Erik J. Geiger

Vascular tissue engineering: the next generation.

It is the ultimate goal of tissue engineering: an autologous tissue engineered vascular graft (TEVG) that is immunologically compatible, nonthrombogenic, and can grow and remodel. Currently, native vessels are the preferred vascular conduit for procedures such as coronary artery bypass (CABG) or peripheral bypass surgery. However, in many cases these are damaged, have already been harvested, or are simply unusable. The use of synthetic conduits is severely limited in smaller diameter vessels due to increased incidence of thrombosis, infection, and graft failure. Current research has therefore energetically pursued the development of a TEVG that can incorporate into a patients circulatory system, mimic the vasoreactivity and biomechanics of the native vasculature, and maintain long-term patency.

Three-Dimensional Virtual Surgery Accuracy for Free Fibula Mandibular Reconstruction: Planned Versus Actual Results

PURPOSE Virtual surgical planning (VSP) can promote efficiency, but the ability to transfer the proposed plan to the actual result has not been adequately studied. The purpose of this study was to morphometrically compare the virtually preplanned scenario with the postoperative 3-dimensional (3D) anatomic result. MATERIALS AND METHODS A retrospective review of 10 patients who underwent mandibular reconstruction using a free fibula flap and VSP were evaluated. Pre- and postoperative Digital Imaging and Communications in Medicine files were imported into Mimics 10.01 software (Materialise, Leuven, Belgium) for surgical planning. Preoperative VSP and 1-week postoperative computed tomographic (CT) scans were evaluated to assess surgical accuracy using VSP. The pre- and postoperative morphometric measurements were compared using the Student t test. RESULTS Twenty CT scans from 10 patients (mean age, 56.9±20.2 yr) who underwent partial mandibular resection were analyzed. The dimensions of the fibula segments after osteotomy showed no difference from the preoperative VSP (mean difference in fibula height, 1.2 mm; mean difference in width, 0.9 mm; mean difference in length, 1.3 mm). The postoperative anterior and posterior mandibular angles differed from the VSP by 12.4° and -12.5°, respectively. The condylar distance and inclination showed a discrepancy of only 1.7 mm and 4.6°, respectively, between VSP and postoperative CT scans. CONCLUSIONS VSP confers reproducible precision and accuracy for free fibular mandibular reconstruction. The benefit was most striking for large reconstructions requiring multiple fibular segments. Future directions include assessing the use of external registration devices to enhance surgical accuracy and to follow patients longitudinally to monitor the long-term benefit of VSP.

Targeting Cancer with a Lupus Autoantibody

A cell-penetrating lupus anti-DNA antibody inhibits DNA repair, sensitizes cancer cells to DNA-damaging therapy in vitro and in vivo, and is synthetically lethal to BRCA2-deficient human cancer cells. Taming the Big Bad Wolf Just like the wolves for which lupus is named, the antibodies involved in its pathogenesis can attack almost any part of a patient, causing widespread damage. Now, Hansen et al. show that these biological wolves can sometimes be tamed and their ferociousness put to use in treating another deadly disease. Lupus is an autoimmune disease associated with antibodies that target host DNA, wreaking havoc on patients’ cells throughout the body. Recently, cancer researchers have tried to co-opt some of these antibodies, particularly those that can penetrate human cells, for use as vehicles for therapeutic agents. While using lupus antibodies to deliver proteins to protect normal cells from therapeutic ionizing radiation delivered to a tumor, researchers discovered that one antibody, 3E10, could itself sensitize cancer cells to radiation treatment. The authors then characterized this observed effect in malignant cells and determined its mechanism. They found that 3E10 bound single-stranded DNA and interfered with its repair, making the cells more susceptible to DNA-damaging agents such as doxorubicin and radiation. In addition, 3E10 alone was toxic to cancer cells with deficient DNA repair pathways, such as those that harbor BRCA2 mutations. Further research is necessary to identify other pathways that make tumor cells susceptible to 3E10 and to analyze the pharmacokinetics and other characteristics of this treatment. However, 3E10 was already shown to be safe in a previous phase 1 trial in lupus patients and should now be able to transition into clinical trials for cancer patients as well. Although researchers have not yet discovered a cure for lupus, the big bad wolf’s offspring may potentially tame another life-threatening illness. Systemic lupus erythematosus (SLE) is distinct among autoimmune diseases because of its association with circulating autoantibodies reactive against host DNA. The precise role that anti-DNA antibodies play in SLE pathophysiology remains to be elucidated, and potential applications of lupus autoantibodies in cancer therapy have not previously been explored. We report the unexpected finding that a cell-penetrating lupus autoantibody, 3E10, has potential as a targeted therapy for DNA repair–deficient malignancies. We find that 3E10 preferentially binds DNA single-strand tails, inhibits key steps in DNA single-strand and double-strand break repair, and sensitizes cultured tumor cells and human tumor xenografts to DNA-damaging therapy, including doxorubicin and radiation. Moreover, we demonstrate that 3E10 alone is synthetically lethal to BRCA2-deficient human cancer cells and selectively sensitizes such cells to low-dose doxorubicin. Our results establish an approach to cancer therapy that we expect will be particularly applicable to BRCA2-related malignancies such as breast, ovarian, and prostate cancers. In addition, our findings raise the possibility that lupus autoantibodies may be partly responsible for the intrinsic deficiencies in DNA repair and the unexpectedly low rates of breast, ovarian, and prostate cancers observed in SLE patients. In summary, this study provides the basis for the potential use of a lupus anti-DNA antibody in cancer therapy and identifies lupus autoantibodies as a potentially rich source of therapeutic agents.

