Four-Year Follow-Up of the World's First Pediatric Bilateral Hand-Forearm Transplants: Do They Grow as Expected?

BACKGROUND: In 2015, the first bilateral pediatric hand-forearm transplant was performed in an 8-year-old boy. The growth rate of the transplanted upper extremities was unknown at the time. METHODS: Forearm and hand radiographs were obtained annually. Radius and ulna measurements were performed by multiple coauthors and mathematically normalized using a standardized methodology. The Greulich and Pyle atlas was used to estimate hand bone age. RESULTS: From July of 2015 to July of 2019, unadjusted bone length (metaphysis to metaphysis) increased 38.8 and 39.6 mm for the left radius and ulna, and 39.5 and 35.8 mm for the right radius and ulna, respectively. Distal physes of the donor limbs increasingly contributed to overall bone length relative to proximal physes. Normalized growth between the two limbs was statistically similar. At each annual follow-up, the bone age increased by 1 year. CONCLUSIONS: Successful pediatric hand-forearm transplantation offers the advantage of growth similar to that of nontransplanted pediatric patients. The transplanted distal physes contributes more to the overall growth, paralleling normal pediatric growth patterns. Chronologic age parallels the increase in bone age. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Are You Thinking About Going Back to School? An Analysis of Plastic Surgery Residents, Alumni, Faculty, and Program Leaders With Advanced Degrees.

BACKGROUND: The number of adults with master's, professional, and doctoral degrees has doubled since 2000. The relevance of advanced degrees in plastic surgery has not been explored. METHODS: Faculty, residents, and recent alumni with advanced degrees from the United States plastic surgery training programs were identified. Degrees were analyzed based on geography, program/hospital rankings, department versus division status, gender, leadership/editorial roles, private versus academic practice, subspecialization training, academic productivity/H-indices, and National Institutes of Health funding. RESULTS: A total of 986 faculties, 1001 residents, and 761 alumni credentials from 95 training programs were reviewed: 9.3% of faculties, 7.1% of residents, and 6.3% of alumni have advanced degrees, majority being men (71%). Residency programs ranked top 10 by Doximity or affiliated with a top 10 medical school/hospital have more faculty/residents/alumni with advanced degrees (P < 0.01). Faculty holding PhDs are less likely fellowship trained (52.5% versus 74.0%, P = 0.034). Master's in Business Administration (MBA) is associated with chair/chief status (30.0% versus 8.57%, P = 0.01) or other major academic title (eg, Dean, Director) (70.0% versus 37.14%, P = 0.01). No significant associations exist between degree type and professor status, research productivity, academic versus private practice, or subspecialization (eg, craniofacial surgery). CONCLUSION: The majority of plastic surgeons with advanced degrees have PhDs, although there is an increasing trend of other research degrees (eg, Master's in Public Health) in current trainees. MBA is associated with chair/chief status or other major academic title. Reasons for obtaining an advanced degree and impact on career deserve further attention.

An evaluation of monthly maintenance therapy among patients receiving intravesical combination gemcitabine/docetaxel for nonmuscle-invasive bladder cancer.

PURPOSE: To report our experience with sequential maintenance intravesical gemcitabine/docetaxel (GEM/DOCE) for patients with nonmuscle-invasive bladder cancer. MATERIALS AND METHODS: Fifty-nine patients who received full GEM/DOCE for nonmuscle-invasive bladder cancer between 2013 and 2018, per the protocol adapted from University of Iowa, were identified and characterized. Patients were treated with 6 weekly instillations of GEM/DOCE and subsequent monthly maintenance installations for those with no evidence of disease at the first surveillance. Student's t test and χ2 test were used to compare continuous and categorical variables as appropriate. For survival analyses, Kaplan-Meier (KM) curves were created to assess disease-free survival (DFS). Overall comparisons of KM survival analysis were conducted using the Wilcoxon test. RESULTS: Among all patients, median follow-up was 24 months. Sixty-six percent of patients received ≥2 intravesical induction therapies prior to receiving GEM/DOCE. Thirty-one patients (63%) failed ≥2 induction courses of Bacillus Calmette-Guérin (BCG) before receiving GEM/DOCE. Overall DFS was 49% at 1 year and 29% at 2 years. For patients who failed ≥1 induction courses of BCG, overall DFS was 48% at 1 year and 32% at 2 years. GEM/DOCE appears to be effective for therapy naïve and patients who have failed previous intravesical therapies (P = 0.39). There were 41 (69.5%) patients who had no evidence of disease at the first surveillance and were eligible for maintenance therapy. Among these patients, 24 were managed with observation alone and 17 with monthly maintenance. Median follow-up for observed patients was 36 months and 26 months for patients with maintenance. DFS at 1 year was 42% for observed patients and 81% for patients receiving maintenance (P = 0.04). DFS at 2 years was 32% for observed patients and 59% for patients receiving maintenance therapy (P = 0.45). For maintenance eligible patients who received ≥1 induction courses of BCG, DFS was 42% for observed patients and 81% for patients receiving maintenance therapy at 1 year and 34% for observed patients and 59% for patients receiving maintenance therapy at 2 years. Pathologic stage at recurrence was similar between observed patients and those receiving maintenance (P = 0.83). KM analyses showed greater DFS for patients receiving maintenance therapy compared to observed patients (P = 0.04). CONCLUSION: Patients who demonstrate initial complete response to GEM/DOCE may benefit from maintenance GEM/DOCE.

