AID in non-Hodgkin B-cell lymphomas: The consequences of on- and off-target activity.

Activation induced cytidine deaminase (AID) is a key element of the adaptive immune system, required for immunoglobulin isotype switching and affinity maturation of B-cells as they undergo the germinal center (GC) reaction in peripheral lymphoid tissue. The inherent DNA damaging activity of this enzyme can also have off-target effects in B-cells, producing lymphomagenic chromosomal translocations that are characteristic features of various classes of non-Hodgkin B-cell lymphoma (B-NHL), and generating oncogenic mutations, so-called aberrant somatic hypermutation (aSHM). Additionally, AID has been found to affect gene expression through demethylation as well as altered interactions between gene regulatory elements. These changes have been most thoroughly studied in B-NHL arising from GC B-cells. Here, we describe the most common classes of GC-derived B-NHL and explore the consequences of on- and off-target AID activity in B and plasma cell neoplasms. The relationships between AID expression, including effects of infection and other exposures/agents, mutagenic activity and lymphoma biology are also discussed.

Large variation in radiation dose for routine abdomen CT: reasons for excess and easy tips for reduction.

OBJECTIVE: To characterize the use and impact of radiation dose reduction techniques in actual practice for routine abdomen CT. METHODS: We retrospectively analyzed consecutive routine abdomen CT scans in adults from a large dose registry, contributed by 95 hospitals and imaging facilities. Grouping exams into deciles by, first, patient size, and second, size-adjusted dose length product (DLP), we summarized dose and technical parameters and estimated which parameters contributed most to between-protocols dose variation. Lastly, we modeled the total population dose if all protocols with mean size-adjusted DLP above 433 or 645 mGy-cm were reduced to these thresholds. RESULTS: A total of 748,846 CTs were performed using 1033 unique protocols. When sorted by patient size, patients with larger abdominal diameters had increased dose and effective mAs (milliampere seconds), even after adjusting for patient size. When sorted by size-adjusted dose, patients in the highest versus the lowest decile in size-adjusted DLP received 6.4 times the average dose (1680 vs 265 mGy-cm) even though diameter was no different (312 vs 309 mm). Effective mAs was 2.1-fold higher, unadjusted CTDIvol 2.9-fold, and phase 2.5-fold for patients in the highest versus lowest size-adjusted DLP decile. There was virtually no change in kV (kilovolt). Automatic exposure control was widely used to modulate mAs, whereas kV modulation was rare. Phase was the strongest driver of between-protocols variation. Broad adoption of optimized protocols could result in total population dose reductions of 18.6-40%. CONCLUSION: There are large variations in radiation doses for routine abdomen CT unrelated to patient size. Modification of kV and single-phase scanning could result in substantial dose reduction. CLINICAL RELEVANCE: Radiation dose-optimization techniques for routine abdomen CT are routinely under-utilized leading to higher doses than needed. Greater modification of technical parameters and number of phases could result in substantial reduction in radiation exposure to patients. KEY POINTS: • Based on an analysis of 748,846 routine abdomen CT scans in adults, radiation doses varied tremendously across patients of the same size and optimization techniques were routinely under-utilized. • The difference in observed dose was due to variation in technical parameters and phase count. Automatic exposure control was commonly used to modify effective mAs, whereas kV was rarely adjusted for patient size. Routine abdomen CT should be performed using a single phase, yet multi-phase was common. • kV modulation by patient size and restriction to a single phase for routine abdomen indications could result in substantial reduction in radiation doses using well-established dose optimization approaches.

Financial Toxicity in Breast Implant-Associated Anaplastic Large Cell Lymphoma.

