EGFR V834L and L858R Comutation Is Associated With Response to Osimertinib in Non-Small-Cell Lung Cancer.

Up-front osimertinib leads to clinical benefit in EGFR V834L and L858R comutated NSCLC.

BRCA1, BRCA2, and Associated Cancer Risks and Management for Male Patients: A Review.

Importance: Half of all carriers of inherited cancer-predisposing variants in BRCA1 and BRCA2 are male, but the implications for their health are underrecognized compared to female individuals. Germline variants in BRCA1 and BRCA2 (also known as pathogenic or likely pathogenic variants, referred to here as BRCA1/2 PVs) are well known to significantly increase the risk of breast and ovarian cancers in female carriers, and knowledge of BRCA1/2 PVs informs established cancer screening and options for risk reduction. While risks to male carriers of BRCA1/2 PVs are less characterized, there is convincing evidence of increased risk for prostate cancer, pancreatic cancer, and breast cancer in males. There has also been a rapid expansion of US Food and Drug Administration-approved targeted cancer therapies, including poly ADP ribose polymerase (PARP) inhibitors, for breast, pancreatic, and prostate cancers associated with BRCA1/2 PVs. Observations: This narrative review summarized the data that inform cancer risks, targeted cancer therapy options, and guidelines for early cancer detection. It also highlighted areas of emerging research and clinical trial opportunities for male BRCA1/2 PV carriers. These developments, along with the continued relevance to family cancer risk and reproductive options, have informed changes to guideline recommendations for genetic testing and strengthened the case for increased genetic testing for males. Conclusions and Relevance: Despite increasing clinical actionability for male carriers of BRCA1/2 PVs, far fewer males than female individuals undergo cancer genetic testing. Oncologists, internists, and primary care clinicians should be vigilant about offering appropriate genetic testing to males. Identifying more male carriers of BRCA1/2 PVs will maximize opportunities for cancer early detection, targeted risk management, and cancer treatment for males, along with facilitating opportunities for risk reduction and prevention in their family members, thereby decreasing the burden of hereditary cancer.

Combined Germline and Mosaic SDHA Mutation Is Associated With a Multicancer Syndrome Including Neuroblastoma, Renal Cancer, and Multifocal GI Tumor.

Highlighting here a patient case with neuroblastoma, renal cancer & GIST from germline SDHA.

Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline ATM sequence variants.

The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOP) Variant Curation Expert Panel (VCEP) is composed of internationally recognized experts in clinical genetics, molecular biology and variant interpretation. This VCEP made specifications for ACMG/AMP guidelines for the ataxia telangiectasia mutated (ATM) gene according to the Food and Drug Administration (FDA)-approved ClinGen protocol. These gene-specific rules for ATM were modified from the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) guidelines and were tested against 33 ATM variants of various types and classifications in a pilot curation phase. The pilot revealed a majority agreement between the HBOP VCEP classifications and the ClinVar-deposited classifications. Six pilot variants had conflicting interpretations in ClinVar and reevaluation with the VCEP's ATM-specific rules resulted in four that were classified as benign, one as likely pathogenic and one as a variant of uncertain significance (VUS) by the VCEP, improving the certainty of interpretations in the public domain. Overall, 28 the 33 pilot variants were not VUS leading to an 85% classification rate. The ClinGen-approved, modified rules demonstrated value for improved interpretation of variants in ATM.

Deciphering the Transcription Factor Landscape in Neuroendocrine Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation.

