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Although breast reconstruction after bilateral mastectomies including a contralateral prophylactic mastectomy is known to have a higher overall complication profile, whether reconstructive complication rates differ between the therapeutic mastectomy and contralateral prophylactic mastectomy sides remains unclear.Women undergoing bilateral mastectomies with autologous or implant-based breast reconstruction for a unilateral breast cancer at a single institution were identified (2009 to 2019). Postoperative complications were stratified by laterality (therapeutic mastectomy versus contralateral prophylactic mastectomy). Paired data were analyzed to compare the risks of complications between prophylactic and therapeutic reconstruction sides in the same patient.A total of 130 patients (260 reconstructions) underwent bilateral autologous or implant-based reconstruction. Although most women underwent a simple mastectomy, a higher proportion of therapeutic mastectomies were modified radical mastectomies including axillary lymph node dissections compared to contralateral prophylactic mastectomies (15.4 percent versus 0 percent). Forty-four percent of women completed postmastectomy radiation therapy of the therapeutic side before definitive reconstruction. Overall, both therapeutic and prophylactic reconstructions had a similar incidence of reconstructive failure (p = 0.57), return to the operating room (p = 0.44), mastectomy skin flap necrosis (p = 0.32), seroma (p = 0.82), fat necrosis (p = 0.16), wound infection (p = 0.56), and cellulitis (p = 0.56). Nearly one-fifth of patients experienced complications limited to the prophylactic side [contralateral prophylactic mastectomy reconstruction complications, n = 26 (20.0 percent); therapeutic mastectomy reconstruction complications, n = 15 (11.5 percent)].Despite a history of local radiation therapy and more extensive oncologic surgery on the therapeutic side, there are no significant differences in the incidence of postsurgical complications on the therapeutic mastectomy and contralateral prophylactic mastectomy sides after bilateral reconstruction.Risk, II.

Background Psychosocial distress, depression, or anxiety can occur in up to 50% of women after a breast cancer diagnosis and mastectomy. The purpose of this study was to assess the potential benefit of lavender oil as a perioperative adjunct to improve anxiety, depression, pain, and sleep in women undergoing microvascular breast reconstruction. Methods This was a prospective, single-blinded, randomized, controlled trial of 49 patients undergoing microvascular breast reconstruction. Patients were randomized to receive lavender oil or placebo (coconut oil) throughout their hospitalization. The effect of lavender oil on perioperative stress, anxiety, depression, sleep, and pain was measured using the hospital anxiety and depression scale, Richards–Campbell Sleep Questionnaire, and the visual analogue scale. Results Twenty-seven patients were assigned to the lavender group and 22 patients were assigned to the control group. No significant differences were seen in the perioperative setting between the groups with regard to anxiety (p = 0.82), depression (p = 0.21), sleep (p = 0.86), or pain (p = 0.30) scores. No adverse events (i.e., allergic reaction) were captured, and no significant differences in surgery-related complications were observed. When evaluating the entire cohort, postoperative anxiety scores were significantly lower than preoperative scores (p Conclusion In the setting of microvascular breast reconstruction, lavender oil and aromatherapy had no significant adverse events or complications; however, there were no measurable advantages pertaining to metrics of depression, anxiety, sleep, or pain as compared with the control group.

BACKGROUND Pelvic washings for patients with endometrial cancer is recommended but not used for staging. The International System for Reporting Serous Fluid Cytology (TIS) has standardized diagnostic categories, but the criteria remain incomplete. The 3 primary goals of this study were to 1) investigate features that distinguish atypical/indeterminate from malignant specimens, 2) measure the level of agreement between chart and reviewer diagnoses, and 3) determine whether the number of years in practice had an effect on the diagnoses rendered. METHODS Pelvic washings and surgical pathology specimens for 52 patients with a chart diagnosis of atypical/indeterminate, suspicious, or malignant cytology and 52 age-matched controls with a negative chart diagnosis were included, reviewed blindly by 2 cytopathologists, and assigned a study diagnosis. Morphologic features were assessed. Agreement between original chart diagnoses and reviewer diagnoses were assessed as well as effect of years in practice. RESULTS The overall cellularity in cell block (CB) slides for the malignant category was significantly increased compared with the atypical/indeterminate category (P < .0001). In addition, the number of atypical groups in ThinPrep for malignant washings was significantly increased compared with the atypical category (P < .001) and the negative and suspicious categories (P < .0001) in the CB. Overall agreement between the original and adjudicated diagnoses was high (γ = 0.983). There was no significant difference between diagnoses rendered and years in practice. CONCLUSION The overall cellularity and number of atypical cells can be used to distinguish between malignant and atypical pelvic washing specimens. There is high reproducibility in the diagnostic categories and high agreement among pathologists, regardless of practice experience. These findings can help refine the criteria for TIS.

Unintentional falls and breast cancer are common among older women, but the associations between them are understudied. We aimed to identify factors associated with falls in older women with breast cancer. We retrospectively reviewed clinical records of older women with breast cancer at Duke Medical Center who had completed the Senior Adult Oncology Program geriatric assessment. Characteristics were compared between women had had at least one fall in the past year and those who did not. Pearson’s Chi-square tests and t tests were used for comparison of groups’ characteristics. Logistic regression determined factors associated with falling. We identified 425 women, age 76.2 years (range 65–89 years), at the time of the assessment. 118 (27.8%) women reported a fall in the prior year. Age, race, ethnicity, and time since diagnosis (all p > 0.05) were similar between groups. In univariate analyses, metastatic disease (p = 0.023) and history of endocrine therapy (p = 0.042) were more common among women who fell. Women who fell had lower systolic (p = 0.001), diastolic (p

BACKGROUND Enhanced recovery after surgery (ERAS) initiatives improve postoperative function and expedite recovery, leading to a decrease in length of stay. The authors noted a high rate of postoperative symptomatic hypotension in patients undergoing abdominal free flap breast reconstruction and wished to explore this observation. METHODS Subjects undergoing abdominal free flap breast reconstruction at the authors' institution from 2013 to 2017 were identified. The ERAS protocol was initiated in 2015 at the authors' hospital; thus, 99 patients underwent traditional management and 138 patients underwent ERAS management. Demographics and perioperative data were collected and analyzed. Postoperative symptomatic hypotension was defined as mean arterial pressure below 80 percent of baseline with symptoms requiring evaluation. RESULTS A significantly higher rate of postoperative symptomatic hypotension was observed in the ERAS cohort compared with the traditional management cohort (4 percent versus 22 percent; p < 0.0001). Patients in the ERAS cohort received significantly less intraoperative intravenous fluid (4467 ml versus 3505 ml; p < 0.0001) and had a significantly increased amount of intraoperative time spent with low blood pressure (22 percent versus 32 percent; p =0.002). Postoperatively, the ERAS cohort had significantly lower heart rate (77 beats per minute versus 88 beats per minute; p < 0.0001) and mean arterial pressure (71 mmHg versus 78 mmHg; p < 0.0001), with no difference in urine output or adverse events. CONCLUSIONS The authors report that ERAS implementation in abdominal free flap breast reconstruction may result in a unique physiologic state with low mean arterial pressure, low heart rate, and normal urine output, resulting in postoperative symptomatic hypotension. Awareness of this early postoperative finding can help better direct fluid resuscitation and prevent episodes of symptomatic hypotension. CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, III.

OBJECTIVES: Racial disparities in survival from endometrial cancer (EC) are well known. Cancer distress has also been associated with worse clinical outcomes. We characterized the association between race/ethnicity, patient distress reported on the National Comprehensive Cancer Network Distress Thermometer and Problem List (NCCN DT & PL), referral to support services, time to surgery, and acceptance of adjuvant therapy in patients with EC. METHODS: We included patients presenting at an academic gynecologic oncology practice from 1/2013–6/2020 who had not received prior EC-directed treatment. Demographics, NCCN DT scores, and treatment details were abstracted from the electronic medical record. Difference in initial DT scores by race/ethnicity and treatment type was tested using general linear modeling. The significance of interaction effects was tested using linear mixed models and logistic regression. RESULTS: 393 non-Hispanic White (NHW) and 134 non-Hispanic Black (NHB) patients were included. Median distress scores were higher in NHW patients compared to NHB patients (4 vs. 2, p 0.25). CONCLUSIONS: An observed difference in NCCN DT leads to racial disparities in referral to support services. The NCCN DT may not adequately measure distress in NHB women with EC.