Assessment of three-dimensional nasolabial response to Le Fort I advancement

BACKGROUND Le Fort I advancement induces soft tissue changes to the nasolabial region. The correlation of sagittal skeletal movement to soft tissue alteration has been studied using 2D methods. However, the influence of maxillary advancement has not been adequately assessed using three-dimensional means. The purpose of this study is to analyze nasolabial changes following Le Fort I advancement using 3D photometric measurements. METHODS Patient demographic information and their amount of advancement were tabulated. Pre- and postoperative 3D photographs (3D VECTRA photosystem, Canfield, Fairfield, NJ) were recorded. Nasolabial anthropometric measurements were performed using the corresponding 3D post-processing software (Mirror). Six month minimum follow-up elapsed before final evaluation. RESULTS Forty-four 3D photo data sets were included. Mean maxillary advancement was 5.5 (±1.9) mm. Male/female ratio was 0.7 with a mean age of 16.7 years. Significant increases (p < 0.0001) were seen in the alar base, alar widths, nostril width, and in the soft triangle and lateral alar angles. Significant decreases (p < 0.0001) were noted in the nasofrontal angle and in nostril height. A significant (p < 0.05) increase of the nasal tip, columella and upper lip projection was seen. Philtral height showed no significant changes (p > 0.05) after maxillary advancement. No significant correlation (p > 0.05) between the degree of soft tissue changes and the amount of maxillary advancement was found. CONCLUSION Le Fort I advancement significantly impacts the nasolabial soft tissue envelope. The 3D soft tissue changes are predictable and similar for any advancement up to 10 mm.

Differences in Short-term Outcomes Between Primary and Revision Anterior Cervical Discectomy and Fusion.

STUDY DESIGN Retrospective cohort study. OBJECTIVE To compare short-term morbidity for primary and revision anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA Revision ACDF procedures are relatively common, yet their risks are poorly characterized in the literature. There is a need to assess the relative risk of revision ACDF procedures compared with primary surgery. METHODS The prospectively collected American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was used to identify patients who underwent primary and revision ACDF from 2005 to 2014. The occurrence of 30-day postoperative complications, readmission, operative time, and postoperative length of stay were compared between primary and revision procedures using multivariate regression to control for patient and operative characteristics. RESULTS A total of 20,383 ACDF procedures were identified, 1219 (6.0%) of which were revision cases. On multivariate analysis, revision procedures were associated with significantly increased risk of any adverse event (relative risk [RR] 2.3, P < 0.001), any severe adverse event (RR 2.2, P < 0.001), thromboembolic events (RR 3.3, P = 0.001), surgical site infections (RR 3.2, P < 0.001), return to the operating room (RR 1.9, P = 0.001), any minor adverse event (RR 2.5, P < 0.001), and blood transfusion (RR 8.3, P < 0.001). Revision procedures had significantly increased risk of readmission within 30 days (RR = 1.6, P = 0.001). Minor, but statistically significant increases in average operative time and postoperative length of stay were identified for revisions procedures (7 min and half a day, respectively [P < 0.001 for both]). CONCLUSION Revision procedures were associated with significantly increased risk of multiple adverse outcomes, including thromboembolic events, surgical site infections, return to the operating room, blood transfusion, and readmission within 30 days. These results are important for patient counseling and risk stratification. LEVEL OF EVIDENCE 3.STUDY DESIGN Retrospective cohort study. OBJECTIVE To compare short-term morbidity for primary and revision anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA Revision ACDF procedures are relatively common, yet their risks are poorly characterized in the literature. There is a need to assess the relative risk of revision ACDF procedures compared to primary surgery. METHODS The prospectively collected American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was used to identify patients that underwent primary and revision ACDF from 2005 to 2014. The occurrence of 30-day postoperative complications, readmission, operative time, and postoperative length of stay were compared between primary and revision procedures using multivariate regression to control for patient and operative characteristics. RESULTS A total of 20,383 ACDF procedures were identified, 1,219 (6.0%) of which were revision cases. On multivariate analysis, revision procedures were associated with significantly increased risk of any adverse event (RR 2.3, p < 0.001), any severe adverse event (RR 2.2, p < 0.001), thromboembolic events (RR 3.3, p = 0.001), surgical site infections (RR 3.2, p < 0.001), return to the operating room (RR 1.9, p = 0.001), any minor adverse event (RR 2.5, p < 0.001), and blood transfusion (RR 8.3, p < 0.001). Revision procedures had significantly increased risk of readmission within 30 days (RR = 1.6, p = 0.001). Minor, but statistically significant increases in average operative time and postoperative length of stay were identified for revisions procedures (7 minutes and half a day, respectively [p < 0.001 for both]). CONCLUSIONS Revision procedures were associated with significantly increased risk of multiple adverse outcomes, including thromboembolic events, surgical site infections, return to the operating room, blood transfusion, and readmission within 30 days. These results are important for patient counseling and risk-stratification. LEVEL OF EVIDENCE 3.