Background and Objective: Prostate cancer (PCa) is a leading cause of cancer mortality in men, with neuroendocrine prostate cancer (NEPC) representing a particularly resistant subtype. The role of transcription factors (TFs) in the progression from prostatic adenocarcinoma (PRAD) to NEPC is poorly understood. This study aims to identify and analyze lineage-specific TF profiles in PRAD and NEPC and illustrate their dynamic shifts during NE transdifferentiation. Methods: A novel algorithmic approach was developed to evaluate the weighted expression of TFs within patient samples, enabling a nuanced understanding of TF landscapes in PCa progression and TF dynamic shifts during NE transdifferentiation. Results: unveiled TF profiles for PRAD and NEPC, identifying 126 shared TFs, 46 adenocarcinoma-TFs, and 56 NEPC-TFs. Enrichment analysis across multiple clinical cohorts confirmed the lineage specificity and clinical relevance of these lineage-TFs signatures. Functional analysis revealed that lineage-TFs are implicated in pathways critical to cell development, differentiation, and lineage determination. Novel lineage-TF candidates were identified, offering potential targets for therapeutic intervention. Furthermore, our longitudinal study on NE transdifferentiation highlighted dynamic TF expression shifts and delineated a three-phase hypothesis for the process comprised of de-differentiation, dormancy, and re-differentiation. and proposing novel insights into the mechanisms of PCa progression. Conclusion: The lineage-specific TF profiles in PRAD and NEPC reveal a dynamic shift in the TF landscape during PCa progression, highlighting three distinct phases of NE transdifferentiation.

Genomic Correlates of Prostate-Specific Membrane Antigen Expression and Response to 177Lu-PSMA-617: A Retrospective Multicenter Cohort Study.

PURPOSE: While 177Lu-PSMA-617 (LuPSMA) is an effective therapy for many patients with metastatic castration-resistant prostate cancer (mCRPC), biomarkers associated with outcomes are not well defined. We hypothesized that prostate cancer mutational profile may associate with clinical activity of LuPSMA. We devised a study to evaluate associations between mCRPC mutational profile with LuPSMA clinical outcomes. METHODS: This was a multicenter retrospective analysis of patients with mCRPC with next-generation sequencing (NGS) who received LuPSMA. PSA50 response (ie, ≥50% decline in prostate-specific antigen [PSA]) rate, PSA progression free survival (PSA PFS), and overall survival (OS) were compared between genetically defined subgroups. RESULTS: One hundred twenty-six patients with NGS results who received at least one cycle of LuPSMA were identified. The median age was 73 (IQR, 68-78) years, 124 (98.4%) received ≥1 prior androgen receptor-signaling inhibitor, and 121 (96%) received ≥1 taxane-based chemotherapy regimen. Fifty-eight (46%) patients with a DNA damage repair gene mutation (DNA damage response group) and 59 (46.8%) with a mutation in TP53, RB1, or PTEN tumor suppressor genes (TSG group) were identified. After adjusting for relevant confounders, the presence of ≥1 TSG mutation was associated with shorter PSA PFS (hazard ratio [HR], 1.93 [95% CI, 1.05 to 3.54]; P = .034) and OS (HR, 2.65 [95% CI, 1.15 to 6.11]; P = .023). There was improved OS favoring the DNA damage response group (HR, 0.37 [95% CI, 0.14 to 0.97]; P = .044) on multivariable analysis. Univariate analysis of patients with ATM mutations had significantly higher rates of PSA50 response, PSA PFS, and OS. CONCLUSION: Outcomes on LuPSMA varied on the basis of mutational profile. Prospective studies to define the clinical activity of LuPSMA in predefined genomic subgroups are justified.

Tranexamic acid in total hip arthroplasty: An umbrella review on efficacy and safety.

Purpose: This comprehensive review was conducted to assess the effects of tranexamic acid (TXA) on blood loss, venous thromboembolism (VTE) risk, and wound complications following total hip arthroplasty (THA). Additionally, it sought to evaluate the effects of various TXA dosages, modes of administration, and combinations with other antifibrinolytic drug. Methods: In search of systematic reviews and meta-analyses on the use of TXA in THA patients, we searched extensively through databases including Scopus, the Cochrane Library, Embase, Medline, the Web of Science, PubMed, and Google Scholar. We discovered 23 meta-analyses covering 32,442 patients overall that fulfilled our study criteria, spanning the period from the creation of these databases until May 2023. Results: This comprehensive review's meta-analyses, which together examined over 35,000 patients, repeatedly demonstrated how TXA administration during THA successfully lowers perioperative blood loss and the need for transfusions. TXA reduced total blood loss by an average of 151-370 ml, postoperative hemoglobin levels by 0.5-1.1 g/dL, and transfusion rates by 19-26% on average when compared to control groups. The information gathered did not indicate that using TXA significantly increased the risk of VTE or wound complications. When comparing different TXA doses, administration techniques, or its use in conjunction with other anti-fibrinolytic therapies, no discernible differences were found in terms of efficacy or safety outcomes. Conclusion: The comprehensive review clearly indicates that TXA improves THA outcomes without increasing the risk of adverse events by lowering blood loss and the requirement for transfusions. This insightful information can help surgeons decide whether to use TXA during THA procedures.

