Obesity, dyslipidemia, and cardiovascular disease: A joint expert review from the Obesity Medicine Association and the National Lipid Association 2024.

BACKGROUND: This joint expert review by the Obesity Medicine Association (OMA) and National Lipid Association (NLA) provides clinicians an overview of the pathophysiologic and clinical considerations regarding obesity, dyslipidemia, and cardiovascular disease (CVD) risk. METHODS: This joint expert review is based upon scientific evidence, clinical perspectives of the authors, and peer review by the OMA and NLA leadership. RESULTS: Among individuals with obesity, adipose tissue may store over 50% of the total body free cholesterol. Triglycerides may represent up to 99% of lipid species in adipose tissue. The potential for adipose tissue expansion accounts for the greatest weight variance among most individuals, with percent body fat ranging from less than 5% to over 60%. While population studies suggest a modest increase in blood low-density lipoprotein cholesterol (LDL-C) levels with excess adiposity, the adiposopathic dyslipidemia pattern most often described with an increase in adiposity includes elevated triglycerides, reduced high density lipoprotein cholesterol (HDL-C), increased non-HDL-C, elevated apolipoprotein B, increased LDL particle concentration, and increased small, dense LDL particles. CONCLUSIONS: Obesity increases CVD risk, at least partially due to promotion of an adiposopathic, atherogenic lipid profile. Obesity also worsens other cardiometabolic risk factors. Among patients with obesity, interventions that reduce body weight and improve CVD outcomes are generally associated with improved lipid levels. Given the modest improvement in blood LDL-C with weight reduction in patients with overweight or obesity, early interventions to treat both excess adiposity and elevated atherogenic cholesterol (LDL-C and/or non-HDL-C) levels represent priorities in reducing the risk of CVD.

Dietary nitrate intake and net nitrite-generating capacity of the oral microbiome interact to enhance cardiometabolic health: Results from the Oral Infections Glucose Intolerance and Insulin Resistance Study (ORIGINS).

Background: We investigated the association between dietary nitrate intake and early clinical cardiometabolic risk biomarkers, and explored whether the oral microbiome modifies the association between dietary nitrate intake and cardiometabolic biomarkers. Methods: Cross-sectional data from 668 (mean [SD] age 31 [9] years, 73% women) participants was analyzed. Dietary nitrate intakes and alternative healthy eating index (AHEI) scores were calculated from food frequency questionnaire responses and a validated US food database. Subgingival 16S rRNA microbial genes (Illumina, MiSeq) were sequenced, and PICRUSt2 estimated metagenomic content. The Microbiome Induced Nitric oxide Enrichment Score (MINES) was calculated as a microbial gene abundance ratio representing enhanced net capacity for NO generation. Cardiometabolic risk biomarkers included systolic and diastolic blood pressure, HbA1c, glucose, insulin, and insulin resistance (HOMA-IR), and were regressed on nitrate intake tertiles in adjusted multivariable linear models. Results: Mean nitrate intake was 190[171] mg/day. Higher nitrate intake was associated with lower insulin, and HOMA-IR but particularly among participants with low abundance of oral nitrite enriching bacteria. For example, among participants with a low MINES, mean insulin[95%CI] levels in high vs. low dietary nitrate consumers were 5.8[5.3,6.5] vs. 6.8[6.2,7.5] (p=0.004) while respective insulin levels were 6.0[5.4,6.6] vs. 5.9[5.3,6.5] (p=0.76) among partcipants with high MINES (interaction p=0.02). Conclusion: Higher dietary nitrate intake was only associated with lower insulin and insulin resistance among individuals with reduced capacity for oral microbe-induced nitrite enrichment. These findings have implications for future precision medicine-oriented approaches that might consider assessing the oral microbiome prior to enrollment into dietary interventions or making dietary recommendations. Clinical Perspective: What is new?: In this population-based study we identified an interaction between dietary nitrate intake and oral nitrite enriching bacteria on cardiometabolic outcomes. Higher dietary nitrate intake was associated with lower insulin and insulin resistance only among participants with low abundance of oral nitrite enriching bacteria. This study suggests that cardiometabolic benefits of nitrate consumption might depend on the host microbiome's capacity to metabolize nitrates.What are the clinical implications?: Among people with low microbiome capacity for nitrate metabolism, higher levels of nitrate might be necessary to realize cardiometabolic benefits.Lack of microbiome assessments in prior studies could partially explain inconsistent findings from previous nitrate supplementation trials and observational studies.Future precision-medicine oriented trials studying the effects of dietary nitrate recommendations on cardiometabolic health, should consider assessing the oral microbiome.