BACKGROUND Patients undergoing mastectomy may not be candidates for immediate free-flap breast reconstruction because of medical comorbidities or postmastectomy radiation therapy. In this setting, flap reconstruction may be intentionally delayed or staged with tissue expander placement ("delayed-immediate" reconstruction). The optimal reconstructive choice and incidence of complications for these approaches remain unclear. METHODS The authors retrospectively identified patients who underwent delayed [n = 140 (72 percent)] or staged [n = 54 (28 percent)] abdominal free-flap breast reconstruction between 2010 and 2018 and compared the incidence of postoperative complications. RESULTS Patients undergoing staged reconstruction had a higher overall incidence of perioperative complications, including surgical-site infection (40.7 percent versus 6.5 percent; p < 0.001), wound healing complications (29.6 percent versus 12.3 percent; p = 0.004), hematoma (11.1 percent versus 0.7 percent; p < 0.001), and return to the operating room (27.8 percent versus 4.4 percent; p < 0.0001). These complications occurred predominately during the expansion stage, resulting in an 18.5 percent (n = 10) rate of tissue expander failure. Mean time from mastectomy to flap reconstruction was 476.8 days (delayed, 536.4 days; staged, 322.4 days; p < 0.001). At the time of flap reconstruction, there was no significant difference in the incidence of complications between the staged cohort versus the delayed cohort, including microsurgical complications (1.9 percent versus 4.3 percent; p = 0.415), total flap loss (0 percent versus 2.1 percent; p = 0.278), or fat necrosis (5.6 percent versus 5.0 percent; p = 0.875). CONCLUSIONS The aesthetic and psychosocial benefits of staged free-flap breast reconstruction should be balanced with the increased risk of perioperative complications as compared to a delayed approach. Complications related to definitive flap reconstruction do not appear to be affected by the approach taken at the time of mastectomy. . CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, III.

Introduction Identification of geriatric syndromes is important for determining functional age and optimizing care for people with cancer. Based on administration of a geriatric screening tool, we aimed to describe needed resources for geriatric syndromes, including lack of social support, depressed mood, deficits in instrumental and activities of daily living (IADL/ADL), falls, nutritional issues, polypharmacy, ability to pay for medications, and memory deficits, in a population of patients with breast cancer. Methods Consecutive medical oncology patients with breast cancer age 65 years and older, seen at a tertiary care center, completed a screening tool, adapted from Overcash 2006, consisting of a nurse-administered memory assessment and a one-page, self-administered questionnaire. Responses identified geriatric syndromes. Demographics and clinical information were retrospectively gathered. Frequencies and means were used to describe data. Results From January 2012 through July 2014, patients (n = 429) completed the screening tool as part of routine care. Study group had mean age 76 years (range 65–89), mean time since diagnosis 6.5 years, 91% non-metastatic disease, mean Charlson Comorbidity score 1.8 (range 0–10). Treatment included partial mastectomy (49%), adjuvant radiation (43%), chemotherapy (25%), and endocrine therapy (61%). The screening tool identified need for social support (8%); depression (31%); mobility issues (20%); falls (28%); nutritional needs (33%); polypharmacy (83%); and memory deficit (19%). Conclusion This screening tool identified geriatric syndromes requiring attention in many patients with breast cancer presenting for medical oncology appointments. In oncology practice, need for referral networks to address geriatric syndromes should be assessed.

Bevacizumab provides benefit in epithelial ovarian cancer (EOC), yet resistance to bevacizumab often occurs. We determined if nintedanib, a tyrosine kinase inhibitor of VEGF, FGF, and PDGF receptors has antitumor activity in bevacizumab-resistant recurrent EOC, tubal, and peritoneal cancer.This phase II study evaluated nintedanib 200 mg/day until disease progression or unacceptable toxicity. The primary objective was 6-month progression free survival (PFS6m). Secondary objectives were response rate and toxicity. Simon two-stage optimal design was used. Baseline angiogenic plasma biomarkers were measured.27 patients were enrolled evaluable for PFS; 26 were evaluable for PFS6m. The median age was 65 years (range 44-73); 89.9% had high-grade serous EOC; 70% received at least2 prior chemotherapies; and 81% (22/27) had chemoresistant disease. With median follow up of 15.6 months (range 2-38) the PFS6m rate was 11.5% (3/26). Three participants had long duration of disease control (8-16 months). Median PFS and overall survival were 1.8 and 16 months, respectively. Response rate was 7.4% (2/27 PR). Thirty-seven percent (10/27) had stable disease, while 56% (15/27) had progressive disease. Adverse events included Grade 3 liver enzyme elevation (15%), Grade 3 diarrhea (7%), Grade 2 fatigue (7%), and Grade 2 nausea/vomiting (15%). PD patients exhibited higher levels of CD73, IL6, and VEGFD (p0.05) compared to PR/SD patients. IL6 was associated with worse PFS (p = 0.03).Single-agent nintedanib has minimal activity in an unselected bevacizumab-resistant EOC population. Nintedanib was tolerable and toxicities were manageable. Plasma CD73, IL6, and VEGFD were identified as prognostic markers for progressive disease, and IL6 was associated with worse PFS confirming similar observations made in patients treated with other anti-angiogenic agents.

Objective The primary aim of this study was to pilot the use of an objective measurement technique to prospectively evaluate the incidence of lower extremity lymphedema (LEL) after minimally invasive staging surgery for endometrial cancer. Secondary objectives included observation of changes in lower extremity function and quality of life in this patient population. Methods A prospective evaluation of LEL was performed in 97 women who underwent minimally invasive staging surgery for endometrial cancer using comparative circumferential volume measurements. Postoperative changes in lower extremity function and global quality of life were also assessed using patient-reported outcome measures. Results Ninety-seven patients were included for lymphedema analysis. The rate of LEL was 25% at 4–6 weeks, 19% at 6–9 months, and 27% at 12–18 months postoperatively. The presence of LEL was associated with a significant worsening from baseline Lower Extremity Functional Scale (LEFS) scores at 4–6 weeks (−27.0% vs −3.7%, p = 0.02) and 6–9 months (−13.0% vs 0%, p = 0.01). LEL was not associated with a change in patient-reported global quality of life. Conclusions Up to one in four women experience lymphedema following surgical staging for endometrial cancer, and its presence is associated with diminished lower extremity function. Larger, prospective trials using the objective methodology piloted in this study should better clarify risk factors and long-term outcomes of this morbidity.

Background Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p Interpretation Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes.

Background Granulosa cell tumors (GCT) variably express estrogen receptors (ER) and progesterone receptors (PR). The goal of this study is to evaluate the relationship between ER and PR expression patterns and clinical outcomes in women with GCT. Methods A multicenter, retrospective analysis was performed of all cases of GCT diagnosed between 1989 and 2012. Immunohistochemical staining for ER and PR was performed on formalin-fixed paraffin embedded (FFPE) tumor tissue and interpreted using a semiquantitative scoring system that incorporated tumor cell staining proportion and intensity. Demographics, disease status, and survival information were collected. Associations between ER and PR staining scores and recurrence-free and overall survival were assessed using univariate Cox proportional hazards models. Results FFPE tumor blocks were available for 149/186 GCT patients. The majority of the women had clinical stage I disease (76%). ER and PR expression was present in 52% and 98% of subjects, respectively. The median composite scores of ER and PR staining were 1 (range 0–8) and 9 (range 0–15), respectively. In univariate analysis, PR composite score >9 was strongly associated with decreased recurrence-free survival (HR = 2.9, 95% CI = 1.5–5.5) and decreased overall survival (HR = 3.7, CI 1.3–10.2). ER composite score was not a significant predictor of recurrence-free survival or overall survival (p = 0.7, HR = 1.1, 95% CI 0.6–2.0 and p = 0.06, HR = 1.1, 95% CI 0.4–2.9, respectively). Conclusions Our results reveal that high PR composite score (≥9) was associated with both decreased recurrence-free and overall survival in patients with GCT while ER expression was not associated with survival outcomes.

To evaluate surgical complexity scores (SCS) and minimally invasive surgery (MIS) at interval debulking surgery (IDS) in advanced epithelial ovarian cancer (EOC) patients receiving neoadjuvant chemotherapy (NACT).A multi-institutional study of NACT with IDS for advanced EOC was conducted. Demographic data were abstracted and SCS assigned based on IDS findings. Disease-specific overall survival (DSS) was defined as the time from completion of adjuvant chemotherapy to death due to disease. Cox proportional hazards regression models were used for univariate and multivariate survival analyses.282 patients were identified; 80.5% had high-grade serous histology and 54.6% were75 (median 63.9; range 34.1-84.8). Approximately 84% were optimally cytoreduced (61% R0; 23%1 cm). In multivariate analyses, age 75+ (p ≤ 0.001), residual disease (1 cm; p = 0.03), and SCS ≥ 3 (p = 0.04) were significantly predictive of worse DSS when morbidity and ASA score were also in the model. When optimally debulked was defined as R0, only age 75+ (0.001) was significantly associated with decreased DSS. In the R0 cohort, SCS did not significantly predict DSS. However, subset analysis defining optimal ≤1 cm, revealed higher SCS was associated with a 1.6-fold increased risk of death (p = 0.02). Fifty-one patients underwent laparoscopic IDS. Twenty-four (47%) were converted to laparotomy to achieve optimal debulking in 21 patients (87.5%); while 25 had laparoscopic optimal cytoreduction (19/25 [76%] R0).In women with advanced EOC treated with NACT, older age, SCS ≥ 3, and residual disease1 cm at IDS were predictors of worse survival. MIS appears safe and feasible with acceptable optimal cytoreduction rates.

