Iatrogenic immunodeficiency-associated lymphoproliferative disorder presenting as small bowel perforation.

A woman in her late 50s on mycophenolate for limited systemic sclerosis presented with abdominal pain. Vital signs and investigative evaluations were normal. Cross-sectional imaging identified gastric and small bowel wall thickening, free fluid, and pneumoperitoneum. In the operating room, a small bowel perforation was found and resected. Postoperatively, immunosuppression was held and she completed a course of amoxicillin/clavulanate. She discharged home and re-presented on postoperative day 8 with seizures and was found to have a frontal brain mass which was biopsied. Pathology from both the resected bowel and brain biopsy demonstrated Epstein-Barr virus-positive B-cell lymphoproliferative disorder with polymorphic B-cell features. The patient's immunosuppression was discontinued, and she was enrolled in a clinical trial for chemotherapy. Lymphoproliferative disorder can present years after immunosuppression initiation with either spontaneous perforation or solid tumour. Pathological assessment determines treatment options. Heightened concern for atypical clinical presentations in immunosuppressed patients is always warranted.

A2/A2B to B deceased donor kidney transplantation in the Kidney Allocation System era.

Kidney transplantation from blood type A2/A2B donors to type B recipients (A2→B) has increased dramatically under the current Kidney Allocation System (KAS). Among living donor transplant recipients, A2-incompatible transplants are associated with an increased risk of all-cause and death-censored graft failure. In light of this, we used data from the Scientific Registry of Transplant Recipients from December 2014 until June 2022 to evaluate the association between A2→B listing and time to deceased donor kidney transplantation (DDKT) and post-DDKT outcomes for A2→B recipients. Among 53 409 type B waitlist registrants, only 12.6% were listed as eligible to accept A2→B offers ("A2-eligible"). The rates of DDKT at 1-, 3-, and 5-years were 32.1%, 61.4%, and 72.1% among A2-eligible candidates and 14.1%, 29.9%, and 44.1% among A2-ineligible candidates, with the former experiencing a 133% higher rate of DDKT (Cox weighted hazard ratio (wHR) = 2.192.332.47; P < .001). The 7-year adjusted mortality was comparable between A2→B and B-ABOc (type B/O donors to B recipients) recipients (wHR 0.780.941.13, P = .5). Moreover, there was no difference between A2→B vs B-ABOc DDKT recipients with regards to death-censored graft failure (wHR 0.771.001.29, P > .9) or all-cause graft loss (wHR 0.820.961.12, P = .6). Following its broader adoption since the implementation of the kidney allocation system, A2→B DDKT appears to be a safe and effective transplant modality for eligible candidates. As such, A2→B listing for eligible type B candidates should be expanded.

Transplant Center Attitudes Toward Early Liver Transplant for Alcohol-associated Liver Disease.

Background: Many centers have removed 6-mo pretransplant alcohol abstinence requirements to provide early liver transplant (ELT) for individuals with severe alcohol-associated liver disease (ALD), but the practice remains controversial. Using data collected from a nationally distributed survey, this study examines the practices and attitudes of transplant centers in the United States regarding ELT. Methods: A 20-item survey designed to assess center practices and provider attitudes was distributed to 225 medical and surgical directors from 143 liver transplant centers via email. Results: Surveys were completed by 28.9% (n = 65) of directors and 39% (n = 56) of transplant centers. All responding centers reported evaluating patients for ELT. Circumstances for considering ELT included <6 mo of survival without a transplant (96.4%) and inability to participate in alcohol addiction therapy pretransplant (75%). Most (66%) directors indicated their center had established criteria for listing candidates with severe ALD for ELT. Regarding important factors for ELT candidate listing, 57.1% indicated patient survival, 37.5% indicated graft survival, and 55.4% indicated having a low risk of relapse. Only 12.7% of directors affirmed the statement, "Six months of pretransplant abstinence decreases the risk of relapse." Conclusions: More centers are providing ELT for severe ALD. Inability to participate in alcohol addiction therapy and <6 mo of survival are commonly reported circumstances for considering ELT. Continued investigation of posttransplant outcomes in patients receiving ELT is essential to establishing a national consensus for distributing this valuable resource.

Entero-Urachal Fistula: An Unusual Initial Presentation of Penetrating and Stricturing Crohn's Disease.

