A novel HLA-DQB2::MET gene fusion variant in lung adenocarcinoma with prolonged response to tepotinib: a case report.

Background: MET rearrangements are infrequently observed in non-small cell lung cancer (NSCLC). Advanced genomic detection techniques have unveiled such infrequent genomic variations, particularly MET fusions in approximately 0.5% of NSCLC patients. Tyrosine kinase inhibitors (TKIs) have revolutionized the standard of care in lung cancer and more recently a second generation MET TKI tepotinib received Food and Drug Administration (FDA) approval for MET exon 14 alterations in metastatic NSCLC. Despite this, the therapeutic landscape for MET-rearranged NSCLC patients remains significantly unexplored. The aim of our report is to detail a unique case of a patient with metastatic lung adenocarcinoma with a novel HLA-DQB2::MET fusion detected by next-generation sequencing (NGS) following previous treatment resistance. Case Description: A 73-year-old female was initially started on carboplatin, pemetrexed and pembrolizumab with maintenance, but eventually had progression in the left upper lobe (LUL). Upon progression she was enrolled in a clinical trial of a monoclonal antibody with or without a PD-1 inhibitor, but brain metastasis progression was eventually detected by magnetic resonance imaging (MRI) requiring stereotactic radiosurgery (SRS) and a craniotomy. The trial drug was eventually discontinued due to progression and toxicity and NGS on bronchoscopy tissue revealed HLA-DQB2::MET fusion. The patient was initiated on tepotinib and continues with clinical and radiological stable disease for over 12 months. The patient's response to a MET inhibitor, tepotinib, underscores the potential efficacy of selective MET inhibitors for individuals with previously unexplored MET fusions. Conclusions: The positive response to tepotinib of a patient with NSCLC harboring a novel MET-Fusion underscores the importance of the use of comprehensive next-generational sequencing-based panels and highlights the necessity for additional research and clinical exploration of selective MET inhibitors for managing NSCLC with MET rearrangements.

Phyllosphere fungal diversity generates pervasive nonadditive effects on plant performance.

Plants naturally harbor diverse microbiomes that can dramatically impact their health and productivity. However, it remains unclear how fungal microbiome diversity, especially in the phyllosphere, impacts intermicrobial interactions and consequent nonadditive effects on plant productivity. Combining manipulative experiments, field collections, culturing, microbiome sequencing, and synthetic consortia, we experimentally tested for the first time how foliar fungal community diversity impacts plant productivity. We inoculated morning glories (Ipomoea hederifolia L.) with 32 phyllosphere consortia of either low or high diversity or with single fungal taxa, and measured effects on plant productivity and allocation. We found the following: (1) nonadditive effects were pervasive with 56% of fungal consortia interacting synergistically or antagonistically to impact plant productivity, including some consortia capable of generating acute synergism (e.g. > 1000% increase in productivity above the additive expectation), (2) interactions among 'commensal' fungi were responsible for this nonadditivity in diverse consortia, (3) synergistic interactions were approximately four times stronger than antagonistic effects, (4) fungal diversity affected the magnitude but not frequency or direction of nonadditivity, and (5) diversity affected plant performance nonlinearly with the highest performance in low-diversity treatments. These findings highlight the importance of interpreting plant-microbiome interactions under a framework that incorporates intermicrobial interactions and nonadditive outcomes to understand natural complexity.

BRAF Mutations in Patients with Myeloid Neoplasms: A Cancer Center Multigene Next-Generation Sequencing Analysis Experience.

BRAF mutations are rare in myeloid neoplasms and are reported to be associated with poor treatment outcomes. The purpose of our study is to characterize BRAF mutations in myeloid neoplasms using a next-generation sequencing (NGS) panel based on the experiences of a single cancer center. We conducted a retrospective review of patients with myeloid neoplasms who underwent the HopeSeq studies between January 2018 and September 2023. A total of 14 patients with myeloid neoplasms carrying BRAF mutations were included in our cohort. The clinical, pathological, and molecular features of these patients were investigated. Our study indicates that BRAF mutations are rare in myeloid neoplasms, constituting only 0.53% (14/2632) of all myeloid neoplasm cases, with the most common BRAF mutation being BRAF V600E (4/14; 28.6%). Interestingly, we observed that six out of seven patients with acute myeloid leukemia (AML) exhibited AML with monocytic differentiation, and all the patients with AML exhibited an extremely poor prognosis compared to those without BRAF mutations. TET2 (5/14; 35.7%), ASXL1 (4/14; 28.6%), and JAK2 (4/14; 28.6%) were the three most frequently co-mutated genes in these patients. Moreover, we noted concurrent KMT2A gene rearrangement with BRAF mutations in three patients with AML (3/7; 42.9%). Our study suggests that although BRAF mutations are rare in myeloid neoplasms, they play a crucial role in the pathogenesis of specific AML subtypes. Furthermore, RAS pathway alterations, including BRAF mutations, are associated with KMT2A gene rearrangement in AML. However, these findings warrant further validation in larger studies.