To describe and evaluate the effects of implementation of a venous thromboembolism (VTE) prophylaxis quality improvement (QI) initiative on a gynecologic oncology service at a single institution.Prior to 2018, no consensus gynecologic oncology VTE prophylaxis protocol existed at the authors' academic institution. Published, evidence-based guidelines were reviewed to create a standardized VTE risk stratification algorithm. Interventions to improve perioperative heparin administration and sequential compression device (SCD) compliance as well as provider/patient education efforts were introduced in January 2018. Initial efforts included nursing and patient SCD education, internal dissemination of VTE prophylaxis guidelines, and creation of a VTE 'dashboard' to track performance. During a second phase, VTE prophylaxis guidelines were reviewed and further refined, non-compliant operative cases reviewed weekly, and guidelines incorporated into the electronic medical record. Performance was measured using Tableau data software (www.tableau.com) and by separately evaluating adherence to the developed guidelines in three retrospective cancer-enriched surgical cohorts (2016-2017, 2018, 2019).Compared to the baseline period, we observed a reduction in VTE rate during the 2018-2019 VTE QI implementation period from 2.1% (19/905) to 1.0% (20/2015, p = 0.02) among gynecologic oncology inpatients. In the retrospective cancer-enriched cohorts, adherence to evidence based guidelines improved: 31.0% in 2016-2017, 69.1% in 2018, and 82.4% in 2019 (p0.001). There were no significant differences in rates of peri-operative blood transfusion, surgical site infections, hematomas, or vaginal cuff dehiscences.Implementation of a robust VTE prophylaxis QI initiative has resulted in improved VTE prophylaxis guideline adherence and higher rates of pre-operative heparin administration.

Recent advances in next-generation sequencing have allowed for an increase in molecular tumor profiling.We sought to assess the actionability and clinical utilization of molecular tumor profiling results obtained via Foundation Medicine tumor sequencing tests in uterine and ovarian cancers.We performed a single-institution retrospective chart review to obtain demographic and clinical information in patients with uterine and ovarian cancer whose tumors were submitted to Foundation Medicine for molecular tumor profiling over a 7-year period. Alterations identified on testing were stratified according to the OncoKB database actionability algorithm. Descriptive statistics were primarily used to analyze the data.Tumors from 185 women with gynecologic cancer were submitted for molecular tumor profiling between 2013 and 2019. The majority of tests (144/185; 78%) were ordered after a diagnosis of recurrence. In 60 (32%), no actionable molecular alteration was identified. Thirteen (7%) identified an alteration that directed to a US Food and Drug Administration-approved therapy in that tumor type, while 112 (61%) had alterations with investigational or hypothetical treatment implications. In patients with any actionable finding, treatment was initiated in 27 (15%) based on these results.The majority of uterine and ovarian cancers (93%) did not have molecular alterations with corresponding Food and Drug Administration-approved treatments. Even in patients with a potentially actionable alteration, gynecologic oncologists were more likely to choose an alternative therapy. Further investigation is warranted to determine which patients with uterine and ovarian cancer are most likely to benefit from molecular tumor profiling and the ideal timing of testing. The potential to identify effective therapeutic options in a minority of patients needs to be balanced with the current limited clinical applicability of these results in most cases.

Background Fat grafting to the reconstructed breast may result in the development of benign lesions on physical examination, prompting further investigation with imaging and biopsy. The aim of this study was to assess the influence of fat grafting on the incidence of imaging and biopsies after postmastectomy reconstruction. Methods Patients who underwent autologous or implant-based reconstruction following mastectomy from 2010 to 2018 were identified. Those receiving fat grafting as part of their reconstructive course were propensity matched 1:1 to those that did not with body mass index, reconstruction timing, and reconstruction type as covariates in a multivariable logistic regression model. Results A total of 186 patients were identified, yielding 93 propensity-matched pairs. Fat-grafted patients had higher incidences of palpable masses (38.0 percent versus 18.3 percent; p = 0.003) and postreconstruction imaging (47.3 percent versus 29.0 percent; p = 0.01), but no significant difference in the number of biopsies performed (11.8 percent versus 7.5 percent; p = 0.32). Imaging was predominately interpreted as normal (Breast Imaging-Reporting and Data System 1, 27.9 percent) or benign (Breast Imaging-Reporting and Data System 2, 48.8 percent), with fat necrosis being the most common finding [n = 20 (45.5 percent)]. No demographic, oncologic, reconstructive, or fat grafting-specific variables were predictive of receiving postreconstruction imaging on multivariate analysis. Fat grafting was not associated with decreased 5-year overall survival or locoregional recurrence-free survival. Conclusions Fat grafting to the reconstructed breast is associated with increased incidences of palpable masses and subsequent postreconstruction imaging with benign radiographic findings. Although the procedure is oncologically safe, both patients and providers should be aware that concerning physical examination findings can be benign sequelae of fat grafting and may lead to increased imaging after breast reconstruction. Clinical question/level of evidence Therapeutic, III.

Purpose: Despite promising advances in breast cancer immunotherapy, augmenting T-cell infiltration has remained a significant challenge. Although neither individual vaccines nor immune checkpoint blockade (ICB) have had broad success as monotherapies, we hypothesized that targeted vaccination against an oncogenic driver in combination with ICB could direct and enable antitumor immunity in advanced cancers. Experimental Design: Our models of HER2+ breast cancer exhibit molecular signatures that are reflective of advanced human HER2+ breast cancer, with a small numbers of neoepitopes and elevated immunosuppressive markers. Using these, we vaccinated against the oncogenic HER2Δ16 isoform, a nondriver tumor-associated gene (GFP), and specific neoepitopes. We further tested the effect of vaccination or anti–PD-1, alone and in combination. Results: We found that only vaccination targeting HER2Δ16, a driver of oncogenicity and HER2-therapeutic resistance, could elicit significant antitumor responses, while vaccines targeting a nondriver tumor-specific antigen or tumor neoepitopes did not. Vaccine-induced HER2-specific CD8+ T cells were essential for responses, which were more effective early in tumor development. Long-term tumor control of advanced cancers occurred only when HER2Δ16 vaccination was combined with αPD-1. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that while vaccination expanded CD8 T cells, only the combination of vaccine with αPD-1 induced functional gene expression signatures in those CD8 T cells. Furthermore, we show that expanded clones are HER2-reactive, conclusively demonstrating the efficacy of this vaccination strategy in targeting HER2. Conclusions: Combining oncogenic driver targeted vaccines with selective ICB offers a rational paradigm for precision immunotherapy, which we are clinically evaluating in a phase II trial (NCT03632941).

Background Unplanned returns to the operating room (OR) may be necessary at times to salvage a compromised free flap. The aim of this study was to assess the influence of attending surgeon continuity on free flap outcomes following a return to the OR. Methods We retrospectively reviewed patients who underwent free flap reconstruction and experienced an unplanned return to the OR within 30 days from 2002 to 2017. Logistic regression modeling was used to determine factors that predict unplanned returns to the OR. Results Of the 1,177 patients were identified, 267 (22.5%) had an unplanned return to the OR. Of these, 69 (5.9%) patients experienced total flap loss. Overall, 216 take-back procedures were performed by the primary surgeons (80.2%), while 50 were performed by covering surgeons (18.8%). Flap loss occurred more frequently during a weekend procedure (p = 0.013). Additionally, when the take-back procedure was performed within 5 days of the original surgery by the primary as opposed to a covering surgeon, patients experienced lower estimated blood loss (75 vs. 150 cc, p = 0.04). Overall, there was a significantly lower incidence of flap loss when the take-back procedure was performed by the primary, as opposed to the covering, surgeon (20 vs. 47%, p = 0.0001). Conclusion Higher rates of flap loss occur when a covering surgeon performs a take-back procedure in comparison to the primary surgeon. It is important to ensure the availability of the primary surgeon in the first few postoperative days following free flap reconstruction. When transfer of care is necessary, photographic or video documentation of the microvascular anastomosis may be helpful in addition to a verbal sign out.

PURPOSE: To evaluate the mammographic sequelae of preoperative accelerated partial breast irradiation (APBI) delivered via either stereotactic radiosurgery or a conventionally fractionated regimen. METHODS AND MATERIALS: This multicenter, retrospective study evaluated surveillance mammograms from patients enrolled in 2 prospective, preoperative APBI clinical trials. At 1 site, 31 patients with cT1N0 invasive carcinomas or low- or intermediate-grade ductal carcinoma in situ (

Background Breast implant placement is the most common method for postmastectomy reconstruction. For patients who develop complications associated with implant-based reconstruction, additional surgeries may be challenging. This study examined implant-based reconstruction failure in patients undergoing salvage with abdominal free tissue transfer. Methods We conducted an Institutional Review Board approved, multicenter retrospective study of patients with implant-based primary breast reconstruction followed by implant removal and subsequent abdominal free tissue transfer between 2006 and 2016. Patient demographics, treatment details, and complications were evaluated. Severity of implant failure was graded as either (1) not severe (delayed salvage reconstruction) or (2) severe (immediate salvage reconstruction). Results Between 2006 and 2016, 115 patients with 180 mastectomy defects underwent primary implant-based reconstruction with subsequent implant removal and abdominally based free tissue reconstruction. Of these, 68 were delayed and 47 were immediate salvage reconstruction. Factors leading to elective removal were capsular contracture, asymmetry, and implant malposition. Factors leading to obligatory removal were infection, delayed wound healing, and implant extrusion. Postmastectomy radiation was significantly associated with immediate salvage reconstruction (p Conclusion Our findings suggest that abdominal free tissue transfer remains a safe and effective salvage modality for implant-based breast reconstruction failure. Patients with severe implant failure were more likely to have received radiation. Surgeons should remain cognizant of this during care of patients.

