Citations

Background: The purpose of this study is to determine the effects of proximal hamate transfer for proximal pole scaphoid reconstruction upon carpal kinematics. Methods: Eight fresh-frozen cadaveric wrists underwent evaluation of their radiocarpal and midcarpal motion after proximal hamate osteotomy. A wrist simulator was used to apply cyclical tension to the flexor carpi ulnaris (FCU), flexor carpi radialis (FCR), extensor carpi ulnaris (ECU), and extensor carpi radialis longus and brevis stitched together (ECR). Kinematic motion was captured using Moiré Phase Tracking 3-dimensional motion-tracking sensors (MPT, Metria Innovation, Inc, Milwaukee, Wisconsin) to evaluate the lunocapitate and scapholunate angles for each condition. Results: During wrist flexion-extension and radial-ulnar deviation, there were no statistically significant differences about the lunocapitate or scapholunate axis between the intact and post-hamate osteotomy conditions. Conclusions: The harvest of the proximal hamate for proximal pole scaphoid reconstruction does not appear to adversely affect wrist kinematics.

Abstract CCGA [NCT02889978] is the largest study of cfDNA-based early cancer detection; the first CCGA learnings from multiple cfDNA assays are reported here. This prospective, multi-center, observational study has enrolled 10,012 of 15,000 demographically-balanced participants at 141 sites. Blood was collected from participants with newly diagnosed therapy-naive cancer (C, case) and participants without a diagnosis of cancer (noncancer [NC], control) as defined at enrollment. This preplanned substudy included 878 cases, 580 controls, and 169 assay controls (n=1627) across 20 tumor types and all clinical stages. All samples were analyzed by: 1) Paired cfDNA and white blood cell (WBC)-targeted sequencing (60,000X, 507 gene panel); a joint caller removed WBC-derived somatic variants and residual technical noise; 2) Paired cfDNA and WBC whole-genome sequencing (WGS; 35X); a novel machine learning algorithm generated cancer-related signal scores; joint analysis identified shared events; and 3) cfDNA whole-genome bisulfite sequencing (WGBS; 34X); normalized scores were generated using abnormally methylated fragments. In the targeted assay, non-tumor WBC-matched cfDNA somatic variants (SNVs/indels) accounted for 76% of all variants in NC and 65% in C. Consistent with somatic mosaicism (i.e., clonal hematopoiesis), WBC-matched variants increased with age; several were non-canonical loss-of-function mutations not previously reported. After WBC variant removal, canonical driver somatic variants were highly specific to C (e.g., in EGFR and PIK3CA, 0 NC had variants vs 11 and 30, respectively, of C). Similarly, of 8 NC with somatic copy number alterations (SCNAs) detected with WGS, 4 were derived from WBCs. WGBS data revealed informative hyper- and hypo-fragment level CpGs (1:2 ratio); a subset was used to calculate methylation scores. A consistent “cancer-like” signal was observed in <1% of NC participants across all assays (representing potential undiagnosed cancers). An increasing trend was observed in NC vs stages I-III vs stage IV (nonsyn. SNVs/indels per Mb [Mean±SD] NC: 1.01±0.86, stages I-III: 2.43±3.98; stage IV: 6.45±6.79; WGS score NC: 0.00±0.08, I-III: 0.27±0.98; IV: 1.95± 2.33; methylation score NC: 0±0.50; I-III: 1.02±1.77; IV: 3.94±1.70). These data demonstrate the feasibility of achieving >99% specificity for invasive cancer, and support the promise of cfDNA assay for early cancer detection. Additional data will be presented on detected plasma:tissue variant concordance and on multi-assay modeling. Citation Format: Alexander A. Aravanis, Geoffrey R. Oxnard, Tara Maddala, Earl Hubbell, Oliver Venn, Arash Jamshidi, Ling Shen, Hamed Amini, John A. Beausang, Craig Betts, Daniel Civello, Konstantin Davydov, Saniya Fazullina, Darya Filippova, Sante Gnerre, Samuel Gross, Chenlu Hou, Roger Jiang, Byoungsok Jung, Kathryn Kurtzman, Collin Melton, Shivani Nautiyal, Jonathan Newman, Joshua Newman, Cosmos Nicolaou, Richard Rava, Onur Sakarya, Ravi Vijaya Satya, Seyedmehdi Shojaee, Kristan Steffen, Anton Valouev, Hui Xu, Jeanne Yue, Nan Zhang, Jose Baselga, Rosanna Lapham, Daron G. Davis, David Smith, Donald Richards, Michael V. Seiden, Charles Swanton, Timothy J. Yeatman, Robert Tibshirani, Christina Curtis, Sylvia K. Plevritis, Richard Williams, Eric Klein, Anne-Renee Hartman, Minetta C. Liu. Development of plasma cell-free DNA (cfDNA) assays for early cancer detection: first insights from the Circulating Cell-Free Genome Atlas Study (CCGA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-343.