Solving Missing Heritability in Patients With Familial Adenomatous Polyposis With DNA-RNA Paired Testing.

PURPOSE: Patients with germline pathogenic variants (PVs) in APC develop tens (attenuated familial adenomatous polyposis [AFAP]) to innumerable (classic FAP) adenomatous polyps in their colon and are at significantly increased lifetime risk of colorectal cancer. Up to 10% of FAP and up to 50% of patients with AFAP who have undergone DNA-only multigene panel testing (MGPT) do not have an identified PV in APC. We seek to demonstrate how the addition of RNA sequencing run concurrently with DNA can improve detection of germline PVs in individuals with a clinical presentation of AFAP/FAP. METHODS: We performed a retrospective query of individuals tested with paired DNA-RNA MGPT from 2021 to 2022 at a single laboratory and included those with a novel APC PV located in intronic regions infrequently covered by MGPT, a personal history of polyposis, and family medical history provided. All clinical data were deidentified in this institutional review board-exempt study. RESULTS: Three novel APC variants were identified in six families and were shown to cause aberrant splicing because of the creation of a deep intronic cryptic splice site that leads to an RNA transcript subject nonsense-mediated decay. Several carriers had previously undergone DNA-only genetic testing and had received a negative result. CONCLUSION: Here, we describe how paired DNA-RNA MGPT can be used to solve missing heritability in FAP families, which can have important implications in family planning and treatment decisions for patients and their families.

Does Approach Matter in Robotic-Assisted Total Hip Arthroplasty? A Comparison of Early Reoperations Between Direct Anterior and Postero-Lateral Approach.

BACKGROUND: There is no consensus on whether direct anterior approach (DAA) or postero-lateral approach (PLA) total hip arthroplasty (THA) confers a lower risk of postoperative complications. Robotic assistance in THA results in a more consistently accurate component position compared to manual THA. The objective of this study was to compare rates of dislocation, reoperation, revision, and patient-reported outcome measures between patients undergoing DAA and PLA robotic-assisted primary THA. METHODS: We identified 2,040 consecutive robotic-assisted primary THAs performed for primary osteoarthritis, using DAA (n = 497) or PLA (n = 1,542) between 2017 and 2020. The mean follow-up was 18 months. Kaplan-Meier analysis estimated survivorship free of dislocation, reoperation, and revision. Achievement of patient acceptable symptom state and minimum clinically important difference were used to compare changes in the Hip Disability and Osteoarthritis Outcome Score, Joint Replacement (HOOS JR) and Visual Analog Scale. RESULTS: Dislocation was rare in this series (14 in 2,040, 0.7%), including 1 of 497 (0.2%) in the DAA cohort and 13 of 1,542 (0.8%) in the PLA cohort (P = .210). There was no difference in 2-year reoperation-free survivorship (97.8 versus 98.6%, P = .59) or revision-free survivorship (98.8 versus 99.0%, P = .87) at any time point. After controlling for age, sex, and body mass index, there was no difference in dislocation, reoperation, or revision. At 6-week follow-up, after controlling for age, sex, and body mass index, patients in the DAA cohort had higher odds of achieving HOOS JR minimum clinically important difference (odds ratio = 2.01, P = .012) and HOOS JR patient acceptable symptom state (odds ratio = 1.72, P = .028). There were no differences in patient-reported outcome measures by 3 months. CONCLUSIONS: For robotic-assisted primary THA, DAA may confer enhanced early (<6 weeks) functional recovery compared to the PLA, but there was no significant difference in postoperative dislocation, reoperation, or revision rates.

Functional analysis and clinical classification of 462 germline BRCA2 missense variants affecting the DNA binding domain.