Objectives Head and neck radiotherapy (RT) is a risk factor for cerebrovascular disease. We performed a retrospective cohort study to evaluate carotid artery stenosis (CAS) incidence in head and neck cancer (HNC) patients undergoing RT, characterizing associated risk factors. Materials and methods Records were retrospectively reviewed for HNC patients undergoing carotid ultrasound screening after definitive or adjuvant RT between January 2000 and May 2016. CAS was defined as ≥50% stenosis on imaging, stroke, or transient ischemic attack. Actuarial CAS rates were calculated by Kaplan-Meier method. Univariate and multivariate analyses predicted CAS risk based on carotid dosimetric and clinical parameters. Results 366 patients met inclusion criteria. Median time from RT completion to last follow-up was 4.1 yr. Actuarial risk for CAS was 29% (95% CI 22–36%) at 8 years. Univariate analysis showed that smoking (HR 1.7; 95% CI 1.1–2.7), hyperlipidemia (HR 1.6; 95% CI 1.03–2.6), diabetes (HR 2.8; 95% CI 1.6–4.8), coronary artery disease (HR 2.4; 95% CI 1.4–4.2), and peripheral artery disease (HR 3.6; 95% CI 1.1–11.6) were significantly associated with increased CAS. In multivariate analysis, diabetes was predictive of time to CAS (HR 1.9; 95% CI 1.1–3.4). Carotid dose parameters were not significantly associated with CAS. Conclusions CAS incidence is high after head and neck radiotherapy, gradually rising over time. No clear dose-response effect between carotid dose and CAS was identified for HNC patients. Carotid artery screening and preventative strategies should be employed in this high-risk patient population.

Purpose Prior studies have demonstrated the importance of treatment duration (TD) in radiation therapy (RT) for cervical cancer, with an 8-week goal based primarily on RT alone. This study uses a contemporary cohort to estimate the time point by which completion of chemoradiation therapy is most critical. Patients and Methods The National Cancer Database was queried for women with nonmetastatic cervical cancer diagnosed from 2004 to 2012 who underwent chemotherapy, external beam RT, and brachytherapy. Data-derived TD cut points for overall survival (OS) were computed by using recursive partitioning analysis with bootstrapped aggregation (bagging) and 10-fold cross-validation. Models were independently trained with 70% of the population and validated on 30% of the population by log-rank test with and without propensity matching. Multivariable Cox proportional hazards regression was performed for the entire cohort. Results In all, 7,355 women were identified with a median TD of 57 days. Bagged recursive partitioning analysis converged to a mean cut point of 66.6 days (median, 64.5 days; interquartile range, 63.5 to 68.5 days). Cross-validation yielded a cut point of 63.3 days. Both cut points differentiated OS in validation. Younger age, recent diagnosis, geographic region, nongovernment insurance, shorter distance to treatment facility, metropolitan location, lower comorbidity, squamous cell carcinoma, lower stage, negative lymph nodes, and shorter TD were independently associated with longer OS. With adjustment, TD within the mean cut point (64.9 days; hazard ratio, 0.79; 95% CI, 0.73 to 0.87) and 56 days (hazard ratio, 0.87; 95% CI, 0.80 to 0.95) were associated with longer OS. Exploratory stratification suggested increasing OS detriment beyond 64 days. Conclusion Shorter chemoradiation TD in cervical cancer is associated with longer survival, and TD should be minimized as much as possible. The data-derived cut point was distributed around 64 days, with a continuous relationship between shorter TD and longer OS.

ObjectiveThe aim of the study was to assess interaction of lymph node dissection (LND), adjuvant chemotherapy (CT), and radiotherapy (RT) in stage I uterine papillary serous carcinoma (UPSC) and uterine clear cell carcinoma (UCC).Methods/MaterialsThe National Cancer Data Base was queried for women diagnosed with International Federation of Gynecology and Obstetrics stage I UPSC and UCC from 1998 to 2012. Overall survival (OS) was estimated for combinations of RT and CT by the Kaplan-Meier method stratified by histology and LND. Multivariate Cox proportional hazard models were generated.ResultsUterine papillary serous carcinoma: 5432 women with UPSC were identified. Uterine papillary serous carcinoma had the highest 5-year OS with CT + RT with (83%) or without LND (76%). On multivariate analyses, CT [hazard ratio (HR), 0.77; P = 0.01] and vaginal cuff brachytherapy (HR, 0.68; P = 0.003) with LND were independently associated with OS. Without LND, vaginal cuff brachytherapy (HR, 0.53; P = 0.03), but not CT (HR, 1.21; P = 0.92), was associated with OS. Uterine clear cell carcinoma: 2516 women with UCC were identified. Uterine clear cell carcinoma with and without LND had comparable 5-year OS for all combinations of CT and RT on univariate and multivariate analyses.ConclusionsIn stage I papillary serous uterine cancer, brachytherapy and CT were associated with increased survival; however, the benefit of chemotherapy was limited to those with surgical staging. In contrast, no adjuvant therapy was associated with survival in stage I uterine clear cell carcinoma, and further investigation to identify more effective therapies is warranted.

Revision procedures address contour irregularities and aesthetic concerns following autologous breast reconstruction. Mental health diagnoses are known to influence patient satisfaction with reconstruction. The authors aimed to identify oncologic, reconstructive, and demographic factors, including mental health diagnoses, associated with the number of revisions after autologous breast reconstruction.The medical records of all adult women undergoing abdominal free flap-based breast reconstruction at a major academic institution between 2011 and 2016 were reviewed. Multivariate logistic regression was used to identify factors associated with receipt of revisions. Negative binomial regression was used to identify characteristics associated with number of revisions received.Of 272 patients identified, 55.2 percent received one revision, 23.2 percent received two revisions, and 10.3 percent received three or more revisions after autologous breast reconstruction (median, one; range, zero to five). After adjustment on multivariate analysis, anxiety (OR, 4.34; p = 0.016) and bilateral reconstruction (OR, 3.10; p = 0.017) were associated with receipt of any revisions; other oncologic and reconstructive factors including breast cancer stage, receipt of radiation therapy, and type or timing of free flap reconstruction were not associated with revisions. Using univariate negative binomial regression, anxiety (incidence rate ratio, 1.34; p = 0.006), Caucasian race (incidence rate ratio, 1.24; p = 0.02), and bilateral reconstruction (incidence rate ratio, 1.39; p = 0.04) were predictive of increased numbers of revisions received. After stepwise selection on multivariate analysis, anxiety remained the only significant predictor of increased numbers of revisions.Preoperative anxiety significantly influences the number of revisions after autologous breast reconstruction. Further research is necessary to better understand the interplay among mental health, patient preference, and outcomes in breast reconstruction.Risk, III.

IntroductionBreast cancer is a major cause of morbidity and mortality for women in Sub-Saharan Africa and for black American women. There is evidence that the pathologic characteristics of breast cancers in both African women and black American women may differ from their counterparts of European ancestry. However, despite the great burden of disease, data on pathologic features of breast carcinoma in Sub-Saharan Africa is limited and often contradictory. This lack of information makes it difficult to prioritize resource use in efforts to improve breast cancer outcomes in the region.MethodsWe examined consecutive cases of breast cancer in Tanzanian women (n = 83), black American women (n = 120), and white American women (n = 120). Each case was assessed for tumor type, grade, mitotic count, ER and HER2 status, and tumor infiltrating lymphocyte involvement.ResultsThe Tanzanian subjects were younger and had higher stage tumors than the subjects in either American group. Breast cancers in the Tanzanian and black American groups were more likely to be high grade (p = 0.008), to have a high mitotic rate (p

ObjectiveEnhanced Recovery After Surgery (ERAS) protocols are designed to mitigate the physiologic stress response created by surgery, to decrease the time to resumption of daily activities, and to improve overall recovery. This study aims to investigate postoperative recovery outcomes following gynecologic surgery before and after implementation of an ERAS protocol.MethodsA retrospective chart review was performed of patients undergoing elective laparotomy at a major academic center following implementation of an ERAS protocol (11/4/2014–7/27/2016) with comparison to a historical cohort (6/23/2013–9/30/2014). The primary outcome was length of hospital stay. Secondary outcomes included surgical variables, time to recovery of baseline function, opioid usage, pain scores, and complication rates. Statistical analyses were performed using Wilcoxon rank sum, Fisher’s exact, and chi squared tests.ResultsOne hundred and thirty-three women on the ERAS protocol who underwent elective laparotomy were compared with 121 historical controls. There was no difference in length of stay between cohorts (median 4 days; P = 0.71). ERAS participants had lower intraoperative (45 vs 75 oral morphine equivalents; P < 0.0001) and postoperative (45 vs 154 oral morphine equivalents; P < 0.0001) opioid use. ERAS patients reported lower maximum pain scores in the post-anesthesia care unit (three vs six; P < 0.0001) and on postoperative day 1 (four vs six; P = 0.002). There was no statistically significant difference in complication or readmission rates.ConclusionsERAS protocol implementation was associated with decreased intraoperative and postoperative opioid use and improved pain scores without significant changes in length of stay or complication rates.

