3,512 Marines, dwell time was calculated as time between deployments, and was analyzed as a ratio over length of first deployment. After adjustment for all covariates, there was an interaction (p = 0.01) between dwell time and combat exposure on mental health referral outcome. For personnel with maximum reported combat exposure, longer dwell times were associated with a 49% to 92% reduced odds of mental health referral. Longer dwell times may be protective against combat-related psychological outcomes. Because multiple deployments are likely to be the norm in future military operations, regulating dwell time, particularly for those with greater risk of combat exposure, should continue to be explored.

Co-occurring mental health and alcohol misuse: dual disorder symptoms in combat injured veterans.

OBJECTIVE: Service members face difficulties during military deployment potentially resulting in morbidities such as posttraumatic stress disorder (PTSD), depression, and alcohol misuse. The co-occurrence of alcohol misuse and mental health disorders is termed dual disorder and has been associated with adverse outcomes. METHODS: The study included 812 high-risk (i.e., endorsing combat exposure with documented combat injury) male U.S. veterans of Operation Iraqi Freedom, injured between October 2004 and November 2007, identified from the Expeditionary Medical Encounter Database. RESULTS: PTSD and depression symptoms were significant correlates of alcohol misuse. Veterans with dual disorder symptoms reported a significantly higher mean number of health complaints on the Post-Deployment Health Reassessment compared with those endorsing only mental health symptoms. CONCLUSIONS: These results highlight how mental health disorders among injured service members increases the odds of problem drinking and those with dual disorder have elevated health complaints.

Investigation of bendamustine HCL in a phase 2 study in women with resistant ovarian cancer.

We investigated the safety and efficacy of 90 mg/m(2) bendamustine HCL, administered intravenously on days 1 and 2 every 28 days in 10 women with platinum and taxane resistant epithelial ovarian cancer. There were no objective tumor responses observed; 2 patients had stable disease. Plasma samples collected at pre-treatment and end of cycle one were analyzed for changes in circulating total cytokeratin 18 and caspase cleaved cytokeratin 18 as exploratory early biomarkers of bendamustine-induced tumor cell death. All patients had measureable levels of both total and cleaved caspase 3 cytokeratin 18, but no relationship with response was possible due to the lack of clinical benefit in treated patients. Due to the high incidence of adverse events and absence of objective responses, only ten patients were treated as predefined by the Simon Two-Stage Design in the protocol. Overall, the regimen was not well tolerated and was associated with fatigue and a greater number of gastrointestinal side effects as compared to previously reported experiences in different patient populations. However, our study subjects did experience less bone marrow suppression. The lack of tolerability could reflect the degree of tumor burden within the peritoneal cavity as well as the high number of prior regimens (median of 5) received by the patients participating in this study.

Phase I trial of intraperitoneal pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer.

PURPOSE: This phase I trial evaluated intraperitoneal (i.p.) pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer. EXPERIMENTAL DESIGN: Dose escalation of day 1 i.p. pemetrexed accrued three patients to each of five dose levels (60-1,000 mg/m(2)), along with day 2 i.p. cisplatin (75 mg/m(2)) and day 8 i.p. paclitaxel (60 mg/m(2)). The goals were to determine maximum tolerated dose (MTD), 18-month progression-free survival (PFS), and pharmacokinetics of i.p. pemetrexed. RESULTS: Cycles, given every 21 days, had an 80% 6-cycle completion rate. There was minimal grade III toxicity in the first 4 dose levels and remarkably an almost complete absence of peripheral neuropathy and alopecia. At the highest dose level, two of three patients experienced ≥ grade III and dose-limiting toxicity (DLT; hematologic, infection, gastrointestinal). There was a pharmacokinetic advantage for i.p. pemetrexed with an intraperitoneal:plasma area under the concentration-time curve ratio of 13-fold. Neither analysis of pharmacokinetic nor homocysteine levels explains the unexpected severity of toxicity in those two patients. On the basis of plasma C(24h) levels, the 42 cycles at ≥ 500 mg/m(2) i.p. pemetrexed without DLT, the MTD appears to be 500 mg/m(2). Median PFS is 30.1 months; 18-month PFS is 78.6% (median follow-up 22.4 months). CONCLUSIONS: This i.p.-only regimen in front-line ovarian cancer is feasible with PFS in line with recent literature. We suggest phase II trials of this regimen in this population with i.p. pemetrexed at 500 mg/m(2). The favorable toxicity profile at doses <1,000 mg/m(2), which needs to be confirmed, appears to compare well with standard combination i.v./i.p. platinum/taxane chemotherapy in this disease.

Dose response of retinol and isotretinoin in the prevention of nonmelanoma skin cancer recurrence.

Using data from a randomized, double blind, study of the efficacy of retinol or isotretinoin vs. placebo on recurrence of nonmelanoma skin cancer in high-risk subjects, a reanalysis of the original intent to treat analysis was performed in a dose-response format. Cox proportional hazards models describe the relationship between dose quartiles of isotretinoin and retinol use and time to first occurrence of squamous cell carcinoma (SCC) or basal cell carcinoma (BCC) in crude and adjusted models. Neither the isotretinoin nor retinol models showed any significance at any quartile for reduction in first BCC or SCC occurrence. Crude and adjusted retinol models show a statistically significant increase in risk of developing an SCC in the first quartile, whereas only the crude model shows a statistically significant increase in risk in the first quartile of the isotretinoin model. For retinol and SCC, hazard ratios (HRs) for the first quartile were as follows: HR = 2.92, 95% confidence interval (CI) = 1.67-5.10 crude; HR = 1.95, 95% CI = 1.00-3.80 adjusted. For isotretinoin and SCC, HRs for the first quartile were as follows: HR = 2.38, 95% CI = 1.35-4.19 crude; HR = 1.69, 95% CI = 0.87-3.31 adjusted. Test for trend was not significant in any of the models. These analyses confirm the results of the original intent to treat analyses and raise an interesting question related to the potential for increased risk for patients in the first quartile of retinol dose.