BACKGROUND: Financial toxicity is a growing concern due to its considerable effects on medical adherence, quality of life, and mortality. The cost associated with breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is substantial from diagnosis to treatment, including adjuvant therapy and surgery. This study aims to assess the prevalence of financial toxicity in BIA-ALCL patients. METHODS: We performed a cross-sectional, survey-based study on women with confirmed cases of BIA-ALCL from December 2019 to March 2023. The primary study outcomes were financial toxicity measured by Comprehensive Score for Financial Toxicity (COST) score and patient-reported financial burden measured by the responses to the Evaluation of the Financial Impact of BIA-ALCL survey. Lower COST scores signify higher financial toxicity. Responses were linked to patient data extracted from the medical records. RESULTS: Thirty-two women treated for confirmed BIA-ALCL were included. Patients were all White and were diagnosed at a median age of 51 years (range, 41-65 years). The mean COST score was 27.9 ± 2.23. Lower COST scores were associated with receipt of radiotherapy ( P = 0.033), exceeding credit card limits ( P = 0.036), living paycheck to paycheck ( P = 0.00027), requiring financial support from friends and family ( P = 0.00044), and instability in household finances ( P = 0.034). CONCLUSIONS: Financial toxicity is prevalent in BIA-ALCL patients and has a substantial impact on patient reported burden. Insurance denial is frequent for patients with a prior history of cosmetic augmentation. Risk assessments and cost discussions should occur throughout the care continuum to minimize financial burden.

Clinical Utility and Reimbursement of Next-Generation Sequencing-Based Testing for Myeloid Malignancies.

Next-generation sequencing is becoming increasingly important for the diagnosis, risk stratification, and management of patients with established or suspected myeloid malignancies. These tests are being incorporated into clinical practice guidelines and many genetic alterations now constitute disease classification criteria. However, the reimbursement for these tests is uncertain. This study analyzed the clinical impact, ordering practices, prior authorization, and reimbursement outcomes of 505 samples from 477 patients sequenced with a 50-gene myeloid next-generation sequencing panel or a 15-gene myeloproliferative neoplasm subpanel. Overall, 98% (496 of 505) of tests provided clinically useful data. Eighty-nine percent of test results, including negative findings, informed or clarified potential diagnoses, 94% of results informed potential prognoses, and 19% of tests identified a potential therapeutic target. Sequencing results helped risk-stratify patients whose bone marrow biopsy specimens were inconclusive for dysplasia, monitor genetic evolution associated with disease progression, and delineate patients with mutation-defined diagnoses. Despite the clinical value, prior authorization from commercial payors or managed government payors was approved for less than half (45%) of requests. Only 51% of all cases were reimbursed, with lack of medical necessity frequently cited as a reason for denial. This study demonstrates the existence of a substantial gap between clinical utility and payor policies on test reimbursement.

Noncoding mutations cause super-enhancer retargeting resulting in protein synthesis dysregulation during B cell lymphoma progression.

Whole-genome sequencing of longitudinal tumor pairs representing transformation of follicular lymphoma to high-grade B cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma) identified coding and noncoding genomic alterations acquired during lymphoma progression. Many of these transformation-associated alterations recurrently and focally occur at topologically associating domain resident regulatory DNA elements, including H3K4me3 promoter marks located within H3K27ac super-enhancer clusters in B cell non-Hodgkin lymphoma. One region found to undergo recurrent alteration upon transformation overlaps a super-enhancer affecting the expression of the PAX5/ZCCHC7 gene pair. ZCCHC7 encodes a subunit of the Trf4/5-Air1/2-Mtr4 polyadenylation-like complex and demonstrated copy number gain, chromosomal translocation and enhancer retargeting-mediated transcriptional upregulation upon lymphoma transformation. Consequently, lymphoma cells demonstrate nucleolar dysregulation via altered noncoding 5.8S ribosomal RNA processing. We find that a noncoding mutation acquired during lymphoma progression affects noncoding rRNA processing, thereby rewiring protein synthesis leading to oncogenic changes in the lymphoma proteome.

Modern Approaches to Breast Neurotization.

Absent or diminished breast sensation is a persistent problem for many postmastectomy patients. Breast neurotization is an opportunity to improve sensory outcomes, which are poor and unpredictable if left to chance. Several techniques for autologous and implant reconstruction have been described with successful clinical and patient-reported outcomes. Neurotization is a safe procedure with minimal risk for morbidity and it presents a fantastic avenue for future research.

Correlation between Relative Value Units and Operative Time for Flap-Based Reconstruction Procedures.