Osteoblastoma of the thumb with a novel PRSS44::ALK fusion and literature review of osteoblastoma of hands and feet bones.

Osteoblastomas (OBs) are benign neoplasms constituting approximately 1% of primary bone tumors with a predilection for the spine and sacrum. We describe an OB of the proximal phalanx of the left thumb in a 38-year-old female. MRI of left hand demonstrated a 29-mm mildly expansile enhancing lesion involving the entire proximal phalanx of the first digit. Histology displayed a bone-forming tumor consisting of trabeculae of remodeled woven bone framed by plump osteoblasts in a vascularized background. Next-generation sequencing analysis identified a PRSS44::ALK fusion gene.

Lack of RBC transfusion independence by Day 30 following allogeneic hematopoietic stem cell transplant strongly predicts inferior survival and high non-relapse mortality in acute myeloid leukemia patients.

BACKGROUND: Studies have suggested that acute myeloid leukemia (AML) patients with incomplete hematologic recovery undergoing allogeneic stem cell transplantation (allo-HSCT) had inferior overall survival (OS). STUDY DESIGN AND METHODS: This single-center, retrospective study of AML patients evaluated the relationship between red blood cell (RBC) and platelet (PLT) transfusion requirements during the first 30 days and long-term outcomes after allo-HSCT through multivariate analyses. RESULTS: A total of 692 AML patients received peripheral blood stem cells (89.2%), marrow (5.6%), or umbilical cord (5.2%) from matched related (37.4%), unrelated (49.1%), or haploidentical (8.2%) donors in 2011-2017. Transfusion requirements during the first 30 days for RBC (89.5% transfused, median 3, range 1-18 units) or PLT (98.2% transfused, median 6, range 1-144 units) were variable. By Day 30, 56.7% (95% confidence interval [CI]: 52.8-60.3%) and 86.1% (95% CI: 83.2-88.5%) had achieved RBC and PLT transfusion independence, respectively. Median follow-up among survivors (n = 307) was 7.1 years (range: 2.7-11.8). Lack of RBC transfusion independence by Day 30 was strongly and independently associated with worse 5-year OS (39.2% vs. 59.6%, adjusted hazard ratio [HR] 1.83, 95% CI: 1.49-2.25), leukemia-free survival (35.8% vs. 55.5%, HR = 1.75, 95% CI: 1.43-2.14), and NRM (29.7% vs. 13.7%, HR = 2.05, 95% CI: 1.45-2.89) (p < .001). There was no difference in relapse rates among patients who achieved or did not achieve RBC (p = .34) or PLT (p = .64) transfusion independence. CONCLUSION: Prolonged RBC dependence predicted worse survival and NRM rates, but not increased relapse. Posttransplant surveillance of such patients should be adjusted with more attention to non-relapse complications.

ETV6::NTRK3-associated papillary adenocarcinoma: let us play it by ear.

Ceruminous glands are modified apocrine glands, situated in the external auditory canal (EAC) that, together with sebaceous glands, produce cerumen. The neoplastic transformation of these structures is exceedingly rare. We encounter two cases of EAC adenocarcinoma with ETV6::NTRK3 fusion. Despite this genetic overlap, the morphology and immunophenotype delineate its clear separation from secretory carcinoma. These cases demonstrate novel primary EAC adenocarcinoma with papillary morphology, which expands the ever-increasing list of ETV6::NTRK3-positive malignancies and which we would like to term ETV6::NTRK3-translocation associated papillary adenocarcinoma. We also advocate the use of molecular techniques in rare tumors of uncertain type or differentiation, to increase understanding and possibilities of reproducible classification of these rare neoplasms. Pathologists and oncologists should recognize this entity, which leads to a direct approach for detecting NTRK fusion for appropriate treatment.

Preparing for the unexpected: Recommendations for returning secondary findings in late-stage cancer care.