Crohn's disease (CD) has a wide variety of clinical presentations, ranging from abdominal pain to stricture and fistula. Fistulas involving the genitourinary tract can be severe and often require surgical intervention. Given the array of presenting symptoms, a delay in diagnosis can occur. We present the case of a healthy active duty soldier, with no previous medical history, found to have CD through an initial presentation of isolated umbilical drainage. Imaging workup identified an entero-uracho-cutaneous fistula with involvement of the transverse colon. Urachal anomalies are uncommon, and entero-urachal fistula as an initial presentation of CD is exceedingly rare. This case highlights the need to consider CD in the differential for patients with umbilical drainage despite a lack of concurrent more frequent presenting symptoms (abdominal pain, bloody diarrhea, and perianal fistula). Maintaining awareness of uncommon initial presentations of CD can minimize delay in diagnosis and thereby mitigate the risk of severe complications.

Patient and Graft Survival After A1/A2-incompatible Living Donor Kidney Transplantation.

ABO type B and O kidney transplant candidates have increased difficulty identifying a compatible donor for living donor kidney transplantation (LDKT) and are harder to match in kidney paired donation registries. A2-incompatible (A2i) LDKT increases access to LDKT for these patients. To better inform living donor selection, we evaluated the association between A2i LDKT and patient and graft survival. Methods: We used weighted Cox regression to compare mortality, death-censored graft failure, and all-cause graft loss in A2i versus ABO-compatible (ABOc) recipients. Results: Using Scientific Registry of Transplant Recipients data 2000-2019, we identified 345 A2i LDKT recipients. Mortality was comparable among A2i and ABOc recipients; weighted 1-/5-/10-y mortality was 0.9%/6.5%/24.2%, respectively, among A2i LDKT recipients versus 1.4%/7.7%/22.2%, respectively, among ABOc LDKT recipients (weighted hazard ratio [wHR], 0.811.041.33; P = 0.8). However, A2i recipients faced higher risk of death-censored graft failure; weighted 1-/5-/10-y graft failure was 5.7%/11.6%/22.4% for A2i versus 1.7%/7.5%/17.2% for ABOc recipients (wHR in year 1 = 2.243.565.66; through year 5 = 1.251.782.53; through year 10 = 1.151.552.07). By comparison, 1-/5-/10-y wHRs for A1-incompatible recipients were 0.631.966.08/0.390.942.27/0.390.831.74. Conclusions: A2i LDKT is generally safe, but A2i donor/recipient pairs should be counseled about the increased risk of graft failure and be monitored as closely as their A1-incompatible counterparts posttransplant.

The Landscape of Nondirected Living Liver Donation in the United States.

BACKGROUND: Living donor liver transplants (LDLTs) including those from nondirected donors (NDDs) have increased during the past decade, and center-level variations in LDLTs have not yet been described. We sought to quantify changes in the volume of NDD transplants over time and variation in NDD volume between transplant centers. We further examined characteristics of living liver donors and identified factors potentially associated with receiving an NDD liver transplant. METHODS: Using Scientific Registry of Transplant Recipients data between March 01, 2002, and December 31, 2020, we compared 173 NDDs with 5704 DLDs and 167 NDD recipients with 1153 waitlist candidates. RESULTS: NDDs increased from 1 (0.4% of LDLTs) in 2002 to 58 (12% of LDLTs) in 2020. Of 150 transplant centers, 35 performed at least 1 NDD transplant. Compared with waitlist candidates, adult NDD recipients were less frequently males (39% versus 62%, P < 0.001), had a lower model for end-stage liver disease (16 versus 18, P = 0.01), and spent fewer days on the waitlist (173 versus 246, P = 0.02). Compared with waitlist candidates, pediatric NDD recipients were younger (50% versus 12% age <2 y, P < 0.001) and more often diagnosed with biliary atresia (66% versus 41%, P < 0.001). Compared with DLDs, NDDs were older (40 versus 35 y, P < 0.001), college educated (83% versus 64%, P < 0.001), White (92% versus 78%, P < 0.001), and more frequently donated left-lateral segment grafts (32.0% versus 14%, P < 0.001). CONCLUSIONS: Liver NDD transplants continue to expand but remain concentrated at a few centers. Graft distribution favors female adults and pediatric patients with biliary atresia. Racial inequities in adult or pediatric center-level NDD graft distribution were not observed.

Evaluation of Early vs Standard Liver Transplant for Alcohol-Associated Liver Disease.