Using topical imiquimod for the management of positive in situ margins after melanoma resection.

The treatment of melanoma in situ (MIS) is controversial with current standard of care being surgical excision with clear margins. Alternative topical therapy with imiquimod has been proposed in recent studies as a possible treatment for MIS. This study aimed to evaluate the use of topical 5% imiquimod as an alternative approach for the treatment of residual melanoma in situ after surgical resection of the primary lesion. A retrospective chart review of all patients treated with topical 5% imiquimod for residual MIS following standard resection with 5–10 mm margins at Yale‐New Haven Hospital from 2008 through 2013 was performed. The pre‐ and posttreatment results were confirmed by diagnostic tissue biopsy. Twenty‐two patients were included in the study. One of these 22 patients was lost to follow up. Twenty patients (95%) had complete resolution of their residual MIS and 1 patient did not respond to imiquimod (5%). No reports of recurrences were noted at the treatment sites. For patients with residual melanoma in situ after the initial excision, topical 5% imiquimod appears to be a reasonable alternative treatment with good clinical and histopathologic success rates.

Surgically Assisted Maxillary Expansion Imparts Three-Dimensional Nasal Change

PURPOSE The impact of surgically assisted maxillary expansion (SAME) on facial soft tissue structures has not been adequately studied using 3-dimensional (3D) objective analysis. The purpose of this study was to analyze nasolabial soft tissue after SAME using 3D photographic technology. MATERIALS AND METHODS This was a retrospective cohort study of patients undergoing SAME in which pre- and postexpansion 3D photographs (3D VECTRA Photosystem, Canfield, Fairfield, NJ) were analyzed. Nasolabial anthropometric measurements were performed using the 3D postprocessing software (Mirror). A follow-up period of at least 6 months was required for final evaluation. Two observers verified the landmarks on each dataset before measuring. Statistical analysis involved the paired t test, the Simes correction for multiple comparisons, and repeated measures analysis of covariance (ANCOVA) to control for age, gender, and the time lag between pre- and postoperative assessments. RESULTS Twelve patients (24 photogrammetric datasets) were included. The male-to-female ratio was 0.5 (mean age, 17.3 yr). Nasal changes after SAME showed significant increases (P < .05) in alar width (from 33.1 to 34.5 mm), sill width (from 9.2 to 9.7 mm), and columella projection (from 94.1 to 95.1 mm) after the Simes correction. ANCOVA showed a significant increase in alar base width. Distinct changes in nostril shape and dimension were found, but lacked statistical significance. CONCLUSION Three-dimensional analysis shows widening of the alar width and alar base width after SAME. The magnitude of nasal change parallels that of expansion at the piriform aperture.

Wound healing complications with intraoperative brachytherapy for head and neck cancer: a unique form of radiation injury.