20-year depressive symptoms, dementia, and structural neuropathology in older women.

INTRODUCTION: The course of depressive symptoms and dementia risk is unclear, as are potential structural neuropathological common causes. METHODS: Utilizing joint latent class mixture models, we identified longitudinal trajectories of annually assessed depressive symptoms and dementia risk over 21 years in 957 older women (baseline age 72.7 years old) from the Women's Health Initiative Memory Study. In a subsample of 569 women who underwent structural magnetic resonance imaging, we examined whether estimates of cerebrovascular disease and Alzheimer's disease (AD)-related neurodegeneration were associated with identified trajectories. RESULTS: Five trajectories of depressive symptoms and dementia risk were identified. Compared to women with minimal symptoms, women who reported mild and stable and emerging depressive symptoms were at the highest risk of developing dementia and had more cerebrovascular disease and AD-related neurodegeneration. DISCUSSION: There are heterogeneous profiles of depressive symptoms and dementia risk. Common neuropathological factors may contribute to both depression and dementia. Highlights The progression of depressive symptoms and concurrent dementia risk is heterogeneous. Emerging depressive symptoms may be a prodromal symptom of dementia. Cerebrovascular disease and AD are potentially shared neuropathological factors.

Corticosteroid Therapy in Acute and Subacute Arachnoiditis - A Case Series.

Arachnoiditis is difficult to treat. Patients are often left frustrated after many failed trials of conservative therapies without symptom resolution. Surgery may provide symptom relief for a short period of time, but their pain often returned. Herein, we present three cases of acute arachnoiditis following three different pain procedures: epidural blood patch, IDDS implant, and epidural steroid injection. The patients were diagnosed and treated with corticosteroids within 10 days of the procedure. Two patients were treated with the same oral steroid regiment, while the third patient was treated with both oral and IV steroid. All three patients had good outcomes at the completion of their steroid therapy. This case series may provide insight into treating acute and subacute arachnoiditis from pain interventions.

Promotion of an Antitumor Immune Program by a Tumor-specific, Complement-activating Antibody.

Tumor-targeting Abs can be used to initiate an antitumor immune program, which appears essential to achieve a long-term durable clinical response to cancer. We previously identified an anti-complement factor H (CFH) autoantibody associated with patients with early-stage non-small cell lung cancer. We cloned from their peripheral B cells an mAb, GT103, that specifically recognizes CFH on tumor cells. Although the underlying mechanisms are not well defined, GT103 targets a conformationally distinct CFH epitope that is created when CFH is associated with tumor cells, kills tumor cells in vitro, and has potent antitumor activity in vivo. In the effort to better understand how an Ab targeting a tumor epitope can promote an effective antitumor immune response, we used the syngeneic CMT167 lung tumor C57BL/6 mouse model, and we found that murinized GT103 (mGT103) activates complement and enhances antitumor immunity through multiple pathways. It creates a favorable tumor microenvironment by decreasing immunosuppressive regulatory T cells and myeloid-derived suppressor cells, enhances Ag-specific effector T cells, and has an additive antitumor effect with anti-PD-L1 mAb. Furthermore, the immune landscape of tumors from early-stage patients expressing the anti-CFH autoantibody is associated with an immunologically active tumor microenvironment. More broadly, our results using an mAb cloned from autoantibody-expressing B cells provides novel, to our knowledge, mechanistic insights into how a tumor-specific, complement-activating Ab can generate an immune program to kill tumor cells and inhibit tumor growth.

A re-activation model for 169Yb intensity modulated brachytherapy sources accounting for spatiotemporal isotopic composition.