Impact of intravesical therapy for non-muscle invasive bladder cancer on the accuracy of urine cytology.

PURPOSE: Urine cytology remains an essential diagnostic tool in the surveillance of patients with non-muscle invasive bladder cancer (NMIBC). The correlation of urine cytology with biopsy specimens to determine its accuracy following induction intravesical therapy has not been investigated. METHODS: A retrospective review was performed of patients who underwent intravesical therapy for biopsy-proven non-muscle invasive disease between 2013 and 2016 at our institution. All patients uniformly underwent cytology and systematic bladder biopsies in the operating room within 12 weeks following intravesical therapy. The accuracy of urinary cytology in predicting high-grade disease recurrence following intravesical therapy was confirmed by correlating cytology results to post-treatment systematic biopsies, regardless of endoscopic findings. Only patients with complete information regarding urine cytology and pathologic biopsy results, both pre- and post-intravesical therapy, were included. RESULTS: 90 cytology samples following intravesical therapy were analyzed from 76 patients who met inclusion criteria. 72 (80.0%) and 18 (20.0%) of the samples were collected from patients initially treated for high- and low-grade disease, respectively. Fifty-six (62.2%) specimens were obtained from patients following induction of bacillus Calmette-Guerin (BCG) therapy; the remainder were from patients treated with intravesical gemcitabine/docetaxel, mitomycin, or BCG/interferon. For patients treated with BCG, cytology was positive for high-grade disease in 8/15 patients with high-grade pathology on follow-up biopsy, thus demonstrating a sensitivity of 53% (95% CI 27-79%), specificity of 95% (95% CI 84-99%), positive predictive value of 80% (95% CI 44-98%), and negative predictive value of 85% (95% CI 71-94%). If cytologic interpretation was broadened to include high-grade and "suspicious for high-grade" findings, sensitivity increased to 67% (95% CI 38-88%) and specificity decreased to 88% (95% CI 74-96%). CONCLUSIONS: While urinary cytology maintains a high specificity following intravesical therapy, it demonstrates a low sensitivity for potentially aggressive high-grade urothelial carcinoma. Further evaluation of more effective, clinic-based enhanced cystoscopy techniques and biomarkers is warranted to better identify patients at risk for disease recurrence following BCG therapy.

Hospital Charges and Length of Stay Following Radical Cystectomy in the Enhanced Recovery After Surgery Era.

OBJECTIVE: To report our center's experience with enhanced recovery after surgery (ERAS) pathway for radical cystectomy (RC), specifically evaluating complications, LOS, 30- and 90-day readmissions, and hospital charges. Pathways of this type have been shown to decrease the length of stay (LOS) and postoperative ileus. However, concerns persist that ERAS is costly and increases readmissions. To date, limited studies have evaluated these concerns. MATERIALS AND METHODS: Our ERAS protocol was implemented for RC in December 2015. Outcomes in ERAS patients were compared with those in RC patients from the time period before ERAS. Patients were excluded if they underwent concomitant nephroureterectomy. RESULTS: Fifty-six consecutive ERAS patients were compared with 54 pre-ERAS patients. The median charge for index hospitalization was $31,090 in the ERAS group and $35,489 in the pre-ERAS group (P = .036). The median LOS was 5.0 days in the ERAS group and 8.5 days in the pre-ERAS group (P = < .001). The pre-ERAS group had a significantly increased use of nasogastric tube (13.8% vs 30.0%) and parenteral nutrition (6.9% vs 20.4%). The overall complication rate (including infectious, renal, deep vein thrombosis and pulmonary embolism, myocardial infarction and stroke, and respiratory and gastrointestinal-related complications) was similar between the 2 groups (51.7% in the ERAS group and 62.0% in the pre-ERAS group, P = .28). Thirty- and 90-day readmissions also remained similar (19.0% vs 14.8%, P = .55, and 31.0% vs 27.7%, P = .64). The most common readmission reason was infection, specifically urinary tract infection. CONCLUSION: Implementation of the ERAS pathway at our center resulted in significantly reduced LOS and total hospital charge, with comparable rates of complication and readmission, highlighting the need for ERAS pathways in patients undergoing RC.

Medical student healthcare consulting groups: A novel way to train the next generation of physician-executives.

Meeting the challenges of the evolving healthcare environment requires leadership of physicians well-trained in clinical medicine and healthcare management. However, many physicians lack training in business and leadership. While some residency programs have management tracks, training at the medical school level is currently lacking. We developed the Hopkins Health Management Advisory Group, an extracurricular program at Johns Hopkins University School of Medicine that exposes medical students to healthcare management and fosters development of leadership skills. Teams of students work directly with health system executives on 3-6 month-long projects using management consulting principles to address problems spanning health system domains, including strategy, operations, and quality improvement. Since the program's inception, 23 students have completed seven projects, with 13 additional students currently working on three more projects. Sponsors leading six out of seven completed projects have implemented recommendations. Qualitative survey respondents have found the program beneficial, with students frequently describing how the program has helped to develop professional skills and foster knowledge about healthcare management. These early assessments show positive impact for both students and the institution, and suggest that such programs can train students in management early and concurrently in their medication education by immersing them in team-based health system projects.