Abstract Background: This is an update of the safety and efficacy of durvalumab monotherapy in pts with locally advanced/metastatic urothelial carcinoma (UC) from an ongoing, phase 1/2 open-label study (NCT01693562). Methods: Pts received 10 mg/kg every 2 weeks up to 12 months or until unacceptable toxicity, progression, or starting another anticancer therapy. Pts were stratified by tumor PD-L1 expression (Ventana PD-L1 [SP263] Assay [PD-L1 cutoff: ≥25% of tumor cells and/or immune cells with membrane staining]) and treatment line. Results: As of the data cutoff (16Oct2017), 201 UC pts with Stage IV disease received treatment, with a median follow-up of 16.9 months (range, 0.4-37.7). Across treatment lines, objective response rate (ORR) by blinded independent central review was 17.4% (95% CI, 12.4, 23.4) in all pts; 27.5% in the PD-L1 ≥25% group vs 5.8% in the PD-L1 <25% group. The responses have been durable regardless of PD-L1 status, with the median duration of response not yet reached in the PD-L1 ≥25% group and 12.2 months in the PD-L1 <25% group. Responses lasted ≥12 mo in 62.9% of responders (max 25.7+ mo). Overall, median OS was 10.5 months (95% CI, 6.9, 15.7); 19.8 months in the PD-L1 ≥25% group vs 4.8 months in the PD-L1 <25% group (Table). Pts previously treated with platinum based chemotherapy also reported similar durable responses. At least one treatment-related AE was reported in 120 pts (59.7%), including fatigue (39 [19.4%]), decreased appetite and rash (18 [9.0%] each), and diarrhea (16 [8.0%]). Grade 3/4 treatment-related AEs occurred in 19 (9.5%) pts; 6 (3.0%) treatment discontinuations and 2 (1.0%) deaths were attributed to treatment-related AEs. Conclusions: With extended follow-up, durvalumab continues to show durable clinical activity in UC pts, especially in the PD-L1 ≥25% group with an acceptable toxicity profile. PD-L1 ≥25%PD-L1 <25%PD-L1 unknownTotalAll UCn=102n=86n=13N=201Confirmed ORR, %27.55.815.417.4(95% CI)(19.1, 37.2)(1.9, 13.0)(1.9, 45.4)(12.4, 23.4)CR, %7.83.57.76.0PR, %19.62.37.711.4Median DoR, monthsNR12.2NRNR(min, max)(2.7, 25.7+)(8.6, 21.7+)(14.5+, 14.6+)(2.7, 25.7+)Median PFS, months (95% CI)1.9 (1.4, 2.7)1.4 (1.3, 1.5)2.8 (1.4, NE)1.5 (1.4, 1.8)6-month PFS rate, %28.68.625.220.412-month PFS rate, %22.37.125.216.2Median OS, months (95% CI)19.8 (9.3, NE)19.8 (9.3, NE)4.8 (3.3, 8.1)NR (4.9, NE)10.5 (6.9, 15.7)6-month OS rate, %67.645.869.258.912-month OS rate, %57.629.561.546.6 Citation Format: Peter O'Donnell, Christophe Massard, Bhumsuk Keam, Sang-We Kim, Terry Friedlander, Myung-Ju Ahn, Michael Ong, Michael Gordon, Marcus Butler, Scott Antonia, Gerardo Colon-Otero, Martin Gutierrez, Sumati Gupta, Alexander Spira, Alexandra Drakaki, Michele Maio, Feng Xiao, Natasha Angra, Shaad Abdullah, Thomas Powles. Updated efficacy and safety profile of durvalumab monotherapy in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT031.