BACKGROUND: Procedures performed by plastic surgeons tend to generate lower work relative value units (RVUs) compared to other surgical specialties despite their major contributions to hospital revenue. The authors aimed to compare work RVUs allocated to all free flap and pedicled flap reconstruction procedures based on their associated median operative times and discuss implications of these compensation disparities. METHODS: A retrospective analysis of deidentified patient data from the American College of Surgeons National Surgical Quality Improvement Program was performed, and relevant CPT codes for flap-based reconstruction were identified from 2011 to 2018. RVU data were assessed using the 2020 National Physician Fee Schedule Relative Value File. The work RVU per unit time was calculated using the median operative time for each procedure. RESULTS: A total of 3991 procedures were included in analysis. With increased operative time and surgical complexity, work RVU per minute trended downward. Free-fascial flaps with microvascular anastomosis generated the highest work RVUs per minute among all free flaps (0.114 work RVU/minute). Free-muscle/myocutaneous flap reconstruction generated the least work RVUs per minute (0.0877 work RVU/minute) among all flap reconstruction procedures. CONCLUSIONS: Longer operative procedures for flap-based reconstruction were designated with higher work RVU. Surgeons were reimbursed less per operative unit time for these surgical procedures, however. Specifically, free flaps resulted in reduced compensation in work RVUs per minute compared to pedicled flaps, except in breast reconstruction. More challenging operations have surprisingly resulted in lower compensation, demonstrating the inequalities in reimbursement within and between surgical specialties. Plastic surgeons should be aware of these discrepancies to appropriately advocate for themselves.

Clavicular reconstruction utilizing free fibula flap with periosteal extension.

Clavicular reconstruction is typically managed conservatively. Despite demonstrating improving outcomes, including range of motion and pain, there are currently no published reports of acute reconstruction with vascularized free fibula flaps (VFFF) or vascularized periosteal extensions in adult patients with clavicular defects. VFFFs have been utilized to correct critical bony defects of the clavicle and chronic nonunions; however, descriptions following acute trauma are rare. Bony union enhancement with periosteal extension has been described in both pediatric and adult populations, but never in the case of clavicular reconstruction. Herein, we seek to fill this gap in the literature by describing the acute reconstruction of a 6.5 cm bony gap in a 29-year-old male following a gunshot wound to the chest, utilizing a 6.5 cm VFFF with periosteal extension, and inset to the internal mammary vessels. The postoperative course was uncomplicated, with bony consolidation noted by 10 weeks, and full, pain-free range of motion at 8 months, showing this technique may be a viable option following acute trauma.

Patient Radiation Doses in IR Procedures: The American College of Radiology Dose Index Registry-Fluoroscopy Pilot.

PURPOSE: To update normative data on fluoroscopy dose indices in the United States for the first time since the Radiation Doses in Interventional Radiology study in the late 1990s. MATERIALS AND METHODS: The Dose Index Registry-Fluoroscopy pilot study collected data from March 2018 through December 2019, with 50 fluoroscopes from 10 sites submitting data. Primary radiation dose indices including fluoroscopy time (FT), cumulative air kerma (Ka,r), and kerma area product (PKA) were collected for interventional radiology fluoroscopically guided interventional (FGI) procedures. Clinical facility procedure names were mapped to the American College of Radiology (ACR) common procedure lexicon. Distribution parameters including the 10th, 25th, 50th, 75th, 95th, and 99th percentiles were computed. RESULTS: Dose indices were collected for 70,377 FGI procedures, with 50,501 ultimately eligible for analysis. Distribution parameters are reported for 100 ACR Common IDs. FT in minutes, Ka,r in mGy, and PKA in Gy-cm2 are reported in this study as (n; median) for select ACR Common IDs: inferior vena cava filter insertion (1,726; FT: 2.9; Ka,r: 55.8; PKA: 14.19); inferior vena cava filter removal (464; FT: 5.7; Ka,r: 178.6; PKA: 34.73); nephrostomy placement (2,037; FT: 4.1; Ka,r: 39.2; PKA: 6.61); percutaneous biliary drainage (952; FT: 12.4; Ka,r: 160.5; PKA: 21.32); gastrostomy placement (1,643; FT: 3.2; Ka,r: 29.1; PKA: 7.29); and transjugular intrahepatic portosystemic shunt placement (327; FT: 34.8; Ka,r: 813.0; PKA: 181.47). CONCLUSIONS: The ACR DIR-Fluoro pilot has provided state-of-the-practice statistics for radiation dose indices from IR FGI procedures. These data can be used to prioritize procedures for radiation optimization, as demonstrated in this work.

