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Abstract: Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 patients with CCUS investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count of <100 × 109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the clonal cytopenia risk score (CCRS), which stratified patients into low- (score of <2.5 points), intermediate- (score of 2.5 to <5), and high-risk (score of ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high-risk (37.2%) groups, respectively, by the Gray test (P < .0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P = .005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Emerging evidence supports the important role of the tumor microbiome in oncogenesis, cancer immune phenotype, cancer progression, and treatment outcomes in many malignancies. In this study, we investigated the metastatic melanoma tumor microbiome and its potential roles in association with clinical outcomes, such as survival, in patients with metastatic disease treated with immune checkpoint inhibitors (ICI). Baseline tumor samples were collected from 71 patients with metastatic melanoma before treatment with ICIs. Bulk RNA sequencing (RNA-seq) was conducted on the formalin-fixed, paraffin-embedded and fresh frozen tumor samples. Durable clinical benefit (primary clinical endpoint) following ICIs was defined as overall survival >24 months and no change to the primary drug regimen (responders). We processed RNA-seq reads to carefully identify exogenous sequences using the {exotic} tool. The age of the 71 patients with metastatic melanoma ranged from 24 to 83 years, 59% were male, and 55% survived >24 months following the initiation of ICI treatment. Exogenous taxa were identified in the tumor RNA-seq, including bacteria, fungi, and viruses. We found differences in gene expression and microbe abundances in immunotherapy-responsive versus nonresponsive tumors. Responders showed significant enrichment of bacteriophages in the phylum Uroviricota, and nonresponders showed enrichment of several bacteria, including Campylobacter jejuni. These microbes correlated with immune-related gene expression signatures. Finally, we found that models for predicting prolonged survival with immunotherapy using both microbe abundances and gene expression outperformed models using either dataset alone. Our findings warrant further investigation and potentially support therapeutic strategies to modify the tumor microbiome in order to improve treatment outcomes with ICIs., Significance: We analyzed the tumor microbiome and interactions with genes and pathways in metastatic melanoma treated with immunotherapy and identified several microbes associated with immunotherapy response and immune-related gene expression signatures. Machine learning models that combined microbe abundances and gene expression outperformed models using either dataset alone in predicting immunotherapy responses., (©2024 The Authors; Published by the American Association for Cancer Research.)

Tumor hypoxia has been shown to predict poor patient outcomes in several cancer types, partially because it reduces radiation's ability to kill cells. We hypothesized that some of the clinical effects of hypoxia could also be due to its impact on the tumor microbiome. Therefore, we examined the RNA sequencing data from the Oncology Research Information Exchange Network database of patients with colorectal cancer treated with radiotherapy. We identified microbial RNAs for each tumor and related them to the hypoxic gene expression scores calculated from host mRNA. Our analysis showed that the hypoxia expression score predicted poor patient outcomes and identified tumors enriched with certain microbes such as Fusobacterium nucleatum. The presence of other microbes, such as Fusobacterium canifelinum, predicted poor patient outcomes, suggesting a potential interaction between hypoxia, the microbiome, and radiation response. To experimentally investigate this concept, we implanted CT26 colorectal cancer cells into immune-competent BALB/c and immune-deficient athymic nude mice. After growth, in which tumors passively acquired microbes from the gastrointestinal tract, we harvested tumors, extracted nucleic acids, and sequenced host and microbial RNAs. We stratified tumors based on their hypoxia score and performed a metatranscriptomic analysis of microbial gene expression. In addition to hypoxia-tropic and -phobic microbial populations, analysis of microbial gene expression at the strain level showed expression differences based on the hypoxia score. Thus, hypoxia gene expression scores seem to associate with different microbial populations and elicit an adaptive transcriptional response in intratumoral microbes, potentially influencing clinical outcomes., Significance: Tumor hypoxia reduces radiotherapy efficacy. In this study, we explored whether some of the clinical effects of hypoxia could be due to interaction with the tumor microbiome. Hypoxic gene expression scores associated with certain microbes and elicited an adaptive transcriptional response in others that could contribute to poor clinical outcomes., (©2024 The Authors; Published by the American Association for Cancer Research.)