Abstract Background: Acquired PARP inhibitor (PARPi) resistance in high-grade serous ovarian cancer (HGSOC) as a result of restored homologous recombination has been observed following secondary mutations that restore full-length protein in BRCA1, BRCA2, RAD51C, and RAD51D. Additionally, loss of BRCA1 methylation has also been shown to confer resistance. However, little is known about the role of RAD51C methylation in acquired PARPi resistance. In ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib in ovarian carcinoma, four (2%) tumors demonstrated RAD51C methylation. The present study utilizes HGSOC patient derived xenografts (PDXs) and recurrent samples from ARIEL2 to assess the role of RAD51C methylation in the development of PARPi resistance. Methods: To drive PARPi resistance, PDX039, an extremely PARPi-sensitive model lacking demonstrable mutations in DNA repair genes, was treated cyclically with niraparib (100 mg/kg) for 21 days, after which the tumor was allowed to regrow and re-established in new mice for the next treatment round. To evaluate the frequency of methylation change, RAD51C methylation was analyzed in 12 rucaparib-treated mice (300 or 450 mg/kg) harboring PDX183, a PARPi-sensitive model without mutations in DNA repair genes. Global changes in gene expression following development of PARPi resistance were assessed by RNA sequencing. RAD51C promoter methylation was evaluated by bisulfite sequencing. Subsequent functional analysis included qRT-PCR, IHC, and western blot. DNA damage response pathways are being evaluated by immunofluorescence ex vivo following niraparib, rucaparib, or IR. Results: PDX039 grew through PARPi treatment by the third and fourth cycle of therapy. RAD51C was the only DNA repair gene to show significant change in RNAseq analysis (log2 fold-change=8.43; p=2e-192), corresponding with a loss of RAD51C methylation. Moreover, after just one round of PARPi treatment, RAD51C methylation was lost in 1 of 12 PARPi-treated PDX183 xenografts. RAD51C methylation loss ultimately resulted in restoration of expression, for which functional analysis is ongoing. Analysis of patient samples is currently underway. Conclusions: In HGSOC PDX models, RAD51C methylation affords PARPi sensitivity in the absence of DNA repair gene mutations. Treatment pressure with PARPi can reverse RAD51C methylation and restore RAD51C expression. Isolated changes in methylation of the RAD51C locus are sufficient to restore HR and convey PARPi resistance. Citation Format: Rachel M. Hurley, Ksenija Nesic, Cordelia McGehee, Olga Kondrashova, Maria I. Harrell, Paula A. Schneider, Xiaonan Hou, Cristina Correia, Karen S. Flatten, Giada V. Zapparoli, Alexander Dobrovic, Kevin K. Lin, Thomas C. Harding, Andrea E. Wahner Hendrickson, Elizabeth M. Swisher, Matthew Wakefield, S. John Weroha, Clare L. Scott, Scott H. Kaufmann. Loss of RAD51C promoter hypermethylation confers PARP inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5885.