BACKGROUND: Intensity modulated brachytherapy based on partially shielded intracavitary and interstitial applicators is possible with a cost-effective 169Yb production method. 169Yb is a traditionally expensive isotope suitable for this purpose, with an average γ-ray energy of 93 keV. Re-activating a single 169Yb source multiple times in a nuclear reactor between clinical uses was shown to theoretically reduce cost by approximately 75% relative to conventional single-activation sources. With re-activation, substantial spatiotemporal variation in isotopic source composition is expected between activations via 168Yb burnup and 169Yb decay, resulting in time dependent neutron transmission, precursor usage, and reactor time needed per re-activation. PURPOSE: To introduce a generalized model of radioactive source production that accounts for spatiotemporal variation in isotopic source composition to improve the efficiency estimate of the 169Yb production process, with and without re-activation. METHODS AND MATERIALS: A time-dependent thermal neutron transport, isotope transmutation, and decay model was developed. Thermal neutron flux within partitioned sub-volumes of a cylindrical active source was calculated by raytracing through the spatiotemporal dependent isotopic composition throughout the source, accounting for thermal neutron attenuation along each ray. The model was benchmarked, generalized, and applied to a variety of active source dimensions with radii ranging from 0.4 to 1.0 mm, lengths from 2.5 to 10.5 mm, and volumes from 0.31 to 7.85 mm3, at thermal neutron fluxes from 1 × 1014 to 1 × 1015 n cm-2 s-1. The 168Yb-Yb2O3 density was 8.5 g cm-3 with 82% 168Yb-enrichment. As an example, a reference re-activatable 169Yb active source (RRS) constructed of 82%-enriched 168Yb-Yb2O3 precursor was modeled, with 0.6 mm diameter, 10.5 mm length, 3 mm3 volume, 8.5 g cm-3 density, and a thermal neutron activation flux of 4 × 1014 neutrons cm-2 s-1. RESULTS: The average clinical 169Yb activity for a 0.99 versus 0.31 mm3 source dropped from 20.1 to 7.5 Ci for a 4 × 1014 n cm-2 s-1 activation flux and from 20.9 to 8.7 Ci for a 1 × 1015 n cm-2 s-1 activation flux. For thermal neutron fluxes ≥2 × 1014 n cm-2 s-1, total precursor and reactor time per clinic-year were maximized at a source volume of 0.99 mm3 and reached a near minimum at 3 mm3. When the spatiotemporal isotopic composition effect was accounted for, average thermal neutron transmission increased over RRS lifetime from 23.6% to 55.9%. A 28% reduction (42.5 days to 30.6 days) in the reactor time needed per clinic-year for the RRS is predicted relative to a model that does not account for spatiotemporal isotopic composition effects. CONCLUSIONS: Accounting for spatiotemporal isotopic composition effects within the RRS results in a 28% reduction in the reactor time per clinic-year relative to the case in which such changes are not accounted for. Smaller volume sources had a disadvantage in that average clinical 169Yb activity decreased substantially below 20 Ci for source volumes under 1 mm3. Increasing source volume above 3 mm3 adds little value in precursor and reactor time savings and has a geometric disadvantage.

Minimal clinically important difference in Alzheimer's disease: Rapid review.

INTRODUCTION: We conducted a rapid systematic review of minimal clinically important differences (MCIDs) for Alzheimer's disease (AD) trial endpoints. METHODS: Two reviewers searched EMBASE, MEDLINE, and PubMed from inception to June 4, 2023. RESULTS: Ten articles were retrieved. For mild cognitive impairment (MCI), a change of +2 to +3 points on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), +1 points on the Clinical Dementia Rating scale sum of boxes (CDR-SB), -5 points on the integrated Alzheimer's Disease Rating Scale (iADRS), or -1 to -2 points on the Mini-Mental State Examination (MMSE) was considered meaningful. For patients with mild AD, a change of +3 on the ADAS-Cog, +2 points on CDR-SB, -9 points on the iADRS, or -2 points on the MMSE was considered meaningful. For patients with moderate to severe AD, a change of +2 points on the CDR-SB or a change of -1.4 to -3 points on the MMSE was considered meaningful. CONCLUSION: This review identified previously published MCIDs for AD trial endpoints. Input from patients and caregivers will be needed to derive more meaningful endpoints and thresholds. HIGHLIGHTS: This systematic rapid review identified thresholds for minimal clinically important differences (MCIDs) for recently used Alzheimer's disease (AD) trial endpoints: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Clinical Dementia Rating scale sum of boxes (CDR-SB), integrated Alzheimer's Disease Rating Scale (iADRS), Mini-Mental State Examination (MMSE). MCIDs were higher for more severe stages of AD. Average treatment effects in recent trials of anti-amyloid disease modifying monoclonal antibodies are lower than previously published MCIDs. In future trials of disease modifying treatments for AD, the proportion of participants in each treatment group that experienced a clinically meaningful decline could be reported. More work is needed to incorporate the values and preferences of patients and care partners in deriving MCIDs.

Prevalence of symptoms of post stroke depression and anxiety in young adults: a systematic review and meta-analysis.