Competing Interests: Declaration of Competing Interest A.B.P. reports research funding from Genentech, Inc. A.E.G reports research funding from Syros Pharmaceuticals. AR has no relevant conflict of interest to disclose.

Evidence supports significant interactions among microbes, immune cells, and tumor cells in at least 10%-20% of human cancers, emphasizing the importance of further investigating these complex relationships. However, the implications and significance of tumor-related microbes remain largely unknown. Studies have demonstrated the critical roles of host microbes in cancer prevention and treatment responses. Understanding interactions between host microbes and cancer can drive cancer diagnosis and microbial therapeutics (bugs as drugs). Computational identification of cancer-specific microbes and their associations is still challenging due to the high dimensionality and high sparsity of intratumoral microbiome data, which requires large datasets containing sufficient event observations to identify relationships, and the interactions within microbial communities, the heterogeneity in microbial composition, and other confounding effects that can lead to spurious associations. To solve these issues, we present a bioinformatics tool, microbial graph attention (MEGA), to identify the microbes most strongly associated with 12 cancer types. We demonstrate its utility on a dataset from a consortium of nine cancer centers in the Oncology Research Information Exchange Network. This package has three unique features: species-sample relations are represented in a heterogeneous graph and learned by a graph attention network; it incorporates metabolic and phylogenetic information to reflect intricate relationships within microbial communities; and it provides multiple functionalities for association interpretations and visualizations. We analyzed 2,704 tumor RNA sequencing samples and MEGA interpreted the tissue-resident microbial signatures of each of 12 cancer types. MEGA can effectively identify cancer-associated microbial signatures and refine their interactions with tumors., Significance: Studying the tumor microbiome in high-throughput sequencing data is challenging because of the extremely sparse data matrices, heterogeneity, and high likelihood of contamination. We present a new deep learning tool, MEGA, to refine the organisms that interact with tumors., (© 2024 The Authors; Published by the American Association for Cancer Research.)

We now recognize that with aging, hematopoietic stem and progenitor cells (HSPCs) acquire mutations that confer a fitness advantage and clonally expand in a process now termed clonal hematopoiesis (CH). Because CH predisposes to a variety of health problems, including cancers, cardiovascular diseases, and inflammatory conditions, there is intense interest in the inherited alleles associated with the development of CH. DNA variants near TERT, SMC4, KPNA4, IL12A, CD164, and ATM confer the strongest associations. In this review, we discuss our current state of knowledge regarding germline predisposition to CH., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest regarding this review., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Emerging evidence supports the important role of the tumor microbiome in oncogenesis, cancer immune phenotype, cancer progression, and treatment outcomes in many malignancies. In this study, we investigated the metastatic melanoma tumor microbiome and potential roles in association with clinical outcomes, such as survival, in patients with metastatic disease treated with immune checkpoint inhibitors (ICIs). Baseline tumor samples were collected from 71 patients with metastatic melanoma before treatment with ICIs. Bulk RNA-seq was conducted on the formalin-fixed paraffin-embedded (FFPE) tumor samples. Durable clinical benefit (primary clinical endpoint) following ICIs was defined as overall survival ≥24 months and no change to the primary drug regimen (responders). We processed RNA-seq reads to carefully identify exogenous sequences using the {exotic} tool. The 71 patients with metastatic melanoma ranged in age from 24 to 83 years, 59% were male, and 55% survived >24 months following the initiation of ICI treatment. Exogenous taxa were identified in the tumor RNA-seq, including bacteria, fungi, and viruses. We found differences in gene expression and microbe abundances in immunotherapy responsive versus non-responsive tumors. Responders showed significant enrichment of several microbes including Fusobacterium nucleatum, and non-responders showed enrichment of fungi, as well as several bacteria. These