Few guidelines exist regarding surveillance and diagnostic imaging after breast reconstruction. This study investigated the influence of breast reconstruction on the frequency of post-mastectomy imaging, the relative utility of imaging, and its effect on overall and locoregional recurrence-free survival.A retrospective review identified breast cancer patients (n = 1,216) who underwent mastectomy with or without reconstruction. Logistic regression identified surgical and oncologic predictors of post-reconstruction imaging. Kaplan-Meier method determined the impact of post-reconstruction imaging on overall and locoregional recurrence-free survival.Overall, 662 (54.4%) patients underwent mastectomy only and 554 (45.6%) underwent breast reconstruction. Patients undergoing reconstruction were more likely to receive imaging compared with patients undergoing mastectomy only (n = 205, 37.0% vs n = 168, 25.4%; p0.0001); however, this difference was not statistically significant after adjusting for age and follow-up time (p = 0.16). Most radiographic studies were Breast Imaging Reporting and Data System (BI-RADS) 1 (n = 58, 30%) or 2 (n = 95, 49%) and were ordered by nonsurgical providers (n = 128, 63%). Post-reconstruction imaging did not influence overall or locoregional recurrence-free survival. The 5-year survival probabilities for breast reconstruction patients who underwent imaging for a palpable mass, surveillance, or who did not undergo imaging were 100%, 95% (95% CI 89% to 100%), and 96% (95% CI 94% to 99%), respectively. Post-reconstruction imaging was not a significant predictor of overall survival (hazard ratio [HR] 0.95; 95% CI 0.61 to 1.46; p = 0.30).The limited utility of routine post-reconstruction imaging should be reinforced when evaluating breast reconstruction patients. Multidisciplinary collaboration should be emphasized when attempting to distinguish benign postoperative findings from a malignant process to reduce unnecessary imaging and biopsy after breast reconstruction.

Purpose To evaluate the feasibility of reducing the dose of consolidation radiation therapy (RT) in diffuse large B-cell lymphoma. Methods and Materials This phase 2 study enrolled patients with diffuse large B-cell lymphoma, not otherwise specified and primary mediastinal (thymic) large B-cell lymphoma in complete response on positron emission tomography-computed tomography imaging after ≥4 cycles of a rituximab/anthracycline-containing combination chemotherapy regimen. Consolidation RT used a dose of 19.5 to 20 Gy. The primary endpoint was 5-year freedom from local recurrence. Results Sixty-two patients were enrolled between 2010 and 2016. Stage distribution was as follows: I to II (n = 49, 79%) and III to IV (n = 13, 21%). Bulky disease (defined as ≥7.5 cm or ≥10 cm) was present in 23 (40%) and 16 (28%) patients, respectively. Chemotherapy was R-CHOP (then list the drugs) in 58 (94%) and R-EPOCH (then list the drugs) in 4 (6%) with a median of 6 cycles. With a median follow-up of 51 months, 7 patients developed disease progression (6 outside the RT field, 1 within the RT field). Freedom from local recurrence at 5 years was 98% (90% lower confidence bound, 88%). Progression-free and overall survival at 5 years were 83% and 90%, respectively. Conclusions With more effective systemic therapy (e.g., addition of rituximab) and more refined chemotherapy response assessment (e.g., positron emission tomography-computed tomography), the dose of RT in combined modality treatment programs may potentially be reduced to 20 Gy. This achieves excellent local control with the potential to decrease acute and long-term side effects.

BACKGROUND: Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T cell infiltration of tumors include vaccines targeting established oncogenic drivers like the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2). METHODS: In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and anti-tumor function were evaluated. We tested VRP-HER2 in a Phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of three doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy. RESULTS: Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was one partial response and two patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n=4) and 32.7 months in cohort 2 (n=18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS. CONCLUSIONS: VRP-HER2 increased HER2-specific memory CD8 T cells and had anti-tumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T cell activity by combining with anti-PD-1.

To retrospectively evaluate perioperative pain and analgesic and antiemetic use in patients who underwent surgical staging for endometrial cancer using traditional versus robotic-assisted laparoscopy.We identified women in a single institution who underwent minimally hysterectomy for endometrial cancer from 2008 to 2012. Patient characteristics and perioperative outcomes, including analgesic and antiemetic use and pain scores, were analyzed. After univariate analysis, a multivariate linear regression model was generated to determine factors associated with narcotic use in the post anesthesia care unit (PACU) (Canadian Task Force Classification II-3).A single academic institution in the United States from 2008 to 2012.Women undergoing total laparoscopic hysterectomy or robotic-assisted laparoscopic hysterectomy for endometrial cancer.Laparoscopic or robotic-assisted laparoscopic hysterectomy.Three hundred thirty-five women were included (213 laparoscopy and 122 robotic-assisted laparoscopy). There was no difference in pain scores at 0 to 6 and 6 to 12 hours after surgery; at 12 to 24 hours, robotic-assisted surgery was associated with higher median pain scores (5/10 vs 4/10, p = .012). Robotic-assisted surgery was associated with a longer anesthesia time (289 vs 255 minutes, p.001), similar antiemetic use (p = .40), and lower narcotic use in the postanesthesia care unit (PACU) (1.3 mg vs 2.5 mg morphine equivalents, p = .003). There was no difference in narcotic use on the postoperative floor (p = .46). In multivariate analysis controlling for age, menopausal status, anesthesia duration, and local anesthetic use, hysterectomy type was not a significant predictor of PACU narcotic use (p = .86).In a retrospective analysis, a robotic-assisted approach to endometrial cancer was not associated with reduced PACU narcotic or antiemetic use compared with the traditional laparoscopic approach. Twenty-four-hour narcotic and antiemetic use was also not different between the 2 approaches.

Radiation therapy is associated with acute treatment-related complications that can lead to decreased quality of life (QOL). Exercise has been shown in other cancer treatment settings to improve negative outcomes. We conducted a prospective pilot study to explore the association between exercise, patient-reported outcomes, and acute radiation therapy toxicities.Women receiving curative breast radiation therapy were enrolled. Each patient completed an exercise behavior/QOL survey before or during the first week of treatment and again during the last week of treatment. Exercise behavior was quantified with the Godin Leisure Time Exercise Questionnaire (metabolic equivalent [MET] hours per week). Measurements to evaluate upper extremity lymphedema and shoulder range of motion were completed. Skin toxicity was assessed weekly. Patient-reported outcomes were measured using standardized questionnaires.Forty-five patients were enrolled. Mean patient age was 54 (range, 28-73) years. Mean METs in the exercise cohort (≥9 METs/wk) was 21 per week (range, 11-38, n = 14); 3 per week (range, 0-8, n = 25) in the nonexercise cohort (9 METs/wk). Women in the exercise cohort showed improvements in treatment-induced quality of life and fatigue (not significant) despite more extensive surgical, medical, and radiation treatment. No differences in treatment-related toxicities, pain, or sleep scores were noted. Lymphedema was mild (3 cm) in the entire patient cohort.The vast majority of current exercise oncology literature implicates physical activity as an independent predictor of QOL in cancer patients. Our study noted similar trends, but they were not statistically significant. This may be due to our finding that patient-reported outcomes with radiation therapy are relatively high compared with other treatment modalities and remain stable throughout treatment. Thus, it may be that radiation therapy has a limited impact on QOL in breast cancer patients. Exercise may be best used as a targeted therapy in patients at high risk for poor QOL or radiation-related toxicities at baseline.

Study Objective To evaluate if the use of Valleylab mode (“V mode”) (Covidien, Mansfield, MA) electrothermal energy for colpotomy during total laparoscopic hysterectomy (LH) results in a smaller margin of thermal injury to the upper vagina compared with traditional cut/coagulate (cut/coag) electrothermal energy. Design Prospective randomized clinical trial (Canadian Task Force classification I). Setting University medical center. Patients A total of 101 subjects who underwent LH between June 2010 and August 2012. Interventions Subjects were randomized to colpotomy by V mode electrothermal energy or cut/coag electrothermal energy. Measurements and Main Results The primary end point was the median depth of thermal injury measured in millimeters. The secondary end points included the proportion of subjects who developed granulation tissue, induration, infection, or dehiscence at the vaginal cuff at 4 weeks, 3 months, or 6 months postoperatively. There was no significant difference in the median depth of thermal injury in the cut/coag and V mode arms (anterior margin: 0.68 mm vs 0.63 mm [p = .94], posterior margin: 0.66 mm vs 0.70 mm [p = .87], respectively). Twenty-seven percent of subjects in each arm developed at least 1 of the clinical end points at 4 weeks, 3 months, or 6 months postoperatively (granulation tissue: 6%–18% vs 8%–21%, induration: 0%–2% vs 4%–5%, infection: 0%–4% vs 0%–10%, dehiscence: 2% vs 0% in the cut/coag and V mode arms, respectively), with no difference between arms (p = 1.0). Conclusion The V mode does not reduce the depth of thermal injury compared with cut/coag electrothermal energy when used for colpotomy incision during total laparoscopic hysterectomy (Clinical Trials.gov ID: NCT02080546).