Abstract Tubo-ovarian high-grade serous cancer (HGSC) is the most common histotype of epithelial ovarian cancer (70%-80%) and the leading cause of death from gynecological malignancy. Novel monoclonal antibody and adoptive cell transfer immunotherapies have found success in cancer in the past five years; however success in HGSC treatment has been elusive thus far. We have recently shown that CD8+ T-lymphocytes infiltrating the tumor proper (TILs) associate in a dose response manner with longer patient survival time regardless of age, stage or residual disease. As understanding host factors associated with this clinically relevant tumor phenotype will contribute to the development of targeted therapies, we sought to identify germline genetic factors associated with CD8+ TIL levels in HGSC. We performed a germline genome-wide association study (GWAS) of CD8+ TILs using 1204 HGSC patients of European ancestry from twelve studies with centralized genotyping, immunohistochemistry, and harmonization of clinical data. Germline genotypes were assayed using the Illumina Infinium OncoArray Beadchip and were imputed to over 11.4 million variants based on the 1000 Genomes Project reference panel. CD8 immunohistochemistry was performed on tissue microarrays using the Leica Bond Rx stainer and scored into four levels of CD8+ TILs per x400 magnification of a 0.55-mm diameter field for each tumor hotspot: none (no CD8+ TILs), low (1-2 CD8+ TILs), moderate (3-19 CD8+ TILs), high (20 or more CD8+ TILs). GWAS used multinomial regression modelling of these four CD8+ TIL levels adjusted for study site, age, and European ancestry principal components. On the average, CD8+ TIL levels were 18%, 19%, 44% and 18% for none, low, moderate and high levels, respectively. As expected, CD8+ TIL levels associated with overall survival time (p < 2.6x10-8), and CD8+ TIL levels and age at diagnosis were similarly distributed across study sites. We identified a region on chromosome 22 with multiple, correlated variants (MAF > 20%) associated with CD8+ TIL levels at p-value < 2.0x10-5. The most statistically significant variant was an indel (rs557925408) located in the an intron of the MYO18B gene (Myosin XVIIIB, p-value < 8.7x10-6). Each copy of this variant associated with a reduced extent of CD8+ TIL infiltration (OR low v none = 0.92; OR moderate v none = 0.61). An independent set of 1200 OncoArray genotyped HGSC cases are undergoing CD8+ TIL scoring in December 2017 and will be included in final genome-wide analysis. This will provide improved statistical power and enable consideration of additional genetic models (e.g., linear trend tests). Comprehensive integrative analysis of germline, tumor, and clinical features provides a model for clinical molecular epidemiology studies and will be key to increasing our understanding of this important HGSC immunophenotype. Citation Format: Yanina Natanzon, Martin Köbel, Stacey J. Winham, Sebastian M. Armasu, Bryan M. McCauley, Robert A. Vierkant, Julie M. Cunningham, David Bowtell, Ian G. Campbell, Jenny Chang-Claude, Anna deFazio, Peter A. Fasching, Mark T. Goodman, Beth Y. Karlan, Francesmary Modugno, Kirsten B. Moysich, Roberta B. Ness, Weiva Sieh, Paul D. Pharoah, Susan J. Ramus, Ellen L. Goode. Tumor-infiltrating CD8-positive T-lymphocytes in tubo-ovarian high-grade serous cancer are associated with multiple germline variants in 22q12.1 in a genome-wide association analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 225.

Abstract Background: Radiologically dense area (DA) on a mammogram represents the stromal and epithelial tissue in the breast, while non-dense area (NDA) represents adipose tissue. Quantitative measurements of DA, NDA as well as the proportion of dense area in the breast (percent density, PD) adjusted for age and body mass index (BMI) have all been associated with breast cancer (BC) risk. Previous genome-wide association studies (GWAS) have identified genetic loci that show association with both mammographic density (MD) phenotypes and BC, but little is known about the genome-wide and local genetic correlation between MD phenotypes and BC. Methods: We estimated the genome-wide and local genetic correlation between MD phenotypes adjusted for age and BMI and BC, leveraging GWAS summary statistics for MD phenotypes based on 12,866 women (MODE consortium) and for BC based on 122,977 cases and 105,974 controls (BCAC consortium). We also conducted partitioned heritability analysis to identify specific functional annotations that contribute to MD heritability. Results: We observed a negative genetic correlation between DA and NDA (-0.62, p=0.002). Both DA and PD showed positive genetic correlations with overall BC (DA: rg=0.24, p=0.004; PD: rg=0.27, p=0.0001), estrogen receptor-positive (ER+) BC (DA: rg=0.23, p=0.005; PD: rg=0.23, p=0.001), and ER- BC (DA: rg=0.26, p=0.01; PD: rg=0.32, p=0.0006). In contrast, NDA showed a nonsignificant negative genetic correlation with BC (rg=-0.11, p=0.21). Local genetic correlation analyses between MD phenotypes and BC reflected known findings including