microbes correlated with immune-related gene expression signatures. Finally, we found that models for predicting prolonged survival with immunotherapy using both microbe abundances and gene expression outperformed models using either dataset alone. Our findings warrant further investigation and potentially support therapeutic strategies to modify the tumor microbiome in order to improve treatment outcomes with ICIs., Competing Interests: Conflicts of Interest AAT: Contracted research grants with institution from Bristol Myers Squib, Genentech-Roche, Regeneron, Sanofi-Genzyme, Nektar, Clinigen, Merck, Acrotech, Pfizer, Checkmate, OncoSec. Personal consultant/advisory board fees from Bristol Myers Squibb, Merck, Easai, Instil Bio Clinigin, Regeneron, Sanofi-Genzyme, Novartis, Partner Therapeutics, Genentech/Roche, BioNTech, Concert AI, AstraZeneca outside the submitted work. EAS: Astellas/Medivation: research support (clinical trial); Johnson & Johnson: advisory board; Merck: advisory board; Vyriad: advisory board; Aura Biosciences: data safety monitoring board CC: None related to this project. Other unrelated projects and clinical trials (research support from Checkmate Pharmaceuticals, Regeneron, Angiodynamics, Optimum Therapeutics) YZ: Advisory Board: Bristol Myers Squibb, Amgen, Roche Diagnostics, Novartis, Janssen, Eisai, Exelixis, Castle Bioscience, Genzyme Corporation, Astrazeneca, Array, Bayer, Pfizer, Clovis, EMD Serono, Myovant. Grant/research support from: Institution clinical trial support from NewLink Genetics, Pfizer, Exelixis, Eisai. DSMC: Janssen Research and Development Consultant honorarium: Pfizer, Novartis JC: Roche/Genentech CEW, SC, RH, LD, MC, ND, RDD, SH, MH, API, NJ, QM, MM, AEGO, LAR, GT, CMU, DS, ACT: None to report

Evidence supports significant interactions among microbes, immune cells, and tumor cells in at least 10-20% of human cancers, emphasizing the importance of further investigating these complex relationships. However, the implications and significance of tumor-related microbes remain largely unknown. Studies have demonstrated the critical roles of host microbes in cancer prevention and treatment responses. Understanding interactions between host microbes and cancer can drive cancer diagnosis and microbial therapeutics (bugs as drugs). Computational identification of cancer-specific microbes and their associations is still challenging due to the high dimensionality and high sparsity of intratumoral microbiome data, which requires large datasets containing sufficient event observations to identify relationships, and the interactions within microbial communities, the heterogeneity in microbial composition, and other confounding effects that can lead to spurious associations. To solve these issues, we present a bioinformatics tool, MEGA, to identify the microbes most strongly associated with 12 cancer types. We demonstrate its utility on a dataset from a consortium of 9 cancer centers in the Oncology Research Information Exchange Network (ORIEN). This package has 3 unique features: species-sample relations are represented in a heterogeneous graph and learned by a graph attention network; it incorporates metabolic and phylogenetic information to reflect intricate relationships within microbial communities; and it provides multiple functionalities for association interpretations and visualizations. We analyzed 2704 tumor RNA-seq samples and MEGA interpreted the tissue-resident microbial signatures of each of 12 cancer types. MEGA can effectively identify cancer-associated microbial signatures and refine their interactions with tumors., Competing Interests: CONFLICTS OF INTEREST Carlos Chan: None related to this project. Other unrelated projects and clinical trials (Research support from Checkmate Pharmaceuticals, Regeneron, Angiodynamics, Optimum Therapeutics) Yousef Zakharia: Advisory Board: Bristol Myers Squibb, Amgen, Roche Diagnostics, Novartis, Janssen, Eisai, Exelixis, Castle Bioscience, Genzyme Corporation, Astrazeneca, Array, Bayer, Pfizer, Clovis, EMD serono, Myovant. Grant/research support from: Institution clinical trial support from NewLink Genetics, Pfizer, Exelixis, Eisai. DSMC: Janssen Research and Development Consultant honorarium: Pfizer, Novartis Ahmad Tarhini: Contracted research grants with institution from Bristol Myers Squib, Genentech-Roche, Regeneron, Sanofi-Genzyme, Nektar, Clinigen, Merck, Acrotech, Pfizer, Checkmate, OncoSec. Personal consultant/advisory board fees from Bristol Myers Squibb, Merck, Easai, Instil Bio Clinigin, Regeneron, Sanofi-Genzyme, Novartis, Partner Therapeutics, Genentech/Roche, BioNTech, Concert AI, AstraZeneca outside the submitted work. Eric Singer: Astellas/Medivation: research support (clinical trial); Johnson & Johnson: advisory board; Merck: advisory board; Vyriad: advisory board; Aura Biosciences: data safety monitoring board Gregory Riedlinger: AstraZeneca advisory board Bryan Schneider: Genentech-Research support (drug supply only); Pfizer-Research support (Drug supply only); Foundation Medicine-research support (sequencing support)