PURPOSE: We conducted qualitative interviews with patients with cancer and providers to identify gaps in clinical care and highlight care delivery solutions for the return of secondary germline findings. METHODS: Twelve patients and 19 cancer providers from the United States were interviewed between January 2019 and May 2021. Interviews elicited feedback about patient information needs, emotional responses to secondary findings, and recommendations for improving pre-test education. RESULTS: Patients' responses ranged from gratitude to regret, depending on how much pre-test counseling they received before tumor testing. Providers cited insufficient clinic time as a major barrier to pretest education, favoring online support tools and standardized pre-test education models. Providers had differing perspectives on how pre-test education should be integrated into clinical workflows but agreed that it should include the differences between somatic and germline testing, the likelihood of medically actionable findings, and the possibility of being referred to a genetics provider. CONCLUSION: The spectrum of participants' responses to their secondary findings underscores the importance of adequate pre-test discussions before somatic sequencing. Although educational interventions could address patients' information needs and augment traditional pre-test counseling, health care systems, labs, and genetic providers may be called on to play greater roles in pre-test education.

Determination of age-dependent bone marrow normocellularity.

OBJECTIVES: Determination of bone marrow cellularity is a key part of bone marrow examination because it provides a small window into a patient's current state of hematopoietic well-being. Traditionally, bone marrow cellularity is estimated semiquantitatively through microscopic examination of core biopsy specimens harvested from the iliac crest of the pelvic bone. Bone marrow cellularity is then designated as hypercellular, normocellular, or hypocellular based on the patient's age. This assessment can have significant clinical impact, but the variation in the age-adjusted normocellularity range is not sufficiently characterized because of a lack of study data, especially in older patients (those older than 70 years of age). This study further established the normal range of bone marrow cellularity, particularly in older adults. METHODS: In this study, 570 benign staging and healthy donor bone marrows from patients 1 year to 93 years of age were analyzed for cellularity. RESULTS: Linear regression modeling demonstrates that cellularity in adults declines approximately 3% per decade, including after the seventh decade of life. The 90% reference interval for normocellularity in United States is 30% to 75% for those aged 18 to 90 years. CONCLUSIONS: The findings revealed a more stable and slower rate of decline in cellularity with age in adults than the widely used linear model of "100% minus the patient age in decades." Normocellularity is better modeled based on age group. In those younger than 20 years of age, normocellularity ranges from 45% to 85% (mean [SD], 65% [20%]), as defined by Friebert et al in 1998. Based on our study finding of a little less than 3% decline per decade of age, the following is our recommendation for normocellularity range: For individuals 20 to 40 years of age, it ranges from 40% to 70% (mean [SD], 55% [15%]); for individuals 40 to 60 years of age, it ranges from 35% to 65% (mean [SD], 50% [15%]); and for individuals older than 60 years of age, it ranges from 30% to 60% (mean [SD], 45% [15%]). Interestingly, those older than 70 years of age do not show a significant decrease from those aged 60 to 69 years.

Measurable residual disease conversion rate with consolidation chemotherapy in acute myeloid leukemia.

The rate of MRD clearance in AML with standard consolidation chemotherapy is not well defined. A multi-institution retrospective analysis was performed on 107 consecutively treated AML patients in morphologic complete remission with detectable MRD post-induction therapy who received standard chemotherapy consolidation. In response to standard intermediate/high-dose cytarabine consolidation therapy, 26 of 60 patients (43.3%) with MRD threshold of detection of at least 0.1% converted to MRD-negative status (undetectable with assay used), and 6 of 47 patients (12.8%) with MRD threshold of detection > 0.1% converted to MRD-negative status. Multivariable logistic regression for patients with MRD threshold of detection of at least 0.1% showed that, when controlling for age, ELN risk category, dose of cytarabine, and use of a combination agent, treatment with 1 cycle of consolidation cytarabine versus ≥2 cycles decreased the odds of conversion of AML to MRD-negative (OR = 0.24, 95% CI 0.07-0.85, p = 0.03).

Heterogeneous landscape promotes distinct microbial communities in an imperiled scrub ecosystem.

Habitat heterogeneity is a key driver of biodiversity of macroorganisms, yet how heterogeneity structures belowground microbial communities is not well understood. Importantly, belowground microbial communities may respond to any number of abiotic, biotic, and spatial drivers found in heterogeneous environments. Here, we examine potential drivers of prokaryotic and fungal communities in soils across the heterogenous landscape of the imperiled Florida scrub, a pyrogenic ecosystem where slight differences in elevation lead to large changes in water and nutrient availability and vegetation composition. We employ a comprehensive, large-scale sampling design to characterize the communities of prokaryotes and fungi associated with three habitat types and two soil depths (crust and subterranean) to evaluate (i) differences in microbial communities across these heterogeneous habitats, (ii) the relative roles of abiotic, biotic, and spatial drivers in shaping community structure, and (iii) the distribution of fungal guilds across these habitats. We sequenced soils from 40 complete replicates of habitat × soil depth combinations and sequenced the prokaryotic 16S and fungal internal transcribed spacer (ITS) regions using Illumina MiSeq. Habitat heterogeneity generated distinct communities of soil prokaryotes and fungi. Spatial distance played a role in structuring crust communities, whereas subterranean microbial communities were primarily structured by the shrub community, whose roots they presumably interacted with. This result helps to explain the unexpected transition we observed between arbuscular mycorrhiza-dominated soils at low-elevation habitats to ectomycorrhiza-dominated soils at high-elevation habitats. Our results challenge previous notions of environmental determinism of microbial communities and generate new hypotheses regarding symbiotic relationships across heterogeneous environments.