Variants of uncertain significance (VUSs) in BRCA2 are a common result of hereditary cancer genetic testing. While more than 4,000 unique VUSs, comprised of missense or intronic variants, have been identified in BRCA2, the few missense variants now classified clinically as pathogenic or likely pathogenic are predominantly located in the region encoding the C-terminal DNA binding domain (DBD). We report on functional evaluation of the influence of 462 BRCA2 missense variants affecting the DBD on DNA repair activity of BRCA2 using a homology-directed DNA double-strand break repair assay. Of these, 137 were functionally abnormal, 313 were functionally normal, and 12 demonstrated intermediate function. Comparisons with other functional studies of BRCA2 missense variants yielded strong correlations. Sequence-based in silico prediction models had high sensitivity, but limited specificity, relative to the homology-directed repair assay. Combining the functional results with clinical and genetic data in an American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP)-like variant classification framework from a clinical testing laboratory, after excluding known splicing variants and functionally intermediate variants, classified 431 of 442 (97.5%) missense variants (129 as pathogenic/likely pathogenic and 302 as benign/likely benign). Functionally abnormal variants classified as pathogenic by ACMG/AMP rules were associated with a slightly lower risk of breast cancer (odds ratio [OR] 5.15, 95% confidence interval [CI] 3.43-7.83) than BRCA2 DBD protein truncating variants (OR 8.56, 95% CI 6.03-12.36). Overall, functional studies of BRCA2 variants using validated assays substantially improved the variant classification yield from ACMG/AMP models and are expected to improve clinical management of many individuals found to harbor germline BRCA2 missense VUS.

Patient Selection in Randomized Controlled Trials of Total Knee Arthroplasty: A Systematic Review Assessing Inclusion Criteria.

BACKGROUND: Patients undergo total knee arthroplasty (TKA) at widely disparate stages of osteoarthritis, raising the possibility of high heterogeneity among patients enrolled in TKA research studies. Obscuration of treatment effectiveness and other problems that may stem from cohort heterogeneity can be controlled in clinical studies by rigorously defining target patients. The purpose of this review was to determine the extent to which randomized controlled trials (RCTs) on TKA use osteoarthritis severity, as defined by radiographic grade or patient-reported outcome measures (PROMs), in their inclusion criteria, and to investigate potential impact on outcome. METHODS: A search of PubMed, Embase, Scopus, Web of Science, and Cochrane databases used a combination of terms involving TKA, PROMs, and radiographic scoring. A total of 1,227 studies were independently reviewed by 2 screeners for the above terms. RCTs with ≥100 patients (236) and with <100 patients (325) undergoing TKA were analyzed with regard to the specific inclusion criteria and recruitment process. RESULTS: Among the identified RCTs with ≥100 patients, 18 (<8%, with a total of 2,952 randomized patients) used specific radiographic scoring or PROM thresholds in their inclusion criteria. Eleven of the 18 studies used specific radiographic scoring, such as the Kellgren-Lawrence or Ahlbäck classifications. Three studies used preoperative PROM thresholds: Knee Society Knee Score of <60, Knee Society Function Score of <60, Oxford Knee Score of <20, and Hospital for Special Surgery Score of <60. Among studies with <100 patients, 48 (<15%) used specific inclusion criteria. CONCLUSIONS: The vast majority of RCTs (>85%) did not enroll patients based on disease severity, as measured by PROM score thresholds or radiographic classifications, in their inclusion criteria. The lack of consistent inclusion criteria likely results in heterogeneous cohorts, potentially undermining the validity of RCTs on TKA. LEVEL OF EVIDENCE: Prognostic Level I . See Instructions for Authors for a complete description of levels of evidence.

Early Periprosthetic Femur Fractures After Primary Cementless Total Hip Arthroplasty: High Risk of Periprosthetic Joint Infection and Subsequent Reoperation.