BACKGROUND: Young adults with stroke have distinct professional and social roles making them vulnerable to symptoms of post-stroke depression (PSD) and post-stroke anxiety (PSA). Prior reviews have examined the prevalence of anxiety and depression in stroke populations. However, there are a lack of studies that have focused on these conditions in young adults. OBJECTIVE: We performed a systematic review and meta-analysis of observational studies that reported on symptoms of PSD, PSA and comorbid PSD/PSA in young adults aged 18 to 55 years of age. METHODS: MEDLINE, EMBASE, SCOPUS and PsycINFO were searched for studies reporting the prevalence of symptoms of PSD and/or PSA in young adults with stroke from inception until June 23, 2023. We included studies that evaluated depression and/or anxiety symptoms with screening tools or interviews following ischemic or hemorrhagic stroke. Validated methods were employed to evaluate risk of bias. RESULTS: 4,748 patients from twenty eligible studies were included. Among them, 2,420 were also evaluated for symptoms of PSA while 847 participants were evaluated for both PSD and PSA symptoms. Sixteen studies were included in the random effects meta-analysis for PSD symptoms, with a pooled prevalence of 31% (95% CI 24-38%). Pooled PSA symptom prevalence was 39% (95% CI 30-48%) and comorbid PSD with PSA symptom prevalence was 25% (95% CI 12-39%). Varying definitions of 'young adult', combinations of stroke subtypes, and methods to assess PSD and PSA contributed to high heterogeneity amongst studies. CONCLUSIONS: We identified high heterogeneity in studies investigating the prevalence of symptoms of PSD and PSA in young adults, emphasizing the importance of standardized approaches in future research to gain insight into the outcomes and prognosis of PSD and PSA symptoms following stroke in young adults. Larger longitudinal epidemiological studies as well as studies on tailored interventions are required to address the mental health needs of this important population. FUNDING: None.

Infiltrative Intramuscular Lipoma with Overlying Fascial Defect in the Anterior Thigh: A Case Report.

This case report details a unique presentation of an infiltrative intramuscular lipoma in the anterior thigh of a 51-year-old female with an overlying fascial defect. The patient reported a progressively enlarging left thigh mass associated with pain exacerbated by knee movement and exercise. MRI revealed a homogeneous intramuscular lipoma without contrast enhancement with a fascial defect. An 8 cm longitudinal incision exposed a 7 x 4 cm fascial defect overlying the lipomatous mass within the rectus femoris muscle. Pathological analysis confirmed an intramuscular lipoma without malignancy. Follow-ups at two, six, and 12 weeks demonstrated pain resolution and no soft tissue bulge. This case underscores the importance of distinguishing intramuscular lipomas from other neoplasms, such as lipomatosis and liposarcomas. The association of a fascial defect with intramuscular lipomas is unprecedented and may be due to the increased pressure on the fascia by the lipoma. The report emphasizes the role of MRI in diagnosis and appropriate surgical management, and highlights the need for further exploration into the etiology of fascial defects associated with intramuscular lipomas.

Quantification of Biopharmaceutically Relevant Nonionic Surfactant Excipients Using Benchtop qNMR.

Nonionic surfactant excipients (NISEs) are commonly added to biologics formulations to mitigate the effects of stress incurred by the active biotherapeutic during manufacturing, transport, and storage. During manufacturing, NISEs are added by dilution of a stock solution directly into a protein formulation, and their accurate addition is critical in maintaining the quality and integrity of the drug product and thus ensuring patient safety. This is especially true for the common NISEs, polysorbates 20 and 80 (PS20 and PS80, respectively) and poloxamer 188 (P188). With the increasing diversity of biologic modalities within modern pharmaceutical pipelines, there is thus a critical need to develop and deploy convenient and user-accessible analytical techniques that can rapidly and reliably quantify these NISEs under biopharmaceutically relevant conditions. We thus pursued 60 MHz benchtop quantitative NMR (qNMR) as a nondestructive and user-friendly analytical technique for the quantification of PS20, PS80, and P188 under such conditions. We demonstrated the ability of benchtop qNMR (1) to quantify simulated PS20, PS80, and P188 stock solutions representative of those used during the drug substance (DS) formulation step in biomanufacturing and (2) to quantify these NISEs at and below their target concentrations (≤0.025% w/v) directly in biologics formulations containing histidine, sucrose, and one of three biotherapeutic modalities (monoclonal antibody, antibody-drug conjugate, and Fc-fusion protein). Our results demonstrate that benchtop qNMR offers a fit-for-purpose, reliable, user-friendly, and green analytical route by which NISE of interest to the biopharmaceutical industry may be readily and reliably quantified. We conclude that benchtop qNMR has the potential to be applied to other excipient formulation components in the presence of various biological modalities as well as the potential for routine integration within analytical and QC laboratories across pharmaceutical development and manufacturing sites.