Allelopathy-selected microbiomes mitigate chemical inhibition of plant performance.

Allelopathy is a common and important stressor that shapes plant communities and can alter soil microbiomes, yet little is known about the direct effects of allelochemical addition on bacterial and fungal communities or the potential for allelochemical-selected microbiomes to mediate plant performance responses, especially in habitats naturally structured by allelopathy. Here, we present the first community-wide investigation of microbial mediation of allelochemical effects on plant performance by testing how allelopathy affects soil microbiome structure and how these microbial changes impact germination and productivity across 13 plant species. The soil microbiome exhibited significant changes to 'core' bacterial and fungal taxa, bacterial composition, abundance of functionally important bacterial and fungal taxa, and predicted bacterial functional genes after the addition of the dominant allelochemical native to this habitat. Furthermore, plant performance was mediated by the allelochemical-selected microbiome, with allelopathic inhibition of plant productivity moderately mitigated by the microbiome. Through our findings, we present a potential framework to understand the strength of plant-microbial interactions in the presence of environmental stressors, in which frequency of the ecological stress may be a key predictor of microbiome-mediation strength.

WT1-mutated acute myeloid leukemia is sensitive to fludarabine-based chemotherapy and conditioning regimens.

We conducted a retrospective analysis of WT1-mutated acute myeloid leukemia (AML) patients who underwent allogeneic stem cell transplant. Thirty-seven patients with WT1-mutated AML were identified. Primary induction failure (40%) and early relapse rate (18%) after idarubicin/cytarabine (7 + 3) chemotherapy were observed. All patients with induction failure subsequently achieved CR with additional chemotherapy. There was no significant difference between outcomes after myeloablative vs. reduced intensity (Fludarabine/Melphalan [Flu/Mel]) conditioning regimens. RFS but not OS was significantly better in patients who received FLAG-IDA prior to transplant and/or a fludarabine-containing conditioning. In an independent ex vivo study, WT1-mutated AML samples exhibited greater sensitivity to fludarabine (p = 0.026) and melphalan (p = 0.0005) than non-WT1-mutated AML samples while there was no difference between sensitivity to cytarabine. Our data favor using a fludarabine-based induction for AML with WT1 mutation instead of 7 + 3. Fludarabine conditioning regimens for alloHCT showed better RFS but not OS.

Multidimensional specialization and generalization are pervasive in soil prokaryotes.

Habitat specialization underpins biological processes from species distributions to speciation. However, organisms are often described as specialists or generalists based on a single niche axis, despite facing complex, multidimensional environments. Here, we analysed 236 environmental soil microbiomes across the United States and demonstrate that 90% of >1,200 prokaryotes followed one of two trajectories: specialization on all niche axes (multidimensional specialization) or generalization on all axes (multidimensional generalization). We then documented that this pervasive multidimensional specialization/generalization had many ecological and evolutionary consequences. First, multidimensional specialization and generalization are highly conserved with very few transitions between these two trajectories. Second, multidimensional generalists dominated communities because they were 73 times more abundant than specialists. Lastly, multidimensional specialists played important roles in community structure with ~220% more connections in microbiome networks. These results indicate that multidimensional generalization and specialization are evolutionarily stable with multidimensional generalists supporting larger populations and multidimensional specialists playing important roles within communities, probably stemming from their overrepresentation among pollutant detoxifiers and nutrient cyclers. Taken together, we demonstrate that the vast majority of soil prokaryotes are restricted to one of two multidimensional niche trajectories, multidimensional specialization or multidimensional generalization, which then has far-reaching consequences for evolutionary transitions, microbial dominance and community roles.

Recurrent/Metastatic Nasopharyngeal Carcinoma Treatment from Present to Future: Where Are We and Where Are We Heading?