Patient Radiation Doses in Interventional Radiology Procedures: Comparison of Fluoroscopy Dose Indices between the American College of Radiology Dose Index Registry-Fluoroscopy Pilot and the Radiation Doses in Interventional Radiology Study.

PURPOSE: To compare radiation dose index distributions for fluoroscopically guided interventions in interventional radiology from the American College of Radiology (ACR) Fluoroscopy Dose Index Registry (DIR-Fluoro) pilot to those from the Radiation Doses in Interventional Radiology (RAD-IR) study. MATERIALS AND METHODS: Individual and grouped ACR Common identification numbers (procedure types) from the DIR-Fluoro pilot were matched to procedure types in the RAD-IR study. Fifteen comparisons were made. Distribution parameters, including the 10th, 25th, 50th, 75th, and 95th percentiles, were compared for fluoroscopy time (FT), cumulative air kerma (Ka,r), and kerma area product (PKA). Two derived indices were computed using median dose indices. The procedure-averaged reference air kerma rate (Ka,r¯) was computed as Ka,r / FT. The procedure-averaged x-ray field size at the reference point (Ar) was computed as PKA / (Ka,r × 1,000). RESULTS: The median FT was equally likely to be higher or lower in the DIR-Fluoro pilot as it was in the RAD-IR study, whereas the maximum FT was almost twice as likely to be higher in the DIR-Fluoro pilot than it was in the RAD-IR study. The median Ka,r was lower in the DIR-Fluoro pilot for all procedures, as was median PKA. The maximum Ka,r and PKA were more often higher in the DIR-Fluoro pilot than in the RAD-IR study. Ka,r¯ followed the same pattern as Ka,r, whereas Ar was often greater in DIR-Fluoro. CONCLUSIONS: The median dose indices have decreased since the RAD-IR study. The typical Ka,r rates are lower, a result of the use of lower default dose rates. However, opportunities for quality improvement exist, including renewed focus on tight collimation of the imaging field of view.

Variation in Antibiotic Treatment Failure Outcome Definitions in Randomised Trials and Observational Studies of Antibiotic Prescribing Strategies: A Systematic Review and Narrative Synthesis.

Antibiotic treatment failure is used as an outcome in randomised trials and observational studies of antibiotic treatment strategies and may comprise different events that indicate failure to achieve a desired clinical response. However, the lack of a universally recognised definition has led to considerable variation in the types of events included. We undertook a systematic review of published studies investigating antibiotic treatment strategies for common uncomplicated infections, aiming to describe variation in terminology and components of the antibiotic treatment failure outcomes. We searched Medline, Embase, and the Cochrane Central Register of Clinical trials for English language studies published between January 2010 and January 2021. The population of interest was ambulatory patients seen in primary care or outpatient settings with respiratory tract (RTI), urinary tract (UTI), or skin and soft tissue infection (SSTI), where different antibiotic prescribing strategies were compared, and the outcome was antibiotic treatment failure. We narratively summarised key features from eligible studies and used frequencies and proportions to describe terminology, components, and time periods used to ascertain antibiotic treatment failure outcomes. Database searches identified 2967 unique records, from which 36 studies met our inclusion criteria. This included 10 randomised controlled trials and 26 observational studies, with 20 studies of RTI, 12 of UTI, 4 of SSTI, and 2 of both RTI and SSTI. We identified three key components of treatment failure definitions: prescription changes, escalation of care, and change in clinical condition. Prescription changes were most popular in studies of UTI, while changes in clinical condition were most common in RTI and SSTI studies. We found substantial variation in the definition of antibiotic treatment failure in included studies, even amongst studies of the same infection subtype and study design. Considerable further work is needed to develop a standardised definition of antibiotic treatment failure in partnership with patients, clinicians, and relevant stakeholders.