positive correlation at 10q21 region between both PD and DA and BC (both p<5x10-7), negative correlation at 22q13.1 between DA and BC (p=4.6x10-6), and positive correlation at 8p11.23 between NDA and BC (p=2.8x10-6). Two known BC regions that have not previously been associated with MD showed suggestive genetic correlations between BC and DA: 1q21.2 (negative genetic correlation, p=1.3x10-4) and 12q21.31 (positive genetic correlation, p=6.7x10-4). In exploratory analyses estimating the genome-wide genetic correlation between MD and hormone-related phenotypes in UK Biobank (n=337,199), we observed nominally significant positive genetic correlations between PD and benign mammary dysplasia (rg=0.45, p=0.01), NDA and endometriosis (rg=0.45, p=0.02), and negative genetic correlation between NDA and menstrual cycle length (rg=-0.30, p=0.05). We identified multiple functional annotations that contribute to MD heritability including histone mark H3K27ac that marks active enhancers (~2,5-fold enrichment in heritability for both DA and NDA) and DNAsel Hypersensitive Sites (DHS, 9.1-fold enrichment in heritability for DA). Conclusion: Our results provide evidence of shared genetic basis between mammographic density and breast cancer. Citation Format: Hongjie Chen, Julie Douglas, William Gordon, Deborah Thompson, Fergus Couch, Peter Fasching, Per Hall, John Hopper, Gertraud Maskarenic, Marina Pollan, Jennifer Stone, Rulla Tamimi, Sara Lindstroem. Evidence for a shared genetic basis between breast cancer and mammographic density phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 224.

Abstract Multiple myeloma (MM) is twice as common in African Americans (AA) compared to European Americans (EA). The reported familial clustering and the elevated MM risk among first-degree relatives of cases implicate genetic susceptibility. Previous genome-wide association studies (GWAS) in EA have identified 16 novel risk loci. In this study, we tested the generalizability of the established risk alleles to AA and conducted a meta-GWAS analysis using two sets of AA to identify additional novel common MM risk variants. In the first study, we genotyped 1,305 incident AA MM cases from the African American Multiple Myeloma Study (AAMMS) using the Illumina HumanCore GWAS array and compared them to 7,078 AA controls from the African Ancestry Prostate Cancer Consortium (AAPC) and African Ancestry Breast Cancer Consortium (AABC) using the Illumina 1M-Duo. In the second study, 95 additional AAMMS cases and 435 AA MM cases from the University of Arkansas for Medical Sciences (UAMS) were genotyped using the Illumina MegaBead Chip and compared to 2,390 AA controls from the Multiethnic Cohort. The Haplotype Reference Consortium (HRC) was used to impute the overlapping typed SNPS from each GWAS case and control set together. Per-allele risk associations were tested for 8,715,278 overlapping genotyped and imputed variants with >1% frequency and >0.8 imputation score using unconditional logistic regression in both sets, and the combined effects were estimated using a fixed-effect meta-analysis. Of the 16 reported risk loci discovered in EA, directional consistency was present for 15 variants; eight of these replicated at nominal significance p<0.05, with the most statistically significant variant being rs4487645 at 7p15.3 (OR=1.38, p=3.56×10-6). AA individuals with polygenic risk scores from these 16 variants (PRS) in the top 10% stratum had a 1.44-fold increased MM risk compared to those with a PRS in the 25th -75th percentiles. Additionally, we identified three suggestive novel loci located at 12q12, 9p24.3 and 9p13.1 at p<1×10-6, with ORs ranging from 1.25-1.55, but none reached genome-wide significance. The variant at 9p24.3 is located in an intron in the KANK1 gene and a correlated SNP in EAs (r2=0.5) is strongly associated with gene expression in neoplastic plasma cells (unpublished, Weinhold and Morgan). Our study replicated most of the reported risk loci discovered among EA, demonstrated that a PRS constructed using the 16 reported risk alleles was associated with MM risk, and provides suggestive evidence for additional loci associated with MM risk in AAs. Citation Format: Zhaohui Du, Chi Song, Kristin Rand, Niels Weinhold, David Van Den Berg, Amie Hwang, Xin Sheng, Victor Hom, Sikander Ailawadhi, Ajay K. Nooka, Seema Singhal, Karen Pawlish, Edward S. Peters, Cathryn Bock, Ann Mohrbacher, Alexander Stram, Sonja I. Berndt, William Blot, John David Carpten, Antoinette Stroup, Andrew Olshan, Wei Zhang, African Ancestry Breast & Prostate Consortium, Stephen Chanock, Jayesh Mehta, Graham A. Colditz, Jeffrey Wolf, Thomas G. Martin, Michael Tomasson, Mark A. Fiala, Howard Terebelo, Nalini Janakiraman, Laurence Kolonel, Loic LeMarchand, Elad Ziv, Daniel Stram, Ravi Vij, Leon Bernal-Mizrachi, Gareth J. Morgan, Jeffrey A. Zonder, Carol Ann Huff, Sagar Lonial, Robert Z. Orlowski, David V. Conti, Christopher A. Haiman, Wendy Cozen. A meta-analysis of genome-wide association studies of multiple myeloma among African Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 223.