Background: Few studies have investigated the effects of exercise on modulation of host factors in cancer patients. We investigated the efficacy of chronic aerobic training on multiple host-related effector pathways in patients with solid tumours. Patients and Methods: Paired peripheral blood samples were obtained from 44 patients with solid tumours receiving cytotoxic therapy and synthetic erythropoietin (usual care; n=21) or usual care plus supervised aerobic training (n=23) for 12 weeks. Samples were characterised for changes in immune, cytokine and angiogenic factors, and metabolic intermediates. Aerobic training consisted of three supervised cycle ergometry sessions per week at 60% to 100% of peak oxygen consumption (VO2peak), 30–45 min per session, for 12 weeks following a nonlinear prescription. Results: The between-group delta change in cardiopulmonary function was +4.1 ml kg −1 min−1, favouring aerobic training (P

Background Stromal tumor-infiltrating lymphocytes (TILs) might predict pathologic complete response (pCR) in patients with HER2-positive (HER2+) breast cancer treated with trastuzumab (H). Docetaxel (T), carboplatin (C), H, and pertuzumab (P) have immune-modulating effects. Pre- and post-treatment immune biomarkers in cancers treated with neoadjuvant TCH with or without P are lacking. In this study we quantified baseline and changes in TILs, cluster of differentiation (CD) 4+, CD8+, FoxP3+, and PD-L1+ cells using immunohistochemistry (IHC) and quantified productive T-cell receptor β (TCRβ) rearrangements and TCRβ clonality using next-generation sequencing (NGS) in 30 HER2+ breast cancer tissues treated with neoadjuvant H with or without P regimens. Materials and Methods Thirty pre- and post-neoadjuvant TCH (n = 4) or TCHP (n = 26) breast cancer tissues were identified. TILs were quantified manually using hematoxylin and eosin. CD4, CD8, FoxP3, and PD-L1 were stained using IHC. TCRβ was evaluated using NGS. Immune infiltrates were compared between pCR and non-pCR groups using the Wilcoxon rank sum test. Results A pCR occurred in 15 (n = 15; 50%) cancers (TCH n = 2; TCHP, n = 13). Pretreatment TILs, CD4+, CD8+, FoxP3+, and PD-L1+ cells were not associated with response (P = .42, P = .55, P = .19, P = .66, P = .87, respectively. Pretreatment productive TCRβ and TCRβ clonality did not predict response, P = .84 and P = .40, respectively). However, post-treatment CD4+ and FoxP3+ cells (T-regulatory cells) were elevated in the non-pCR cohort (P = .042 and P = .082, respectively). Conclusion An increase in regulatory T cells in non-pCR tissues suggests the development of an immunosuppressive phenotype. Further investigation in a larger cohort of samples is warranted to validate these findings.

Aerobic exercise training (AET) is an effective adjunct therapy to attenuate the adverse side-effects of adjuvant chemotherapy in women with early breast cancer. Whether AET interacts with the antitumor efficacy of chemotherapy has received scant attention. We carried out a pilot study to explore the effects of AET in combination with neoadjuvant doxorubicin–cyclophosphamide (AC+AET), relative to AC alone, on: (i) host physiology [exercise capacity (VO2 peak), brachial artery flow-mediated dilation (BA-FMD)], (ii) host-related circulating factors [circulating endothelial progenitor cells (CEP) cytokines and angiogenic factors (CAF)], and (iii) tumor phenotype [tumor blood flow (15O–water PET), tissue markers (hypoxia and proliferation), and gene expression] in 20 women with operable breast cancer. AET consisted of three supervised cycle ergometry sessions/week at 60% to 100% of VO2 peak, 30 to 45 min/session, for 12 weeks. There was significant time × group interactions for VO2 peak and BA-FMD, favoring the AC+AET group (P < 0.001 and P = 0.07, respectively). These changes were accompanied by significant time × group interactions in CEPs and select CAFs [placenta growth factor, interleukin (IL)-1β, and IL-2], also favoring the AC+AET group (P < 0.05). 15O–water positron emission tomography (PET) imaging revealed a 38% decrease in tumor blood flow in the AC+AET group. There were no differences in any tumor tissue markers (P > 0.05). Whole-genome microarray tumor analysis revealed significant differential modulation of 57 pathways (P < 0.01), including many that converge on NF-κB. Data from this exploratory study provide initial evidence that AET can modulate several host- and tumor-related pathways during standard chemotherapy. The biologic and clinical implications remain to be determined. Cancer Prev Res; 6(9); 925–37. ©2013 AACR.

Objectives (1) To describe the prevalence, timing and setting of documented end-of-life (EOL) discussions in patients with advanced ovarian cancer; and (2) to assess the impact of timing and setting of documented end-of-life discussions on EOL quality care measures. Methods A retrospective study of women who died of ovarian cancer diagnosed between 1999 and 2008 was conducted. The following are the EOL quality measures assessed: chemotherapy in the last 14days of life, >1 hospitalization in the last 30days, >1 ER visit in the last 30days, intensive care unit (ICU) admission in the last 30days, dying in an acute care setting, admitted to hospice ≤3days. Results One hundred seventy-seven (80%) patients had documented end-of-life discussions. Median interval from EOL discussion until death was 29days. Seventy-eight patients (44%) had EOL discussions as outpatient and 99 (56%) as inpatient. Sixty-four out of 220 (29%) patients' care did not conform to at least one EOL quality measure. An EOL discussion at least 30days before death was associated with a lower incidence of: chemotherapy in the last 14days of life ( p =0.003), >1 hospitalization in the last 30days ( p p =0.005), dying in acute care setting ( p =0.01), admitted to hospice ≤3days ( p =0.02). EOL discussion as outpatient was associated with fewer patients hospitalized >1 in the last 30days of life ( p Conclusions End-of-life care discussions are occurring too late in the disease process. Conformance with EOL quality measures can be achieved with earlier end-of-life care discussions.

Purpose While consolidation radiation therapy (i.e., RT administered after chemotherapy) is routine treatment for patients with early-stage diffuse large B-cell lymphoma (DLBCL), the role of consolidation RT in stage III-IV DLBCL is controversial. Methods and Materials Cases of patients with stage III-IV DLBCL treated from 1991 to 2009 at Duke University, who achieved a complete response to chemotherapy were reviewed. Clinical outcomes were calculated using the Kaplan-Meier method and were compared between patients who did and did not receive RT, using the log-rank test. A multivariate analysis was performed using Cox proportional hazards model. Results Seventy-nine patients were identified. Chemotherapy (median, 6 cycles) consisted of anti-CD20 antibody rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 65%); cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; 22%); or other (13%). Post-chemotherapy imaging consisted of positron emission tomography (PET)/computed tomography (CT) (73%); gallium with CT (14%); or CT only (13%). Consolidation RT (median, 25 Gy) was given to involved sites of disease in 38 (48%) patients. Receipt of consolidation RT was associated with improved in-field control (92% vs. 69%, respectively, p = 0.028) and event-free survival (85% vs. 65%, respectively, p = 0.014) but no difference in overall survival (85% vs. 78%, respectively, p = 0.15) when compared to patients who did not receive consolidation RT. On multivariate analysis, no RT was predictive of increased risk of in-field failure (hazard ratio [HR], 8.01, p = 0.014) and worse event-free survival (HR, 4.3, p = 0.014). Conclusions Patients with stage III-IV DLBCL who achieve negative post-chemotherapy imaging have improved in-field control and event-free survival with low-dose consolidation RT.

Purpose: We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in the treatment of advanced and recurrent epithelial ovarian cancer. Experimental Design: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics, and pharmacodynamics. Using a “3+3” design, cohorts of three to six patients received paclitaxel (175 mg/m2) and carboplatin (AUC 6) every 3 weeks with escalating doses of dasatinib (100, 120, and 150 mg daily), followed by an eight-patient expansion cohort. Results: Twenty patients were enrolled between June 2007 and December 2009. The median age was 61 years (range: 42–82) with a median of 2 prior regimens (range: 0–6), and 71% had platinum-sensitive disease. There were three to six patients in each cohort, and eight in the expansion cohort. Pharmacokinetics were observed over the first two cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3–4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3–4), and fatigue (10% grade 3). The RR was 40% [three complete responses, (15%); five partial responses, (25%)],10 patients (50%) had stable disease, and two were not evaluable. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively. Conclusions: Due to the high incidence of myelosuppression with subsequent cycles, the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity. Clin Cancer Res; 18(19); 5489–98. ©2012 AACR.