Oncological Outcomes of Sequential Intravesical Gemcitabine and Docetaxel in Patients with Non-Muscle Invasive Bladder Cancer.

BACKGROUND: Bacillus Calmette-Guérin (BCG) unresponsive/relapsing patients with non-muscle invasive bladder cancer (NMIBC) who prefer bladder preservation over radical cystectomy (RC) or those who do not qualify for surgery may be offered intravesical therapies. Gemcitabine (GEM) combined with Docetaxel (DOCE) has been offered at Johns Hopkins Hospital (JHH). OBJECTIVE: To evaluate experience with GEM/DOCE, to confirm safety of the regimen, to identify populations that may benefit most, and to consider the appropriate endpoints for judging efficacy of second line therapies. METHODS: Thirty-three patients who received full induction GEM/DOCE since 2011, per the protocol adapted from U. Iowa, were identified and characterized. Multivariable logistic regression was used to determine factors associated with recurrence. Cox proportional hazard models evaluated risk factors for disease-free survival (DFS) and high-grade recurrence-free survival (HG-RFS). RESULTS: There were no serious adverse effects of therapy. Across all patients, median follow-up time was 18.6 months with a median DFS of 6.5 months, 42% 1-year, and 24% 2-year DFS. Median HG-RFS was 17.1 months with 56% 1-year and 42% 2-year HG-RFS. Among patients initially presenting with HG-NMIBC, 46% (13/28) had HG recurrence. BCG unresponsive/relapsing patients (N = 25) displayed 49% 1-year HG-RFS and 34% 2-year HG-RFS. In total, there were 5 LG and 16 HG recurrences, with 5 progressions and 8 cystectomies among these. CONCLUSIONS: GEM/DOCE is a well-tolerated therapy that deserves further study as an alternative to immediate RC for highly selected patients with HG-NMIBC. BCG naïve patients responded more effectively than BCG unresponsive/relapsing patients. As anticipated, GEM/DOCE efficacy was improved for HG only patients.

High dose-rate Intra-Operative Radiation Therapy During High Risk Genitourinary Surgery: Initial Observations and a Proposal for its Study in Bladder Cancer.

BACKGROUND: High dose-rate Intra-Operative Radiation Therapy (HD-IORT) is used to provide effective local control for patients with high-risk locally advanced or recurrent tumors. However, the utility of HD-IORT for patients with bladder cancer has not been studied. OBJECTIVE: To characterize our institutional experience with HD-IORT in patients with cancer requiring genitourinary surgery, in an effort to identify patients with bladder cancer that may benefit from HD-IORT. METHODS: We performed a retrospective review of all patients who have undergone HD-IORT during genitourinary surgery at our institution. Patients were stratified by surgical margin status, and primary outcomes assessed were overall survival, recurrence free survival and 90-day complications. Patients undergoing cystectomy and HD-IORT with sarcomatoid urothelial cancer were compared to a similar cohort undergoing cystectomy alone. A sample case of one such patient is discussed in detail. RESULTS: 84 patients at our institution have undergone HD-IORT with genitourinary surgery. Positive surgical margin status was the greatest predictor of both OS (HR = 3.42) and RFS (HR = 2.61). The overall 90-day complication rate was 61%, with wound infections (43%) and GI complications (21%) being most common. 4 of these patients had sarcomatoid urothelial histology, and all are still alive with >2 yrs follow up. This compares to a 52% 1 yr survival in our sarcomatoid urothelial cohort (25 pts) that did not undergo HD-IORT. CONCLUSIONS: Our institutional experience with HD-IORT has been promising, particularly among patients with locally advanced disease and sarcomatoid histology. We are currently enrolling patients in a multi-institutional registry to assess the utility of HD-IORT in high risk bladder cancer.

Interdomain communication in the endonuclease/motor subunit of type I restriction-modification enzyme EcoR124I.

Restriction-modification systems protect bacteria from foreign DNA. Type I restriction-modification enzymes are multifunctional heteromeric complexes with DNA-cleavage and ATP-dependent DNA translocation activities located on endonuclease/motor subunit HsdR. The recent structure of the first intact motor subunit of the type I restriction enzyme from plasmid EcoR124I suggested a mechanism by which stalled translocation triggers DNA cleavage via a lysine residue on the endonuclease domain that contacts ATP bound between the two helicase domains. In the present work, molecular dynamics simulations are used to explore this proposal. Molecular dynamics simulations suggest that the Lys-ATP contact alternates with a contact with a nearby loop housing the conserved QxxxY motif that had been implicated in DNA cleavage. This model is tested here using in vivo and in vitro experiments. The results indicate how local interactions are transduced to domain motions within the endonuclease/motor subunit.