A Novel Technique for Muscle Flap Preservation in Posterolateral Muscle-Sparing Thoracotomy.

SUMMARY: The muscle-sparing thoracotomy offers several benefits over the traditional posterolateral thoracotomy approach for surgically accessing the chest cavity. Some of the potential advantages of preserving the latissimus dorsi and serratus anterior muscles include both functional benefits and potential use of these muscles for future flap reconstruction. Nevertheless, the muscle-sparing thoracotomy technique has traditionally been described with a wide exposure and, as a result, a theoretically higher risk of seroma and hematoma formation due to the increased dead space. The authors propose a new approach to muscle-sparing thoracotomy to avoid the disadvantages of each technique. By defining two subcutaneous anatomical triangles that can be safely lifted without disrupting the latissimus dorsi and serratus anterior muscles' blood supply, this novel approach provides good exposure, preserves muscle flaps for future use, and minimizes dead space. As a result, this novel muscle-sparing thoracotomy technique has the potential to minimize postoperative complications and maximize patient outcomes.

Phenogenomic heterogeneity of post-transplant plasmablastic lymphomas.

Plasmablastic lymphoma (PBL) is a rare and clinically aggressive neoplasm that typically occurs in immunocompromised individuals, including those with HIV infection and solid organ allograft recipients. Most prior studies have focused on delineating the clinicopathologic features and genetic attributes of HIV-related PBLs, where MYC deregulation and EBV infection, and more recently, mutations in JAK/STAT, MAP kinase, and NOTCH pathway genes have been implicated in disease pathogenesis. The phenotypic spectrum of post-transplant (PT)-PBLs is not well characterized and data on underlying genetic alterations are limited. Hence, we performed comprehensive histopathologic and immunophenotypic evaluation and targeted sequencing of 18 samples from 11 patients (8 males, 3 females, age range 12-76 years) with PT-PBL; 8 de novo and 3 preceded by other types of PTLDs. PT-PBLs displayed morphologic and immunophenotypic heterogeneity and some features overlapped those of plasmablastic myeloma. Six (55%) cases were EBV+ and 5 (45%) showed MYC rearrangement by fluorescence in situ hybridization. Recurrent mutations in epigenetic regulators (KMT2/MLL family, TET2) and DNA damage repair and response (TP53, mismatch repair genes, FANCA, ATRX), MAP kinase (KRAS, NRAS, HRAS, BRAF), JAK/STAT (STAT3, STAT6, SOCS1), NOTCH (NOTCH1, NOTCH3, SPEN), and immune surveillance (FAS, CD58) pathway genes were observed, with EBV+ and EBV- cases exhibiting similarities and differences in their mutational profiles. Clinical outcomes also varied, with survival ranging from 0-15.9 years postdiagnosis. Besides uncovering the biological heterogeneity of PT-PBL, our study highlights similarities and distinctions between PT-PBLs and PBLs occurring in other settings and reveals potentially targetable oncogenic pathways in disease subsets.

Diagnostic reference levels and median doses for common clinical indications of CT: findings from an international registry.