There is a high risk of relapse in stage IIIB/IIIC melanoma. The utility of 2-[fluorine-18]-fluoro-2-deoxy-D-glucose positron emission tomography integrated with computed tomography (FDG-PET/CT) in these patients to evaluate response to treatment or for surveillance after treatment is currently not well defined.Prospective data from 2 centers identified 97 patients with stage IIIB/IIIC extremity melanoma undergoing isolated limb infusion (ILI) who had whole body FDG-PET/CT scans before and every 3 months after treatment. Clinical response was determined at 3 months by Response Evaluation Criteria In Solid Tumors.Complete response (CR) after ILI occurred in 33% (32/97) of patients. FDG-PET/CT accurately identified 59% of patients who were CRs (19/32), whereas 41% (13/32) had residual metabolic activity in the extremity that was histologically negative for melanoma. The 3-year disease-free rate was 62.2% (95% CI: 40.1%-96.4%) for those patients who were CRs by both clinical/pathologic examination and FDG-PET/CT (n = 19) compared to only 29.4% (95% CI: 9.9%-87.2%) of those CRs who still had residual FDG-PET/CT activity (n = 13). FDG-PET/CT was utilized for surveillance of disease recurrence outside the regional field of treatment. Fifty-two percent (51/97) of patients developed disease outside the extremity at a median time of 212 days from pre-ILI FDG-PET/CT. In 47% (29/62) of these cases, the recurrence was resected.Although FDG-PET/CT does not appear to accurately identify patients who appear to be CRs to ILI, it does appear to identify a subgroup of patients whose regional progression-free survival is markedly worse. However, FDG-PET/CT appears to be an excellent method for surveillance in stage IIIB/IIIC patients after ILI with ability to identify surgically resectable recurrent disease in these high-risk patients.

To assess the impact of increasing experience with intensity-modulated radiation therapy (IMRT) after extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM).The records of all patients who received IMRT following EPP at Duke University Medical Center between 2005 and 2010 were reviewed. Target volumes included the preoperative extent of the pleural space, chest wall incisions, involved nodal stations, and a boost to close/positive surgical margins if applicable. Patients were typically treated with 9-11 beams with gantry angles, collimator rotations, and beam apertures manually fixed to avoid the contalateral lung and to optimize target coverage. Toxicity was graded retrospectively using National Cancer Institute common toxicity criteria version 4.0. Target coverage and contralateral lung irradiation were evaluated over time by using linear regression. Local control, disease-free survival, and overall survival rates were estimated using the Kaplan-Meier method.Thirty patients received IMRT following EPP; 21 patients also received systemic chemotherapy. Median follow-up was 15 months. The median dose prescribed to the entire ipsilateral hemithorax was 45 Gy (range, 40-50.4 Gy) with a boost of 8-25 Gy in 9 patients. Median survival was 23.2 months. Two-year local control, disease-free survival, and overall survival rates were 47%, 34%, and 50%, respectively. Increasing experience planning MPM cases was associated with improved coverage of planning target volumes (P=.04). Similarly, mean lung dose (P.01) and lung V5 (volume receiving 5 Gy or more; P.01) values decreased with increasing experience. Lung toxicity developed after IMRT in 4 (13%) patients at a median of 2.2 months after RT (three grade 3-4 and one grade 5). Lung toxicity developed in 4 of the initial 15 patients vs none of the last 15 patients treated.With increasing experience, target volume coverage improved and dose to the contralateral lung decreased. Rates of pulmonary toxicity were relatively low. However, both local and distant control rates remained suboptimal.

Even after complete response (CR) to regional chemotherapy for in-transit melanoma, many patients develop recurrence. Understanding the probability, location, and timing of recurrences can optimize management strategies for this patient population.A prospective database identified patients who underwent 81 first-time hyperthermic isolated limb perfusions (HILPs) and 133 first-time isolated limb infusions (ILIs). Response was defined using the response evaluation criteria in solid tumors; recurrence was defined as development of new disease after in-field CR.HILP exhibited a significantly higher CR rate than ILI (44 vs. 28 %, p = .01). Among 36 HILP-CRs and 37 ILI-CRs, the 3-year recurrence rate was 65 % (95 % confidence interval [95 % CI]: 43-79 %) and 85 % (95 % CI: 63-94%), respectively. Median time to first recurrence was longer for HILP-CR than ILI-CR (23 vs. 8 months, p = .02). There was no statistically significant difference in median time to in-field recurrence between HILP-CR and ILI-CR (46 vs. 25 months, p = .15), but HILP-CR showed a longer median time to out-of-field recurrence (42 vs. 14 months, p = .02). Finally, the overall survival (OS) difference between HILP-CR and ILI-CR (3-year survival: 77 vs. 54 %) did not achieve statistical significance (p = .10).In the largest series comparing patterns of recurrence, we demonstrate that out-of-field recurrence after CR to HILP occurs later than after CR to ILI, though control of in-field disease remains similar. There remains no statistically significant difference in overall survival after CR to the 2 procedures.

The impact of activating KIR (aKIR) and inhibitory KIR (iKIR) on OS, relapse-related mortality (RRM) and acute GVHD (aGVHD) was prospectively studied in 84 adults with high-risk hematologic malignancies receiving reduced intensity conditioning (RIC) T-cell depleted hematopoietic SCT (HSCT) from haploidentical related donors. In this clinical model, freedom from RRM is dependent on GVL effect. Patients were divided into myeloid (n=49) and lymphoid (n=35) malignancy groups. KIR-ligand and ligand-ligand models were studied in both GVH and rejection directions and statistically correlated with outcome measures. In the myeloid group, OS was higher (P=0.009) and RRM was lower (P=0.036) in patients missing HLA-C group2 ligand to donor iKIR. OS was higher if patients had >1 missing ligand (P=0.018). In lymphoid malignancy, missing ligand to donor KIR had no impact on OS or RRM. However, OS was better with donor aKIR 2DS2 (P=0.028). There was a trend towards shorter OS in recipient with KIR 2DS1, 2DS5 and 3DS1, although sample sizes were too small to provide inferential statistics. Findings in lymphoid malignancy patients should be further studied. These results suggest that the absence of appropriate HLA ligands in the recipient to donor iKIR may induce GVL without aGVHD in myeloid malignancy patients undergoing TCD-RIC transplants.

Ampullary carcinoma is a rare malignancy. Despite radical resection, survival rates remain low with high rates of local failure. We performed a single-institution outcomes analysis to define the role of concurrent chemoradiotherapy (CRT) in addition to surgery. A retrospective analysis was performed of all patients undergoing potentially curative pancreaticoduodenectomy for adenocarcinoma of the ampulla of Vater at Duke University Hospitals between 1976 and 2009. Time-to-event analysis was performed comparing all patients who underwent surgery alone to the cohort of patients receiving CRT in addition to surgery. Local control (LC), disease-free survival (DFS), overall survival (OS), and metastases-free survival (MFS) were estimated using the Kaplan–Meier method. A total of 137 patients with ampullary carcinoma underwent Whipple procedure. Of these, 61 patients undergoing resection received adjuvant (n = 43) or neoadjuvant (n = 18) CRT. Patients receiving chemoradiotherapy were more likely to have poorly differentiated tumors (P = .03). Of 18 patients receiving neoadjuvant therapy, 67% were downstaged on final pathology with 28% achieving pathologic complete response (pCR). With a median follow-up of 8.8 years, 3-year local control was improved in patients receiving CRT (88% vs 55%, P = .001) with trend toward 3-year DFS (66% vs 48%, P = .09) and OS (62% vs 46%, P = .074) benefit in patients receiving CRT. Long-term survival rates are low and local failure rates high following radical resection alone. Given patterns of relapse with surgery alone and local control benefit in patients receiving CRT, the use of chemoradiotherapy in selected patients should be considered.

Objective To validate the Mayo algorithm to intraoperatively identify women with endometrial cancer in whom lymphadenectomy may be safely omitted. Methods A multi-center retrospective chart review 1977–2010 was completed using two independent institutional endometrial cancer databases. Eligibility criteria were grade 1 or 2 endometrial carcinoma, low-risk histology, and myometrial invasion ≤ 50% on intraoperative pathology consultation; patients were considered to satisfy the Mayo criteria if, in addition to these, tumor diameter on the final pathology report was ≤ 2 cm. Analysis of nodal metastases, recurrent disease, and progression-free survival (PFS) using the Kaplan–Meier method was performed. Results Six hundred and two patients met inclusion criteria for the study. Of 110 patients satisfying the Mayo algorithm with an adequate lymphadenectomy, 2 (1.8%) were diagnosed with lymph node metastasis and 4 (3.6%) subsequently developed recurrent disease. The Mayo algorithm identified with a 98.2% negative predictive value women who would not benefit from a lymphadenectomy. There was no significant difference in recurrence rate or PFS between women who underwent lymphadenectomy and those who did not when the Mayo algorithm was satisfied. Conclusions The Mayo algorithm intraoperatively identifies tumor characteristics of low-risk disease in endometrial carcinoma that predict a very low likelihood of nodal metastasis and recurrence. Although a small number of patients with advanced stage disease may be missed when applying the Mayo criteria, there is no apparent survival benefit to lymphadenectomy for patients satisfying this algorithm, and these data support its use at other institutions.