Pavement ant extract is a chemotaxis repellent for C. elegans.

Ant behavior relies on a collection of natural products, from following trail pheromones during foraging to warding off potential predators. How nervous systems sense these compounds to initiate a behavioral response remains unclear. Here, we used Caenorhabditis elegans chemotaxis assays to investigate how ant compounds are detected by heterospecific nervous systems. We found that C. elegans avoid extracts of the pavement ant ( Tetramorium immigrans ) and either osm-9 or tax-4 ion channels are required for this response. These experiments were conducted in an undergraduate laboratory course, demonstrating that new insights into interspecies interactions can be generated through genuine research experiences in a classroom setting.

Outpatient treatment with concomitant vaccine-boosted convalescent plasma for patients with immunosuppression and COVID-19.

Although severe coronavirus disease 2019 (COVID-19) and hospitalization associated with COVID-19 are generally preventable among healthy vaccine recipients, patients with immunosuppression have poor immunogenic responses to COVID-19 vaccines and remain at high risk of infection with SARS-CoV-2 and hospitalization. In addition, monoclonal antibody therapy is limited by the emergence of novel SARS-CoV-2 variants that have serially escaped neutralization. In this context, there is interest in understanding the clinical benefit associated with COVID-19 convalescent plasma collected from persons who have been both naturally infected with SARS-CoV-2 and vaccinated against SARS-CoV-2 ("vax-plasma"). Thus, we report the clinical outcome of 386 immunocompromised outpatients who were diagnosed with COVID-19 and who received contemporary COVID-19-specific therapeutics (standard-of-care group) and a subgroup who also received concomitant treatment with very high titer COVID-19 convalescent plasma (vax-plasma group) with a specific focus on hospitalization rates. The overall hospitalization rate was 2.2% (5 of 225 patients) in the vax-plasma group and 6.2% (10 of 161 patients) in the standard-of-care group, which corresponded to a relative risk reduction of 65% (P = 0.046). Evidence of efficacy in nonvaccinated patients cannot be inferred from these data because 94% (361 of 386 patients) of patients were vaccinated. In vaccinated patients with immunosuppression and COVID-19, the addition of vax-plasma or very high titer COVID-19 convalescent plasma to COVID-19-specific therapies reduced the risk of disease progression leading to hospitalization.IMPORTANCEAs SARS-CoV-2 evolves, new variants of concern (VOCs) have emerged that evade available anti-spike monoclonal antibodies, particularly among immunosuppressed patients. However, high-titer COVID-19 convalescent plasma continues to be effective against VOCs because of its broad-spectrum immunomodulatory properties. Thus, we report clinical outcomes of 386 immunocompromised outpatients who were treated with COVID-19-specific therapeutics and a subgroup also treated with vaccine-boosted convalescent plasma. We found that the administration of vaccine-boosted convalescent plasma was associated with a significantly decreased incidence of hospitalization among immunocompromised COVID-19 outpatients. Our data add to the contemporary data providing evidence to support the clinical utility of high-titer convalescent plasma as antibody replacement therapy in immunocompromised patients.

Associations of plasma proteomics and age-related outcomes with brain age in a diverse cohort.