BackgroundIntraoperative brachytherapy (IOBT) to the tumor bed coupled with surgery has been shown to increase survival and to improve locoregional disease control after head and neck tumor extirpation. Flap reconstruction attempts to restore patient anatomy, while also covering the radioactive implants. The purpose of this study was to better characterize the wound healing complications experienced by patients undergoing reconstruction in the setting of IOBT after tumor ablation, as well as to identify risk factors predicting complications and the need for reoperation. MethodsA retrospective chart review of patients receiving IOBT for head and neck cancer at Yale-New Haven Hospital between 2005 and 2013 was conducted. Patient, tumor, treatment, and reconstructive details were recorded. The number and type of flap complications, as well as instances in which patients had to be taken back to the operating room, were documented. Bivariate and multivariate logistic regressions were performed to identify risk factors associated with the occurrence of 1 or more flap complications, as well as the need for reoperation. ResultsNinety-three patients aged 31 to 93 years (mean, 64 ± 12 years) who underwent IOBT with flap reconstruction were included in the study. Of these, 94% had a prior history of radiation (external beam or previous IOBT). Overall, 48 (51.6%) patients experienced at least 1 flap complication, the most common of which was flap dehiscence (32% of patients). Thirty-two patients (34% of the cohort) had to be taken back to the operating room at least once for flap debridement or a revision procedure. On multivariate analysis, only the placement of mandibular hardware during flap reconstruction was significantly associated with the risk of developing any type of flap complication (odds ratio, 3.7; P = 0.009) or with subsequent return to the operating room (odds ratio, 3.9; P = 0.012). ConclusionsThis study, the largest of its kind, demonstrated a very high complication rate for flaps used to cover brachytherapy implants in this patient cohort. However, many of the patient complications could be managed nonoperatively. Avoiding the use of mandibular hardware with IOBT suggests a method of reducing complications with reconstruction.

Pedicle versus free flap reconstruction in patients receiving intraoperative brachytherapy

Abstract Introduction This study compared complication rates between pedicle flaps and free flaps used for resurfacing of intraoperative brachytherapy (IOBT) implants placed following head and neck tumour extirpation to help clarify the ideal reconstructive procedure for this scenario. Patients and methods A retrospective review of reconstructions with IOBT at our institution was conducted. Patient and treatment details were recorded, as were the number and type of flap complications, including re-operations. Logistic regressions compared complications between flap groups. Results Fifty free flaps and 55 pedicle flaps were included. On multivariate analysis, free flap reconstruction with IOBT was significantly associated with both an increased risk of having any flap complication (OR = 2.9, p = 0.037) and with need for operative revision (OR = 3.5, p = 0.048) compared to pedicle flap reconstruction. Conclusions In the setting of IOBT, free flaps are associated with an increased risk of having complications and requiring operative revisions.

Abstract 4319: Lupus antibody-based cancer therapy.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC A subset of autoantibodies produced by patients with systemic lupus erythematosus (SLE) penetrates into cell nuclei and binds DNA, and we believe that such antibodies may have applications in cancer therapy. We have discovered that the cell-penetrating, nuclear-localizing anti-DNA lupus antibody 3E10 inhibits key steps in DNA single- and double-strand break repair and has potential for development as a targeted therapy for tumors harboring deficiencies in DNA repair. 3E10 preferentially binds DNA substrates with free single-strand tails and interferes with both base excision repair and homology-directed repair (HDR) in vitro, and HDR efficiency is reduced in cells treated with 3E10 as measured in the chromosome-based DR-GFP fluorescent reporter assay. The binding of 3E10 to DNA can be directly visualized under electron microscopy (EM), and EM studies confirmed that 3E10 interferes with RAD51 filament formation, which is a critical step in HDR. The 3E10 single chain variable fragment penetrates into human tumor xenografts in nude mice, and 3E10 sensitizes cancer cells and tumors to DNA-damaging therapy. In addition, 3E10, by itself, is toxic to BRCA2-deficient cancer cells but not to repair-proficient cells, and when combined with a DNA-damaging agent, 3E10 has a very large cytotoxic effect on BRCA2-deficient cancer cells. The synthetically lethal effect of 3E10 on BRCA2-deficient cancer cells is consistent with our finding that 3E10 inhibits DNA repair, and it suggests that 3E10 has potential as a targeted therapy for tumors harboring deficiencies in DNA repair, such as certain breast, ovarian, and prostate cancers. Of note, patients with SLE have lower than expected incidence rates of breast, ovarian, and prostate cancers, and it is tempting to speculate that the circulating cell-penetrating anti-DNA autoantibodies provide patients with SLE some protection against the development of DNA repair-deficient tumors. In summary, our work with the 3E10 antibody has provided proof of principle for the development of a lupus antibody as a cancer therapy and opened up new avenues for exploration into the biology of lupus antibodies. Citation Format: James E. Hansen, Grace Chan, Yanfeng Liu, Denise C. Hegan, Shibani Dalal, Eloise Dray, Youngho Kwon, Yuanyuan Xu, Xiaohua Xu, Elizabeth Peterson-Roth, Erik Geiger, Yilun Liu, Joseph Gera, Joann B. Sweasy, Patrick Sung, Sara Rockwell, Robert N. Nishimura, Richard H. Weisbart, Peter M. Glazer. Lupus antibody-based cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4319. doi:10.1158/1538-7445.AM2013-4319