Background: The medial femoral condyle free vascularized bone flap is a valuable alternative to other types of vascularized bone grafts. The donor-site morbidity and functional outcomes after flap harvest have not been fully appreciated. The authors report the postoperative outcomes and analyze the impact of increasing the size of the flap on knee donor-site morbidity. Methods: A retrospective chart review of patients who underwent medial femoral condyle flap surgery between 2001 and 2012 at their institution was performed. The size of the flap was stratified, based on the largest dimension, into three groups. Demographics, outcomes, and complications related to the flap donor site were recorded and analyzed. Subsequently, functional status was assessed by administering a validated condition-specific measure. A univariate logistic regression analysis was performed, and results were analyzed. Results: A total of 75 patients were identified. Average age was 29.5 ± 15.2 years. Average follow-up time was 13 months. The overall complication rate was 18.6 percent. Paresthesia in the saphenous nerve distribution was the most common complication. Increasing the size of the flap resulted in a significant elevation in complication risk (p < 0.05). A total of 47 patients completed the Lower Extremity Functional Scale questionnaire. The average Lower Extremity Functional Scale score was 72.12 ± 14.18. Fifty-one percent (n = 24) scored 80 points, indicating a normal level of function on average. Conclusions: The medial femoral condyle flap has overall acceptable donor-site morbidity, with a good level of function postoperatively. Larger flaps are associated with a greater number of complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Background: Outcomes following revision surgery for scaphoid nonunions with osteonecrosis are guarded. We hypothesized that use of free vascularized medial femoral condyle (MFC) bone grafts can lead to healing of the nonunion, increase vascularity of the proximal pole, and restore scaphoid architecture, resulting in acceptable functional outcomes. Methods: We performed a retrospective review of 49 patients who were treated with an MFC bone graft, between May 2005 and September 2016, after prior failure of operative treatment for scaphoid nonunion. The mean time from the injury to the revision surgery with the MFC bone graft was 24 months, and the mean time from the prior, failed surgery was 15 months. Thirty-six of the 49 patients had had a prior bone graft procedure and 6 patients had had 2 previous surgical procedures for the nonunion. The initial internal fixation of the scaphoid fracture was with a scaphoid screw in 43 patients. All patients had documented osteonecrosis of the proximal pole at the time of our surgery. Carpal indices, time to union, pain scores, functional outcomes, and complications were recorded. Results: Forty-one (84%) of the 49 previously operated on scaphoid nonunions healed at a mean of 16 weeks (range, 9 to 31 weeks) after the MFC bone-grafting as confirmed on computed tomography (CT). Radiographs demonstrated significant improvement in carpal alignment following the surgery with the MFC bone graft. Comparison between preoperative and postoperative values showed a trend toward improved grip strength and no important change in total wrist range of motion. Subsequent procedures were performed in 29 patients, 21 of whom had planned Kirschner wire removal. All 24 patients in whom scaphoid union had been achieved and who were available for follow-up were able to work or attend school full-time, and 88% were satisfied or very satisfied with their wrist function. Age, smoking status, body mass index, time to surgery, and preoperative radiographic findings were not found to be significant predictors of failure. Conclusions: MFC grafts increase vascularity and restore scaphoid architecture, promoting union in most patients with the combination of proximal pole osteonecrosis, carpal collapse, and failed prior scaphoid nonunion surgery. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.