Background As multidisciplinary cancer treatment evolves, strategies to identify patients needing early resection/salvage are necessary. Some have suggested that vocal cord function after organ-preservation treatment may be an indicator. Methods A retrospective review was performed of patients presenting with fixed or impaired vocal cord function at a tertiary center. Local recurrence rates were examined in patients with and without improved/normal mobilization after treatment. Results Sixty-nine patients met the inclusion criteria, with 35 patients having vocal cord fixation and 34 patients with impaired mobility. After treatment, 44 patients had normalization of vocal cord function, while 25 patients did not, with 2-year local control rates of 70% and 77%, p = .23, respectively. No difference in local control was found between patients with normalized/improved cord function (n = 53) and those who remained the same/worsened (n = 16; p = .81). Conclusion Therapy-induced changes in vocal cord mobility did not correlate with local recurrence. Other criteria are needed to identify patients most likely to benefit from early surgical resection/salvage after organ preservation. © 2011 Wiley Periodicals, Inc. Head Neck, 2011

Background Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) are used to manage advanced extremity melanoma, but no consensus exists as to which treatment is preferable and how to monitor patients post-treatment. Study Design Using a prospectively maintained database, we reviewed our experience with melphalan-based HILP (which included 62 first-time and 10 second-time) and ILI (which included 126 first-time and 18 second-time) procedures performed in 188 patients. PET/CT was obtained 3 months postregional treatment for 1 year and then every 6 months thereafter. Results Overall response rate (complete response [CR] + partial response) of HILP was 81% (80% CI, 73−87%), and overall response rate from ILI was 43% (80% CI, 37−49%) for first-time procedures only. HILP had a CR rate of 55% with a median duration of 32 months, and ILI had a CR rate of 30% with median duration of 24 months. Patients who experienced a regional recurrence after initial regional treatment were more likely to achieve a CR after repeat HILP (50%, n=10) compared with repeat ILI (28%, n=18). Although the spectrum of toxicity was similar for ILI and HILP, the likelihood of rare catastrophic complication of limb loss was greater with HILP (2 of 62) than ILI (0 of 122). PET/CT was effective for surveillance after regional therapy to identify regional nodal and pulmonary disease that was not clinically evident, but often amenable to surgical resection (25 of 49; 51% of cases). In contrast, PET/CT was not effective at predicting complete response to treatment with an accuracy of only 50%. Conclusions In the largest single-institution regional therapy series reported to date, we found that although ILI is effective and well-tolerated, HILP is a more definitive way to control advanced disease.

Snail1 and ZEB1 are transcriptional repressors that drive tumor initiation and metastasis in animal models. Snail1 and ZEB1 are frequently coexpressed in tumor cell lines, suggesting that these factors may cooperate to promote tumor progression. However, coexpression of these transcriptional repressors in primary human cancer specimens has not been investigated. Previous studies assessed expression in primary breast cancers of Snail1 messenger RNA, which does not reflect Snail1 activity because Snail1 is subject to posttranslational modifications that inhibit its nuclear localization/activity. In the current study, using breast tumor cell lines of known Snail1 and ZEB1 expression status, we developed immunohistochemistry protocols for detecting nuclear Snail1 and nuclear ZEB1 proteins. Using these protocols, we assessed nuclear Snail1 and nuclear ZEB1 expressions in primary human breast cancers of varying subtypes (n = 78). Nuclear Snail1 and estrogen receptor α expressions were inversely associated in primary breast cancers, and nuclear Snail1 was expressed in approximately 80% of triple-negative breast cancers (lacking estrogen receptor α, progesterone receptor, and human epidermal growth factor receptor 2 overexpression). In contrast, nuclear ZEB1 was expressed at a significantly lower frequency in these breast cancers. Notably, nuclear Snail1 protein was detected in 45% of ductal carcinoma in situ specimens (n = 29), raising the important possibility that nuclear Snail1 expression in early stage breast lesions may predict future development of invasive breast cancer. Collectively, our studies demonstrate frequent expression of nuclear Snail1, but not nuclear ZEB1, in invasive, triple-negative breast cancers as well as in intraductal carcinomas.

Purpose: p53 as a prognostic and predictive factor in early-stage breast cancer has had mixed results. We studied p53 protein expression, by immunohistochemistry, in a randomized clinical trial of stage II patients treated with adjuvant doxorubicin and cyclophosphamide with or without paclitaxel [Cancer and Leukemia Group B (CALGB) 9344, INT0148]. Patients and Methods: Epithelial p53 expression was evaluated using two immunohistochemical antibodies (DO7 and 1801) in formalin-fixed, paraffin-embedded tissue from patients with node-positive breast cancer who were randomized to four cycles of cyclophosphamide and one of three doses of doxorubicin (60, 75, or 90 mg/m2; AC) and to receive four subsequent cycles of paclitaxel (T) or not. Prognostic and predictive value of p53 protein expression was assessed, independent of treatment assignment, for escalating doses of doxorubicin or addition of T with endpoints of relapse-free (RFS) and overall survival (OS). Results: Of 3,121 patients, 1,887 patient specimens treated on C9344 were obtained, passed quality control, and evaluated for p53 expression. Expression was 23% and 27% for mAbs 1801 and D07, respectively, with 92% concordance. In univariate analysis, p53 positivity was associated with worse OS with either antibody, but only p53 staining with monoclonal antibody 1801 had significantly worse RFS. In multivariate analysis, p53 was not predictive of RFS or OS from either doxorubicin dose escalation or addition of paclitaxel regardless of the antibody. Conclusion: Nuclear staining of p53 by immunohistochemistry is associated with worse prognosis in node-positive patients treated with adjuvant doxorubicin-based chemotherapy but is not a useful predictor of benefit from doxorubicin dose escalation or the addition of paclitaxel. Clin Cancer Res; 17(15); 5170–8. ©2011 AACR.

ObjectivesTo determine utility scores for health states relevant to the treatment of early-stage, high-risk cervical cancer.MethodsSeven descriptive health states incorporating the physical and emotional aspects of medical treatment, recovery, and prognosis were developed. Forty-five female volunteers valuated each health state using the visual analogue score (VAS) and time trade off (TTO) methods. Treatment options were ranked by mean and median TTO scores. The 95% confidence intervals were calculated to determine the statistical significance of ranking preferences. The Wilcoxon rank-sum test was used to compare central tendencies related to age, race, parity, and subject history of abnormal cervical cytology.ResultsVAS and TTO scores were highly correlated. Volunteers ranked minimally invasive radical hysterectomy with low-risk features as most preferred (mean TTO = 0.96; median TTO = 1.00) and aborted radical hysterectomy followed by chemoradiation as least preferred (mean TTO = 0.69; median TTO = 0.83). Health states that included radical surgery were ranked higher than those that included chemoradiation, either in the adjuvant or primary setting. When survival was comparable, volunteers rated radical hysterectomy with high-risk pathology followed by adjuvant chemoradiation (mean TTO = 0.78; median TTO = 0.92; 95% CI: 0.69–0.87) similarly to chemoradiation alone (mean TTO = 0.76; median TTO 0.90; 95% CI: 0.66–0.86; p = NS). Utility scores for the majority of health states were not significantly associated with age, race, parity, or subject history of abnormal cervical cytology.ConclusionSubjects consistently preferred surgical excision to treat early-stage, high-risk cervical cancer and chose a minimally invasive approach. Such utility scores can be used to incorporate quality-of-life effects into comparative-effectiveness models for cervical cancer.

Preliminary studies using directed-donor ex vivo expanded human mesenchymal stem cells (hMSCs) have shown promise in the treatment of acute graft-versus-host disease (aGVHD). However, their production is cumbersome and standardization is difficult. We describe the first experience of using a premanufactured, universal donor, formulation of hMSCs (Prochymal) in children (n = 12; 10 boys; 9 Caucasian; age range: 0.4-15 years) with treatment-resistant grade III and IV aGVHD who received therapy on compassionate use basis between July 2005 and June 2007 at 5 transplant centers. All patients had stage III or IV gut (GI) symptoms and half had additional liver and/or skin involvement. Disease was refractory to steroids in all cases and additionally to a median of 3 other immunosuppressive therapies. The hMSCs (8 × 10(6)cells/kg/dose in 2 patients and 2 × 10(6)cells/kg/dose in the rest) were infused intravenously over 1 hour twice a week for 4 weeks. Partial and mixed responders received subsequent weekly therapy for 4 weeks. HLA or other matching was not needed. The hMSCs were started at a median of 98 days (range: 45-237) posttransplant. A total of 124 doses were administered, with a median of 8 doses (range: 2-21) per patient. Overall, 7 (58%) patients had complete response, 2 (17%) partial response, and 3 (25%) mixed response. Complete resolution of GI symptoms occurred in 9 (75%) patients. Two patients relapsed after initial response and showed partial response to retreatment. The cumulative incidence of survival at 100 days from the initiation of Prochymal therapy was 58%. Five of 12 patients (42%) were still alive after a median follow-up of 611 days (range: 427-1111) in surviving patients. No infusional or other identifiable acute toxicity was seen in any patient. Multiple infusions of hMSCs were well tolerated and appeared to be safe in children. Clinical responses, particularly in the GI system, were seen in the majority of children with severe refractory aGVHD. Given the favorable results observed in a patient population with an otherwise grave prognosis, we conclude that hMSCs hold potential for the treatment of aGVHD, and should be further studied in phase III trials in pediatric and adult patients.