Machine learning models are increasingly being used to estimate "brain age" from neuroimaging data. The gap between chronological age and the estimated brain age gap (BAG) is potentially a measure of accelerated and resilient brain aging. Brain age calculated in this fashion has been shown to be associated with mortality, measures of physical function, health, and disease. Here, we estimate the BAG using a voxel-based elastic net regression approach, and then, we investigate its associations with mortality, cognitive status, and measures of health and disease in participants from Atherosclerosis Risk in Communities (ARIC) study who had a brain MRI at visit 5 of the study. Finally, we used the SOMAscan assay containing 4877 proteins to examine the proteomic associations with the MRI-defined BAG. Among N = 1849 participants (age, 76.4 (SD 5.6)), we found that increased values of BAG were strongly associated with increased mortality and increased severity of the cognitive status. Strong associations with mortality persisted when the analyses were performed in cognitively normal participants. In addition, it was strongly associated with BMI, diabetes, measures of physical function, hypertension, prevalent heart disease, and stroke. Finally, we found 33 proteins associated with BAG after a correction for multiple comparisons. The top proteins with positive associations to brain age were growth/differentiation factor 15 (GDF-15), Sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SEVP 1), matrilysin (MMP7), ADAMTS-like protein 2 (ADAMTS), and heat shock 70 kDa protein 1B (HSPA1B) while EGF-receptor (EGFR), mast/stem-cell-growth-factor-receptor (KIT), coagulation-factor-VII, and cGMP-dependent-protein-kinase-1 (PRKG1) were negatively associated to brain age. Several of these proteins were previously associated with dementia in ARIC. These results suggest that circulating proteins implicated in biological aging, cellular senescence, angiogenesis, and coagulation are associated with a neuroimaging measure of brain aging.

Site-Specific Conjugation of Native Antibody: Transglutaminase-Mediated Modification of a Conserved Glutamine While Maintaining the Primary Sequence and Core Fc Glycan via Trimming with an Endoglycosidase.

A versatile chemo-enzymatic tool to site-specifically modify native (nonengineered) antibodies is using transglutaminase (TGase, E.C. 2.3.2.13). With various amines as cosubstrates, this enzyme converts the unsubstituted side chain amide of glutamine (Gln or Q) in peptides and proteins into substituted amides (i.e., conjugates). A pleasant surprise is that only a single conserved glutamine (Gln295) in the Fc region of IgG is modified by microbial TGase (mTGase, EC 2.3.2.13), thereby providing a highly specific and generally applicable conjugation method. However, prior to the transamidation (access to the glutamine residue by mTGase), the steric hindrance from the nearby conserved N-glycan (Asn297 in IgG1) must be reduced. In previous approaches, amidase (PNGase F, EC 3.5.1.52) was used to completely remove the N-glycan. However, PNGase F also converts a net neutral asparagine (Asn297) to a negatively charged aspartic acid (Asp297). This charge alteration may markedly change the structure, function, and immunogenicity of an IgG antibody. In contrast, in our new method presented herein, the N-glycan is trimmed by an endoglycosidase (EndoS2, EC 3.2.1.96), hence retaining both the core N-acetylglucosamine (GlcNAc) moiety and the neutral asparaginyl amide. The trimmed glycan also reduces or abolishes Fc receptor-mediated functions, which results in better imaging agents by decreasing nonspecific binding to other cells (e.g., immune cells). Moreover, the remaining core glycan allows further derivatization such as glycan remodeling and dual conjugation. Practical and robust, our method generates conjugates in near quantitative yields, and both enzymes are commercially available.

Interplay of Oncoplastic Reconstruction and Adjuvant Radiation Therapy in Breast Cancer.

Purpose: Oncoplastic breast surgery (OBS) combines breast cancer tumor removal with the cosmetic benefits of plastic surgery at the time of breast-conserving surgery. Potential advantages of OBS include wider surgical margins around the tumor bed, while the natural shape and appearance of the breast are maintained more than standard lumpectomy procedures. However, limited information is available regarding the potential effect on adjuvant radiation treatment planning. Materials and Methods: Women with localized breast cancer undergoing lumpectomy with immediate OBS and adjuvant radiation therapy between 2014 and 2019 were reviewed. OBS was performed using volume displacement techniques and patients received whole-breast irradiation with 3-dimensional conformal radiation therapy. Results: Volume of additional ipsilateral breast tissue removed during OBS ranged from 21 to 2086 cm3 (median, 304 cm3), 29% of patients had >500 cm3 of tissue removed. Surgical margins were positive in 12.5% and were not affected by volume of breast tissue removed (445 vs 439 cm3). Patients with surgical clips more often received a lumpectomy bed boost (75.9% vs 50.0%), boost volumes were on average 157 cm3 with clips versus 205 cm3 without clips. Mean V105 was comparable in patients with >500 cm3 tissue removed and irradiated breast volume >1000 cm3, while higher absolute volumes were found in patients with >26 cm posterior separation (58.0 cm3 vs 102.7 cm3; P = .07). No meaningful difference was observed in Dmax or radiation coverage (95% of the volume receiving 95% of the prescription dose) for patients with >26 cm posterior separation, >500 cm3 of breast tissue removed, or irradiated breast volume >1000 cm3. Conclusions: Radiation dosimetry plans for patients undergoing oncoplastic surgery were acceptable and no significant radiation or surgical advantage was gained in patients with more tissue removed. Our study stresses the importance of clear communication between surgeons and radiation oncologists about sufficient marking of the lumpectomy cavity, using practices that minimize the need for re-excisions and minimize lumpectomy cavity disruption during rearrangement.