OPINION STATEMENT: Nasopharyngeal carcinoma (NPC) is distinct in its anatomic location and biology from other epithelial head and neck cancer (HNC). There are 3 WHO subtypes, which considers the presence of Epstein-Barr virus (EBV) and other histopathology features. Despite the survival benefit obtained from modern treatment modalities and techniques specifically in the local and locally advanced setting, a number of patients with this disease will recur and subsequently die of distant metastasis, locoregional relapse, or both. In the recurrent setting, the ideal therapy approach continues to be a topic of discussion and current recommendations are platinum-based combination chemotherapy. Phase III clinical trials which led to the approval of pembrolizumab or nivolumab for head and neck squamous cell carcinoma (HNSCC) specifically excluded NPC. No immune checkpoint inhibitor therapy, to date, has been approved by the FDA to treat NPC although the National Comprehensive Cancer Network (NCCN) recommendations do include use of these agents. Hence, this remains the major challenge for treatment options. Nasopharyngeal carcinoma is challenging as it is really 3 different diseases, and much research is required to determine best options and sequencing of those options. This article is going to address the data to date and discuss ongoing research in EBV + and EBV - inoperable recurrent/metastatic NPC patients.

Past microbial stress benefits tree resilience.

Soil microbiota from stressful environments provide an avenue for climate resilience.

Complete response to chemoimmunotherapy with bevacizumab in synchronous multiple primary cancers: pulmonary adenocarcinoma and sarcomatoid carcinoma.

A small percentage of patients have multiple synchronous primary cancers at presentation. In the last five years, many regimens associated with immunotherapy and chemotherapy were approved for first-line metastatic non-small-cell lung cancer (NSCLC) and other solid tumors, but the study of immunotherapy when multiple cancers are present in one patient remains incomplete. Next-generation sequencing biomarkers and immunotherapy markers including PD-L1 can be effectively utilized in the diagnosis and treatment plan for multiple synchronous primary cancers. Immune biomarkers and PD-L1 expression warrant individualized treatments in synchronous primary adenocarcinoma and pulmonary sarcomatoid carcinoma. We describe the case of a patient with pulmonary sarcomatoid carcinoma and lung adenocarcinoma, metastatic to brain de novo. The patient achieved a complete response after only three cycles of carboplatin, paclitaxel, bevacizumab, and atezolizumab and remains free of any evidence of disease after 18 mo of maintenance therapy.

Early Stage and Locally Advanced Nasopharyngeal Carcinoma Treatment from Present to Future: Where Are We and Where Are We Going?

OPINION STATEMENT: Nasopharyngeal carcinoma (NPC) is a rare malignancy, endemic in China, that is commonly diagnosed in locally advanced scenarios. Its pathogenesis is strongly associated with Epstein-Barr virus (EBV), an infection for which measuring EBV plasma DNA levels has helped as a prognostic factor guiding treatment options, including a stronger treatment in those with high titers. Additionally, tobacco and alcohol are often implicated in EBV-negative patients. The local disease is treated with radiotherapy alone, preferentially intensity modulated radiotherapy. For locally advanced disease, the backbone treatment is concurrent chemoradiotherapy with the ongoing research dilemma being adding adjuvant chemotherapy or induction chemotherapy. The ongoing research is focused not only on identifying patients that will benefit from adjuvant or induction chemotherapy, but also on identifying the best chemotherapeutic regimen, regimen alternatives to diminish toxicity, the role that immune checkpoint inhibitors play, and the use of molecularly guided treatment targeting patients with NPC whether driven by EBV or tobacco and alcohol. Knowing the precise oncogenesis of NPC not only offers a better understanding of the role that EBV plays in this tumor but also helps create targeted therapies that could potentially block important pathways such as the NF-κB pathway. Much is yet to be done, but the prognosis and management of NPC patients have changed drastically, offering precise treatment methods and excellent control of the disease, even in locally advanced scenarios.

Ph-like acute lymphoblastic leukemia in adults: understanding pathogenesis, improving outcomes, and future directions for therapy.

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subgroup of B cell ALL with distinct genotypes, unified by gene expression profile similar to Ph-positive ALL, but lacking the BCR::ABL1 fusion. Ph-like ALL patients respond inadequately to conventional chemotherapy with higher rates of induction failure, persistent measurable residual disease, and lower survival rates compared to other B cell ALL subtypes. Considering Ph-like ALL's chemo-refractory nature, there is an interest in pursuing innovative therapeutic approaches to treat, including the combination of tyrosine kinase inhibitors with frontline regimens, and early introduction of novel antibody-drug conjugates and immunotherapies. Accurate diagnosis and disease-risk stratification are key to increase access for high-risk patients to allogeneic hematopoietic cell transplantation in their first complete remission. In this review, we will discuss our current knowledge of pathogenesis of Ph-like ALL, diagnostic strategies, as well as emerging data on new and current treatment strategies for this disease.