Importance: Traditionally, liver transplant (LT) for alcohol-associated liver disease (ALD) requires 6 months of abstinence. Although early LT before 6 months of abstinence has been associated with decreased mortality for decompensated ALD, this practice remains controversial and concentrated at a few centers. Objective: To define patient, allograft, and relapse-free survival in early LT for ALD, and to investigate the association between these survival outcomes and early vs standard LT. Design, Setting, and Participants: This cohort study analyzed all patients with ALD who underwent their first LT at a single academic referral center between October 1, 2012, and November 13, 2020. Patients with known pretransplant hepatocellular carcinoma, hepatitis B or C, or an alternative cause of liver failure were excluded. Follow-up period was defined as the time from LT to the most recent encounter with a transplant center or death. Exposures: The exposure of interest was early LT, which was defined as less than 180 days of pre-LT abstinence. Standard LT was defined as 180 days or more of pre-LT abstinence. Patients were separated into early LT and standard LT by time from abstinence to LT. Main Outcomes and Measures: The outcomes were patient, allograft, relapse-free, and hazardous relapse-free survival for patients who underwent early LT or standard LT. These groups were compared by log-rank testing of Kaplan-Meier estimates. Hazardous relapse was defined as binge, at-risk, or frequent drinking. Abstinence was reassessed at the most recent follow-up visit for all patients. Results: Of the 163 patients with ALD included in this study, 88 (54%) underwent early LT and 75 (46%) underwent standard LT. This cohort had a mean (SD) age at transplant of 52 (10) years and was predominantly composed of 108 male patients (66%). Recipients of early LT vs standard LT were younger (median [interquartile range (IQR)] age, 49.7 [39.0-54.2] years vs 54.6 [48.7-60.0] years; P < .001) and had a higher median (IQR) Model for End-stage Liver Disease score at listing (35.0 [29.0-39.0] vs 20.0 [13.0-26.0]; P < .001). Both recipients of early LT and standard LT had similar 1-year patient survival (94.1% [95% CI, 86.3%-97.5%] vs 95.9% [95% CI, 87.8%-98.7%]; P = .60), allograft survival (92.7% [95% CI, 84.4%-96.7%] vs 90.5% [95% CI, 81.0%-95.3%]; P = .42), relapse-free survival (80.4% [95% CI, 69.1%-88.0%] vs 83.5% [95% CI, 72.2%-90.6%]; P = .41), and hazardous relapse-free survival (85.8% [95% CI, 75.1%-92.2%] vs 89.6% [95% CI, 79.5%-94.9%]; P = .41). Conclusions and Relevance: Adherence to the 6-month rule was not associated with superior patient survival, allograft survival, or relapse-free survival among selected patients. This finding suggests that patients with ALD should not be categorically excluded from LT solely on the basis of 6 months of abstinence, but rather alternative selection criteria should be identified that are based on need and posttransplant outcomes.

The uncharacterized SANT and BTB domain-containing protein SANBR inhibits class switch recombination.

Class switch recombination (CSR) is the process by which B cells switch production from IgM/IgD to other immunoglobulin isotypes, enabling them to mount an effective immune response against pathogens. Timely resolution of CSR prevents damage due to an uncontrolled and prolonged immune response. While many positive regulators of CSR have been described, negative regulators of CSR are relatively unknown. Using an shRNA library screen targeting more than 28,000 genes in a mouse B cell line, we have identified a novel, uncharacterized protein of 82kD (KIAA1841, NM_027860), which we have named SANBR (SANT and BTB domain regulator of CSR), as a negative regulator of CSR. The purified, recombinant BTB domain of SANBR exhibited characteristic properties such as homodimerization and interaction with corepressor proteins, including HDAC and SMRT. Overexpression of SANBR inhibited CSR in primary mouse splenic B cells, and inhibition of CSR is dependent on the BTB domain while the SANT domain is largely dispensable. Thus, we have identified a new member of the BTB family that serves as a negative regulator of CSR. Future investigations to identify transcriptional targets of SANBR in B cells will reveal further insights into the specific mechanisms by which SANBR regulates CSR as well as fundamental gene regulatory activities of this protein.

Recurrence and Complications in Pediatric and Adolescent Papillary Thyroid Cancer in a High-Volume Practice.