Clonal hematopoiesis (CH) represents clonal expansion of mutated hematopoietic stem cells detectable in the peripheral blood or bone marrow through next generation sequencing. The current prevailing model posits that CH mutations detected in the peripheral blood mirror bone marrow mutations with clones widely disseminated across hematopoietic compartments. We sought to test the hypothesis that all clones are disseminated throughout hematopoietic tissues by comparing CH in hip vs peripheral blood specimens collected at the time of hip replacement surgery. Here, we show that patients with osteoarthritis have a high prevalence of CH, which involve genes encoding epigenetic modifiers and DNA damage repair pathway proteins. Importantly, we illustrate that CH, including clones with variant allele frequencies >10%, can be confined to specific bone marrow spaces and may be eliminated through surgical excision. Future work will define whether clones with somatic mutations in particular genes or clonal fractions of certain sizes are either more likely to be localized or are slower to disseminate into the peripheral blood and other bony sites., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Second- and third-generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) are associated with cardiovascular adverse events (CVAEs) in patients with Philadelphia chromosome-positive (Ph+) leukemia., Objectives: We hypothesized that second- and third-generation BCR-ABL1 TKIs may cause CVAEs through the activation of Rho-associated coiled-coil containing kinase (ROCK)., Methods: Peripheral blood mononuclear cells from 53 Ph+ patients on TKIs and 15 control patients without Ph+ leukemia were assessed for ROCK activity through capillary electrophoresis (median follow-up = 26 months [Q1-Q3: 5-37 months]). We also investigated the effects of TKIs and ROCK on endothelial dysfunction in vitro, which could contribute to CVAEs., Results: Patients receiving second- and third-generation TKIs had 1.6-fold greater ROCK activity compared with patients receiving imatinib and control patients. Elevated ROCK activity was associated with an increased incidence of CVAEs in Ph+ leukemia patients. In endothelial cells in vitro, we found that dasatinib and ponatinib treatment led to changes in actin intensity and endothelial permeability, which can be reversed by pharmacologic inhibition of ROCK. Ponatinib led to decreased cell proliferation, but this was not accompanied by senescence. Dasatinib and ponatinib treatment led to phosphor-inhibition of endothelial nitric oxide synthase and decreased nitric oxide production. ROCK inhibition reversed endothelial permeability and endothelial nitric oxide synthase-related endothelial dysfunction. Imatinib and nilotinib induce phosphorylation of p190RhoGAP., Conclusions: Our findings suggest ROCK activity may be a prognostic indicator of CVAEs in patients receiving BCR-ABL1 TKIs. With further study, ROCK inhibition may be a promising approach to reduce the incidence of CVAEs associated with second- and third-generation BCR-ABL1 TKIs., Competing Interests: This work was supported by a Stanford Medical Scholars Fellowship and AHA Predoctoral Fellowship to Dr Yu; National Heart, Lung, and Blood Institute T32-HL007381 to Dr Sladojevic; grant support from Ariad to Dr Larson; and National Institutes of Health R01-HL136962 to Dr Liao. Dr Larson reports being a consultant or advisor to Amgen, Ariad/Takeda, Celgene/Bristol Myers Squibb, CVS/Caremark, Epizyme, MorphoSys, and Novartis; has received clinical research support to his institution from Astellas, Celgene, Cellectis, Daiichi Sankyo, Forty-Seven/Gilead, Novartis, and Rafael Pharmaceuticals; and has received royalties from UpToDate. Dr Liao reports being a consultant or advisor to Esperion. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: Given the locally destructive osteolytic nature of primary B-cell lymphoblastic lymphoma (B-LBL) of the spine, careful attention is needed to identify clinical signs and symptoms as well as radiological findings of spinal instability because these lesions may warrant resection, decompression, and instrumentation with posterolateral fusion. Our objective was to summarize the presenting symptoms, clinical features, potential treatment modalities, and clinical outcome of cases described in the literature., Methods: We undertook a systematic literature review to identify all relevant cases and case series describing primary manifestations B-LBL of the spine using Pubmed/Medline. We summarized the findings in accordance with the PRISMA guidelines. We also present a case illustration., Results: Together with our case, 9 cases of primary B-LBL of the spine were identified in 6 male and 3 female patients (age 8-58 years, median 31 years). Back pain was the most common symptom, and five patients also had neurological signs of spinal cord compression. T1-weighted MRI contrast enhancement was seen in 5 cases. Surgery was performed in 5 patients with progression of neurological deficits. Steroid treatment was also given in 3 patients preoperatively. Seven patients had chemotherapy after diagnosis. During follow-up of 1 month to 1 year, 2 cases of recurrence and 4 cases of complete remission were noted; however, with the short follow-up time, patient prognosis overall remains unclear., Conclusions: Primary B-LBL of the spine represents a rare clinical entity whose management mandates a multidisciplinary approach. Careful attention must be paid to the neurological status of the patient, as well as to imaging that may highlight potential local instability of the spine., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by a reciprocal translocation [t(9;22)(q34;q11.2)] that leads to the fusion of ABL1 gene sequences (9q34) downstream of BCR gene sequences (22q11) and is cytogenetically visible as Philadelphia chromosome (Ph). The resulting BCR/ABL1 chimeric protein is a constitutively active tyrosine kinase that activates multiple signaling pathways, which collectively lead to malignant transformation. During the early (chronic) phase of CML (CP-CML), the myeloid cell compartment is expanded, but differentiation is maintained. Without effective therapy, CP-CML invariably progresses to blast phase (BP-CML), an acute leukemia of myeloid or lymphoid phenotype. The development of BCR-AB1 tyrosine kinase inhibitors (TKIs) revolutionized the treatment of CML and ignited the start of a new era in oncology. With three generations of BCR/ABL1 TKIs approved today, the majority of CML patients enjoy long term remissions and near normal life expectancy. However, only a minority of patients maintain remission after TKI discontinuation, a status termed treatment free remission (TFR). Unfortunately, 5-10% of patients fail TKIs due to resistance and are at risk of progression to BP-CML, which is curable only with hematopoietic stem cell transplantation. Overcoming TKI resistance, improving the prognosis of BP-CML and improving the rates of TFR are areas of active research in CML., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aim: Chronic lymphocytic leukemia (CLL) has been shown to cluster in families. First-degree relatives of individuals with CLL have an ~8 fold increased risk of developing the malignancy. Strong heritability suggests pedigree studies will have good power to localize pathogenic genes. However, CLL is relatively rare and heterogeneous, complicating ascertainment and analyses. Our goal was to identify CLL risk loci using unique resources available in Utah and methods to address intra-familial heterogeneity., Methods: We identified a six-generation high-risk CLL pedigree using the Utah Population Database. This pedigree contains 24 CLL cases connected by a common ancestor. We ascertained and genotyped eight CLL cases using a high-density SNP array, and then performed shared genomic segment (SGS) analysis - a method designed for extended high-risk pedigrees that accounts for heterogeneity., Results: We identified a genome-wide significant region ( P = 1.9 × 10 -7 , LOD-equivalent 5.6) at 2q22.1. The 0.9 Mb region was inherited through 26 meioses and shared by seven of the eight genotyped cases. It sits within a ~6.25 Mb locus identified in a previous linkage study of 206 small CLL families. Our narrow region intersects two genes, including CXCR4 which is highly expressed in CLL cells and implicated in maintenance and progression., Conclusion: SGS analysis of an extended high-risk CLL pedigree identified the most significant evidence to-date for a 0.9 Mb CLL disease locus at 2q22.1, harboring CXCR4. This discovery contributes to a growing literature implicating CXCR4 in inherited risk to CLL. Investigation of the segregating haplotype in the pedigree will be valuable for elucidating risk variant(s).