BACKGROUND: Periprosthetic femur fracture (PFF) following total hip arthroplasty (THA) is a leading cause of early reoperation. The objective of this study was to compare rates of periprosthetic joint infection (PJI) and reoperation following PFFs occurring early postoperatively to those that occurred late. METHODS: We retrospectively identified 173 consecutive surgically managed PFFs following primary THA. Cases were categorized as "early" if they occurred within 90 days of THA (n = 117) or "late" if they occurred following the initial 90 days (n = 56). Mean age at time of PFF was 68 years (range, 26 to 96) and 60% were women. Mean body mass index was 29 (range, 16 to 52). Mean follow-up was 2 years (range, 0 to 13). Kaplan-Meier survival analysis estimated cumulative incidences of PJI and reoperation. RESULTS: Early PFFs had higher 2-year cumulative incidence of PJI (11% versus 0%, P < .001) and reoperation (24% versus 13%, P = .110). Following early PFF, 27 patients required reoperation (ie, 13 for PJI, 5 for instability, 2 for re-fracture, 2 for painful hardware, 2 for non-union, 1 for adverse local tissue reaction, 1 for aseptic loosening, and 1 for leg-length discrepancy). Following late PFF, 5 patients required reoperation (ie, 3 for instability, 1 for re-fracture, and 1 for non-union). CONCLUSIONS: There are greater incidences of PJIs and overall reoperations following early PFFs compared to late PFFs after THA. In addition to focusing efforts on prevention of early PFFs, surgeons should consider antiseptic interventions to mitigate the increased risk of PJI after treatment of early PFF.

Scalable and Consolidated Microbial Platform for Rare Earth Element Leaching and Recovery from Waste Sources.

Chemical methods for the extraction and refinement of technologically critical rare earth elements (REEs) are energy-intensive, hazardous, and environmentally destructive. Current biobased extraction systems rely on extremophilic organisms and generate many of the same detrimental effects as chemical methodologies. The mesophilic methylotrophic bacterium Methylobacterium extorquens AM1 was previously shown to grow using electronic waste by naturally acquiring REEs to power methanol metabolism. Here we show that growth using electronic waste as a sole REE source is scalable up to 10 L with consistent metal yields without the use of harsh acids or high temperatures. The addition of organic acids increases REE leaching in a nonspecific manner. REE-specific bioleaching can be engineered through the overproduction of REE-binding ligands (called lanthanophores) and pyrroloquinoline quinone. REE bioaccumulation increases with the leachate concentration and is highly specific. REEs are stored intracellularly in polyphosphate granules, and genetic engineering to eliminate exopolyphosphatase activity increases metal accumulation, confirming the link between phosphate metabolism and biological REE use. Finally, we report the innate ability of M. extorquens to grow using other complex REE sources, including pulverized smartphones, demonstrating the flexibility and potential for use as a recovery platform for these critical metals.

Preclinical Evaluation of Gastrin-Releasing Peptide Receptor Antagonists Labeled with 161Tb and 177Lu: A Comparative Study.

To elucidate potential benefits of the Auger-electron-emitting radionuclide 161Tb, we compared the preclinical performance of the gastrin-releasing peptide receptor antagonists RM2 (DOTA-Pip5-d-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2) and AMTG (α-Me-Trp8-RM2), each labeled with both 177Lu and 161Tb. Methods: 161Tb/177Lu labeling (90°C, 5 min) and cell-based experiments (PC-3 cells) were performed. In vivo stability (30 min after injection) and biodistribution studies (1-72 h after injection) were performed on PC-3 tumor-bearing CB17-SCID mice. Results: Gastrin-releasing peptide receptor affinity was high for all compounds (half-maximal inhibitory concentration [nM]: [161Tb]Tb-RM2, 2.46 ± 0.16; [161Tb]Tb-AMTG, 2.16 ± 0.09; [177Lu]Lu-RM2, 3.45 ± 0.18; [177Lu]Lu-AMTG, 3.04 ± 0.08), and 75%-84% of cell-associated activity was receptor-bound. In vivo, both AMTG analogs displayed distinctly higher stability (30 min after injection) and noticeably higher tumor retention than their RM2 counterparts. Conclusion: On the basis of preclinical results, [161Tb]Tb-/[177Lu]Lu-AMTG might reveal a higher therapeutic efficacy than [161Tb]Tb-/[177Lu]Lu-RM2, particularly [161Tb]Tb-AMTG because of additional Auger-electron emissions at the cell membrane level.

Diet quality is associated with nutrition knowledge and physical activity in the US military veterans enrolled in university programmes.