BACKGROUND: Treatment approaches for pediatric papillary thyroid cancer (PTC) are historically extrapolated from adult experience. However, pediatric PTC demonstrates a greater propensity for lymph node involvement, early metastases, and recurrence, highlighting the need for pediatric-specific treatment paradigms. MATERIALS AND METHODS: A retrospective review included patients with PTC aged ≤21 y, with ≥18 mo of follow-up, treated between 2002 and 2015. Fisher's exact test and Cox proportional hazard were used to estimate the effect of risk factors on disease recurrence. RESULTS: Seventy-two cases of PTC were identified with median age of 17.0 y and median follow-up of 64.1 mo. Disease recurred at a median of 24.6 mo (range 7.8-78.1) in 7 of 51 (13.7%) of patients with disease limited to the thyroid or central neck, 7 of 18 (39%) patients with lateral neck disease at presentation who underwent a compartment-based resection, and three of three patients (100%) with lateral neck disease who sought care after non-compartment-based resection. There were no deaths from disease. Univariate predictors of recurrence included tumor size >2 cm (P = 0.005), lateral neck disease (P = 0.004), lymphovascular invasion (P = 0.017), extracapsular invasion (P < 0.0001), multifocality (P = 0.03), and non-Caucasian race (P = 0.05). Multivariate analysis identified race (P = 0.05) as an independent predictor of recurrence. In patients without lateral neck disease, there was a trend toward lower recurrence in patients undergoing thyroidectomy with central neck dissection compared with thyroidectomy alone (P = 0.07). CONCLUSIONS: Pediatric PTC is associated with excellent survival, although recurrence is common in patients with lateral node involvement. Predictors of recurrence are multifactorial and may be influenced by extent of disease, patient or tumor biology, and aggressiveness of resection. LEVEL OF EVIDENCE: Prognosis study, level IV, retrospective case series.

A novel near-peer reflective writing workshop.

BACKGROUND: Training in clinical medicine involves exposure to complex ethical and emotional situations. Reflection aids in the development of personal belief systems and improves self-awareness. Students may be reluctant to participate when reflection is mandatory and may be concerned about retaliation when the facilitator has a role in evaluations. Near-peers are institutional equals with more experience than the participants and may be well suited to facilitate reflection. METHODS: A quarterly near-peer-facilitated reflective writing workshop (RWW) was implemented in the mandatory clinical curriculum at a single institution. Qualitative feedback forms were solicited and were analysed through an iterative and inductive consensus process. An end-of-year web-based survey was distributed to test the hypotheses generated from our analysis of the feedback forms. RESULTS: There were 82 responses (80%) to the web-based survey and 266 (65%) feedback forms were collected. Although few students reported using writing as a coping mechanism, the RWW was viewed favourably, with 62% indicating that they would attend if optional. The structured prompts aided reflection. Students reported a higher likelihood of discussing difficult topics (doubts about medicine as a career, personal shortcomings, harassment and burnout) in sessions led by a near-peer than by a faculty member. The workshop created a safe space to reflect, increased a sense of camaraderie and helped normalise experiences. [The workshop] humanised the clinical experience, gave new perspective and reminded students of their positive personal accomplishments DISCUSSION: The near-peer-facilitated RWW is a novel intervention aimed at developing reflective practice and coping with the challenges of entering clinical medicine. It is highly structured and has been incorporated into the mandatory curriculum. It was well received by students, is generalisable and is easily implementable.

Military Medicine and the Academic Surgery Gender Gap.