Recent advances in culture-free methods of studying the human microbiome, coupled with strong bioinformatics tools, have provided new insights on the role of the human microbiome in health and disease. The human gut, in particular, houses a vast number and diverse variety of microbes. A plethora of evidence has demonstrated the significant effects of the gut microbiome on local and systemic immunity. Studies in hematopoietic stem cell transplantation recipients provided early evidence of the involvement of the gut microbiome in the development of graft-versus-host disease and its related mortality. Cancer immunotherapy and checkpoint inhibitors, in particular, harness the power of the host's immune system to fight a range of malignancies. Resistance to immunotherapy and fatal immune-related adverse events both continue to be challenges in the field. The role of the human gut microbiome in affecting the response to immunotherapy was recently uncovered through a series of preclinical and clinical studies. The evidence presented in these studies provides tremendous potential for gut microbes to be used for biomarker development and therapeutic intervention trials.

Purpose of Review: To review the diagnosis of individuals with hereditary hematopoietic malignancies (HHMs) that predispose to myelodysplastic syndrome and acute myeloid leukemia, barriers to HHM diagnosis, and unaddressed questions and controversies within the HHM field., Recent Findings: Pathogenic germline mutations in approximately a dozen genes predispose to HHMs, and many more genes are likely to be involved. Many of these HHM genes have only been identified recently. HHM phenotypes are diverse, but may be categorized as "purely" myeloid syndromes, syndromes with abnormal platelet number/function, and HHMs with additional organ system involvement. A number of questions remain unanswered in this emerging field, including the ideal diagnostic approach for patients at risk for HHMs, the optimal surveillance of unaffected carriers, and how to personalize care for individuals with HHMs. The field of HHMs is evolving rapidly. Ongoing research in this area will eventually inform the care of patients with both somatic and hereditary cancer syndromes, but much work remains to be done.

The treatment of acute promyelocytic leukemia (APL) has evolved rapidly in the past two decades after the introduction of highly active drugs, including tretinoin (all- trans-retinoic acid) and arsenic trioxide. It is now possible to treat this disease without the use of traditional cytotoxic chemotherapy. Today's clinical guidelines include multiple regimens, some of which continue to use cytotoxic chemotherapy. This leaves the practicing oncologist with multiple treatment options when faced with a new case of APL. In an effort to standardize our approach to the treatment of newly diagnosed APL, we sought to develop a set of treatment recommendations at our institution. We identified eight major controversial issues in the treatment of APL. These controversial issues include the optimal dose and schedule of both all- trans-retinoic acid and arsenic trioxide, the optimal regimen for high-risk APL, the need for intrathecal prophylaxis, the use of prophylactic corticosteroids, and the need for maintenance therapy after consolidation. We reviewed the relevant literature and used the Delphi method among the coauthors to reach consensus for recommendations on the basis of the best available data and our own clinical experience. In this clinical review, we present our consensus recommendations, the reasoning behind them, and the grading of the evidence that supports them.