Effect of Posterior Tibial Slope on Outcomes After Posterior Cruciate Ligament Reconstruction.

Background: Increased posterior tibial slope (PTS) leads to a relative anterior translation of the tibia on the femur. This is thought to decrease the stress on posterior cruciate ligament (PCL) reconstruction (PCLR) grafts. Purpose/Hypothesis: The purpose of this study was to analyze the effect of PTS on knee laxity, graft failure, and patient-reported outcome (PRO) scores after PCLR without concomitant anterior cruciate ligament reconstruction (ACLR). It was hypothesized that patients with higher PTS would have less knee laxity, fewer graft failures, and better PROs compared with patients with lower PTS. Study Design: Case-control study; Level of evidence, 3. Methods: All patients who underwent PCLR between 2001 and 2020 at a single institution were identified. Patients were excluded if they underwent concomitant or prior ACLR or proximal tibial osteotomy, were younger than 18 years, had <2 years of in-person clinical follow-up, and did not have documented PRO scores (Lysholm score and International Knee Documentation Committee [IKDC] score). Data were collected retrospectively from a prospectively gathered database. PTS measurements were recorded from perioperative lateral knee radiographs. A linear regression model was created to analyze PTS in relation to PRO scores. Patients with a grade 1 (1-5 mm) or higher posterior drawer were compared with those who had a negative posterior drawer. Results: A total of 37 knees met inclusion criterion; the mean age was 30.7 years at the time of surgery. The mean clinical follow-up was 5.8 years. No significant correlation was found between either the Lysholm score or the IKDC score and the PTS. Twelve knees (32.4%) had a positive posterior drawer at final follow-up. The mean PTS in knees with a positive posterior drawer was 6.2°, whereas that for knees with a negative posterior drawer was 8.3° (P = .08). No significant differences in PRO scores were identified for knees with versus knees without a positive posterior drawer. No documented graft failures or revisions were found. Conclusion: No significant differences were found in PROs or graft failure rates based on PTS at a mean of 5.8 years after PCLR. Increased tibial slope trended toward being protective against a positive posterior drawer, although this did not reach statistical significance.

Radiotherapy for Advanced Hodgkin Lymphoma with Initial Bulk: A Combined Analysis of Two Randomized Trials.

Purpose: The role of consolidative radiation therapy (RT) in patients with advanced Hodgkin lymphoma with initial bulk is unclear. GITIL/FIL HD0607 and FIL HD0801, 2 randomized controlled trials with similar design and methodologies, did not identify a benefit to consolidative RT after a metabolic complete response to 6 cycles of doxorubicin, bleomycin, vinblastine and dacarbazine. However, their limited sample sizes reduced statistical power to detect a small but clinically meaningful benefit to RT. Methods and Materials: In a secondary analysis of these 2 phase 3 trials, reconstructed patient data were used to compare outcomes for early and complete responders randomized to no RT or RT to the site(s) of initial bulk. Estimates of progression-free survival (PFS) in the intent-to-treat (ITT) and per-protocol (PP) analyses were generated using the combined data and compared between groups using the log-rank test. Results: A total of 412 patients were included in the ITT analysis, and 373 patients were included in the PP analysis. Median age was 30 to 32 years, 42% of patients were stage IIB, and 73% of bulky sites were located in the mediastinum. For the no RT versus RT groups, 5-year ITT PFS estimates were 90.1% versus 90.1%, respectively (P = .81). Five-year PP PFS rates were 90.9% versus 92.9%, respectively (P = .31). There was no observed difference between no RT and RT groups in subgroups according to size of bulky disease: 5 to 7 cm (P = .78), 7 to 10 cm (P = .25), and >10 cm (P = .69). Conclusions: In this combined analysis of 2 randomized phase 3 clinical trials, consolidative RT to initial sites of bulky nodal involvement was not associated with a PFS benefit in patients with advanced Hodgkin lymphoma in metabolic complete response after 2 and 6 cycles of doxorubicin, bleomycin, vinblastine and dacarbazine.