INTRODUCTION: Military veterans are at greater risk for chronic medical conditions, many of which are associated with greater body mass index (BMI). Detrimental changes to diet and physical activity (PA) levels after separation from military service contribute to this disparity which may be mitigated by nutrition education (NE) during service. METHODS: We conducted a survey in student veterans attending two southeastern US universities to determine current nutrition knowledge and hypothesised that NE received during time of service would be associated with better current diet quality (DQ), PA and BMI. Food group knowledge (FGK), and nutrient knowledge, DQ measured by Healthy Eating Index (HEI), and PA reported in metabolic equivalent minutes per week (MET-min/week) were assessed using previously validated questionnaires. Height and weight were also self-reported to calculate BMI. Differences in these variables between NE groups were assessed using Mann-Whitney U tests. Change in DQ, PA and BMI were assessed with Wilcoxon signed rank tests. Stepwise backward regression analysis was used to identify significant predictors related to HEI and BMI status. RESULTS: Sixty-three out of 83 total responses were valid. Respondents were 60% male, 81% white, 43% and 27% served in the Army and Navy, respectively and 30% reported receiving NE while in the military. Veterans who received NE while serving did not have higher FGK, nutrition knowledge, current DQ, MET-min/week or BMI than their counterparts. Overall, respondents reported decreased MET-min/week (p<0.001), increased BMI (p=0.01) and no change in DQ. PA (p=0.014) and FGK (p<0.001) were significant predictors of current DQ, while no variables significantly predicted current BMI. CONCLUSIONS: Inverse relationships between BMI and PA were observed after separation from duty. These results warrant the development and implementation of effective lifestyle interventions in veterans to prevent chronic disease and improve quality of life.

Evaluation of the Aggressive-Variant Prostate Cancer Molecular Signature in Clinical Laboratory Improvement Amendments (CLIA) Environments.

Aggressive-variant prostate cancers (AVPCs) are a subset of metastatic castrate-resistant prostate cancers (mCRPCs) characterized by defects in ≥ two of three of TP53, RB1, and PTEN (AVPCm), a profile linked to lineage plasticity, androgen indifference, and platinum sensitivity. Men with mCRPC undergoing biopsies for progression were assessed for AVPCm using immunohistochemistry (IHC), next-generation sequencing (NGS) of solid tumor DNA (stDNA), and NGS of circulating tumor DNA (ctDNA) assays in CLIA-certified labs. Biopsy characteristics, turnaround times, inter-reader concordance, and inter-assay concordance were assessed. AVPCm was detected in 13 (27%) patients via IHC, two (6%) based on stDNA, and seven (39%) based on ctDNA. The concordance of the IHC reads between pathologists was variable. IHC had a higher detection rate of AVPCm+ tumors with the shortest turnaround times. stDNA had challenges with copy number loss detection, limiting its detection rate. ctDNA detected the greatest proportion of AVPCm+ tumors but had a low tumor content in two thirds of patients. These data show the operational characteristics of AVPCm detection using various assays, and inform trial design using AVPCm as a criterion for patient selection or stratification.

On antigen-specific signals, immune class regulation and energetics: Report III from the workshops on foundational concepts of immune regulation.

This is a report from a one-week workshop held in Athens, Greece in July of 2022. The workshop aimed to identify emerging concepts relevant to the fundamentals of immune regulation and areas for future research. Theories of immune regulation emphasize the role of T cell help or co-stimulation (signal 2). The workshop participants considered how new data on the characteristics of agonist antigens, the role of the antigen receptor signals (signal 1) in driving fate decisions, the effect of energetics on immunity and a better understanding of class-control in the immune response, may impact theories of immune regulation. These ideas were discussed in the context of tumour immunology, autoimmunity, pregnancy and transplantation. Here we present the discussions as a narrative of different viewpoints to allow the reader to join the conversation. These discussions highlight the evolving understanding of the nature of specific antigen recognition and how both antigen-specific and non-specific mechanisms impact immune responses.

Robotic mitral valve re-repair with removal of transcatheter mitral valve repair clips.

We demonstrate a totally endoscopic and percutaneous approach to robotic mitral valve re-repair after the failure of transcatheter edge-to-edge repair.

Tumor Mutational Burden Testing in Solid Tumors.

A 58-year-old man with diabetes, chronic kidney disease, and JAK2-positive myeloproliferative neoplasm is referred for newly diagnosed oligometastatic prostate cancer with substantial urinary symptoms. What would you do next?