OB JECTIVES: The European Society of Radiology identified 10 common indications for computed tomography (CT) as part of the European Study on Clinical Diagnostic Reference Levels (DRLs, EUCLID), to help standardize radiation doses. The objective of this study is to generate DRLs and median doses for these indications using data from the UCSF CT International Dose Registry. METHODS: Standardized data on 3.7 million CTs in adults were collected between 2016 and 2019 from 161 institutions across seven countries (United States of America (US), Switzerland, Netherlands, Germany, UK, Israel, Japan). DRLs (75th percentile) and median doses for volumetric CT-dose index (CTDIvol) and dose-length product (DLP) were assessed for each EUCLID category (chronic sinusitis, stroke, cervical spine trauma, coronary calcium scoring, lung cancer, pulmonary embolism, coronary CT angiography, hepatocellular carcinoma (HCC), colic/abdominal pain, appendicitis), and US radiation doses were compared with European. RESULTS: The number of CT scans within EUCLID categories ranged from 8,933 (HCC) to over 1.2 million (stroke). There was greater variation in dose between categories than within categories (p < .001), and doses were significantly different between categories within anatomic areas. DRLs and median doses were assessed for all categories. DRLs were higher in the US for 9 of the 10 indications (except chronic sinusitis) than in Europe but with a significantly higher sample size in the US. CONCLUSIONS: DRLs for CTDIvol and DLP for EUCLID clinical indications from diverse organizations were established and can contribute to dose optimization. These values were usually significantly higher in the US than in Europe. KEY POINTS: • Registry data were used to create benchmarks for 10 common indications for CT identified by the European Society of Radiology. • Observed US radiation doses were higher than European for 9 of 10 indications (except chronic sinusitis). • The presented diagnostic reference levels and median doses highlight potentially unnecessary variation in radiation dose.

Vascularized Scapular Bone Grafting: Indications, Techniques, Clinical Outcomes, and Alternatives.

Spinal fusion can be challenging to obtain in patients with complex spinal pathology. Medial scapular vascularized bone grafts (S-VBGs) are a novel approach to supplement cervicothoracic arthrodesis in patients at high risk of failed spinal fusion. In this article, we discuss the benefits of using VBGs compared with both nonvascularized bone grafts and free vascularized bone flaps and the surgical technique, feasibility, and limitations specific to the S-VBG.

Safety Considerations of Fat Grafting in Buttock Augmentation.

Autologous fat grafting for buttock augmentation is one of the fastest growing plastic surgery procedures, but has also received significant publicity for the relatively high mortality rate secondary to fat emboli. The literature has grown exponentially in the past 5 years on this subject, helping to clarify our knowledge and providing recommendations to minimize risks, including avoiding intramuscular injections, placing the patient in the jackknife position, and utilizing larger-bore cannulas. Since the application of these recommendations, the rate of pulmonary fat embolism has decreased from 0.097% to 0.04%, with a current mortality of 1 in 14,921, making it statistically safer than abdominoplasty. Despite the evolution in our knowledge, techniques, and outcomes, it remains of utmost importance to properly select and educate patients about the safety of fat grafting for buttock augmentation. Level of Evidence: 4.

Modifiable factors and their association with self-reported knee function and activity after anterior cruciate ligament reconstruction: a systematic review and meta-analysis.

OBJECTIVE: To determine if body mass index (BMI), smoking status, prehabilitation or time to reconstruction are associated with recovery of self-reported knee function and activity after ACL reconstruction (ACLR). DATA SOURCES: Four electronic databases were systematically searched. STUDY SELECTION: English language articles were included if: (1) participants aged 16-70 years had primary or first revision ACLR with autograft, following complete rupture; and (2) the association between one of four modifiable factors: (1) BMI; (2) smoking; (3) prehabilitation; or (4) time to reconstruction with self-reported knee function and activity, ACL graft rupture or return to sport was evaluated. RESULTS: Twelve articles (representing 11 studies) were included. Meta-analyses found low-quality evidence of no difference in self-reported knee function (d = -0.07, 95% CI -0.37 to 0.23, I2 = 0%) or activity levels (d = 0.11, 95% CI -0.2 to 0.41, I2 = 0%) between acute and subacute ACLR. There was no difference in the relative risk of ACL graft rupture with the timing of ACLR (one study). Meta-analysis demonstrated very low-quality evidence that smokers had worse self-reported functional outcomes after ACLR compared to non-smokers (d = -0.58, 95% CI -0.788 to -0.28, I2 = 59%). One study suggested an inverse relationship between BMI and knee-related quality of life after ACLR. One RCT suggested prehabilitation may reduce time to return to sport. CONCLUSION: Low-quality evidence suggests there is no difference in delaying ACLR and very low-quality evidence suggests smokers have worse self-reported functional outcome after ACLR compared to non-smokers. High-quality RCTs are needed to confirm the relationship between the four modifiable factors studied and ACLR outcome.