INTRODUCTION: Gender disparity in academic medicine has been well described in the civilian sector. This has not yet been evaluated in the military health system where hundreds of female surgeons are practicing. Military service limits factors such as part time work and control over time spent away from family, which are often cited as contributors to the pay and promotion gap in civilian academic medicine. The military has explicit policies to limit discrimination based on gender. Pay between men and women is equal as it is based on rank and time in rank. One would expect to see less disparity in promotion through the academic ranks for military female surgeons given this otherwise equal treatment. This has not previously been objectively tracked or reported. It is beneficial to characterize the military academic medicine gender gap and benchmark against national data to define the academic gender gap and lay the groundwork for future work to identify factors contributing to the observed difference. MATERIAL AND METHODS: This study was granted exemption from the Walter Reed National Military Medical Center (WRNMMC) Internal Review Board (IRB). The Uniformed Services University (USU) Department of Surgery academic appointment list was reviewed to assess female representation in the categories of Instructor, Assistant Professor, Associate Professor, Professor, and Other. Defense Manpower Data Center (DMDC) and the US Navy Bureau of Medicine and Surgery (BUMED) were assessed for total numbers of female surgeons on active duty, and numbers were compared with nationally published Association of American Medical Colleges (AAMC) data using a logistic regression model. RESULTS: There was a higher proportion of women in academic positions in the civilian cohort than in the military cohort (OR: 1.84; CI: 1.53-2.21, p < .0001). This difference was observed at every level of academic achievement. A higher percentage of women were observed at lower levels of professorship than at higher levels; instructors were more likely to be women than assistant professor (OR: 1.44, CI:1.16-1.79), associate professor (OR: 2.24, CI: 1.77-2.84), or full professor (OR:4.61, CI: 3.57-5.94). CONCLUSIONS: Fewer female surgeons in military medicine hold academic appointment when compared with their counterparts in civilian medicine. Similar to the civilian sector, military academic surgery also demonstrates less likelihood of female representation in higher academic stations. This discrepancy in representation follows a linear trend over the different ranks. This discrepancy has not been previously documented. The military offers a unique opportunity to study the issue of gender imbalance in academic promotion practices given its otherwise equal treatment of males and females. Additional studies will be necessary to understand uniformed female surgeons' barriers to academic advancement.

Lymph node ratio predicts recurrence in pediatric papillary thyroid cancer.

BACKGROUND: Regional lymph node (LN) metastasis at the time of presentation plays a significant role in predicting recurrence in patients with papillary thyroid cancer (PTC). Multiple studies in the adult population have demonstrated that the lymph node ratio (LNR) in both the central and lateral neck can improve the accuracy of recurrence prediction, but this ratio has not been studied in the pediatric population. In this study, we sought to investigate the LNR in the central and lateral compartments as a prognostic predictor for recurrence in pediatric patients with PTC. METHODS: A retrospective analysis of pediatric patients (≤21 years old) at a single institution between 2002 and 2014 who underwent total thyroidectomy with prophylactic central neck dissection (TTpCND) with at least 3 sampled nodes or total thyroidectomy with unilateral modified radical neck dissection (TTMRND) with at least 10 sampled nodes, and on whom at least 24 months of follow up data were available was performed. The LNR was defined as the ratio of metastatic LNs to total number of investigated LNs. Recurrence after TTpCND and TTMRND was examined separately as a function of LNR, using the value of 0.45 as a cutoff. RESULTS: Forty-eight patients met inclusion criteria. Thirty-two underwent TTpCND, and sixteen underwent TTMRND. Median age at time of operation was 17 years (range 6-20), and median duration of follow-up was 53.5 months (range 24-183). In the TTpCND, LNR ranged from 0 to 1.0. There were two recurrences among the eight patients (25%) undergoing TTpCND in patients with LNRs >0.45 and a single recurrence among the 24 patients (4.2%) undergoing TTpCND with an LNR ≤0.45. In the TTMRND, LNR ranged from 0.1 to 1.0. There were 3 recurrences in 12 patients with LNR ≤0.45 (30.8%%) and 4 recurrences in 4 patients with LNR >0.45 (100%) (p = 0.03). CONCLUSIONS: Although limited by small sample size, LNR may be a useful predictor to stratify the likelihood of recurrence in pediatric patients undergoing TTpCND or TTMRND for pathologic N1a or N1b PTC. TYPE OF STUDY: Prognosis study / retrospective case series. LEVEL OF EVIDENCE: Level IV.

A DNA break- and phosphorylation-dependent positive feedback loop promotes immunoglobulin class-switch recombination.

The ability of activation-induced cytidine deaminase (AID) to efficiently mediate class-switch recombination (CSR) is dependent on its phosphorylation at Ser38; however, the trigger that induces AID phosphorylation and the mechanism by which phosphorylated AID drives CSR have not been elucidated. Here we found that phosphorylation of AID at Ser38 was induced by DNA breaks. Conversely, in the absence of AID phosphorylation, DNA breaks were not efficiently generated at switch (S) regions in the immunoglobulin heavy-chain locus (Igh), consistent with a failure of AID to interact with the endonuclease APE1. Additionally, deficiency in the DNA-damage sensor ATM impaired the phosphorylation of AID at Ser38 and the interaction of AID with APE1. Our results identify a positive feedback loop for the amplification of DNA breaks at S regions through the phosphorylation- and ATM-dependent interaction of AID with APE1.