Shoot hydraulic impairments induced by root waterlogging: parallels and contrasts with drought.

Soil waterlogging and drought correspond to contrasting water extremes resulting in plant dehydration. Dehydration in response to waterlogging occurs due to impairments to root water transport, but no previous study has addressed whether limitations to water transport occur beyond this organ or whether dehydration alone can explain shoot impairments. Using common bean (Phaseolus vulgaris) as a model species, we report that waterlogging also impairs water transport in leaves and stems. During the very first hours of waterlogging, leaves transiently dehydrated to water potentials close to the turgor loss point, possibly driving rapid stomatal closure and partially explaining the decline in leaf hydraulic conductance. The initial decline in leaf hydraulic conductance (occurring within 24 h), however, surpassed the levels predicted to occur based solely on dehydration. Constraints to leaf water transport resulted in a hydraulic disconnection between leaves and stems, furthering leaf dehydration during waterlogging and after soil drainage. As leaves dehydrated later during waterlogging, leaf embolism initiated and extensive embolism levels amplified leaf damage. The hydraulic disconnection between leaves and stems prevented stem water potentials from declining below the threshold for critical embolism levels in response to waterlogging. This allowed plants to survive waterlogging and soil drainage. In summary, leaf and stem dehydration are central in defining plant impairments in response to waterlogging, thus creating similarities between waterlogging and drought. Yet, our findings point to the existence of additional players (likely chemicals) partially controlling the early declines in leaf hydraulic conductance and contributing to leaf damage during waterlogging.

Influence of Thyroglobulin (Tg) Autoantibodies on Tg levels Measured by Different Methodologies: (IMA, LC-MS/MS and RIA).

CONTEXT: Serum thyroglobulin (Tg) measured by Immunometric assays (IMA) is prone to underestimation due to Tg autoantibody (TgAb) interference, often prompting reflex Tg measurement by liquid chromatography/tandem mass spectrometry (MS) or radioimmunoassay (RIA). OBJECTIVE: IMA, MS and RIA methodologies were used to measure serum Tg in TgAb-negative (TgAb-) and TgAb-positive (TgAb+) patients with either distant metastatic thyroid cancer (DTC) or hyperthyroidism (HY) - patients in whom a detectable serum Tg would be expected. CONCLUSIONS: 1) Between-method Tg variability necessitates method continuity when monitoring the Tg trends of TgAb- DTC patients. 2) The presence and concentration of TgAb appeared to have a lowering effect on serum Tg measured by all methodologies (IMA, MS and RIA). 3) Since the reliability of Tg measured in the presence of TgAb is often uncertain, the TgAb trend (measured by the same method) may be a useful surrogate DTC tumor marker.

Exogenous Nitric Oxide Alleviates Water Deficit and Increases the Seed Production of an Endemic Amazonian Canga Grass.

Open pit mining can cause loss in different ecosystems, including damage to habitats of rare and endemic species. Understanding the biology of these species is fundamental for their conservation, and to assist in decision-making. Sporobolus multiramosus is an annual grass endemic to the Amazon canga ecosystems, which comprise rocky outcrop vegetation covering one of the world's largest iron ore reserves. Here, we evaluated whether nitric oxide aids S. multiramosus in coping with water shortages and examined the physiological processes behind these adaptations. nitric oxide application improved the water status, photosynthetic efficiency, biomass production, and seed production and germination of S. multiramosus under water deficit conditions. These enhancements were accompanied by adjustments in leaf and root anatomy, including changes in stomata density and size and root endodermis thickness and vascular cylinder diameter. Proteomic analysis revealed that nitric oxide promoted the activation of several proteins involved in the response to environmental stress and flower and fruit development. Overall, the results suggest that exogenous nitric oxide has the potential to enhance the growth and productivity of S. multiramosus. Enhancements in seed productivity have significant implications for conservation initiatives and can be applied to seed production areas, particularly for the restoration of native ecosystems.

Understanding plant responses to saline waterlogging: insights from halophytes and implications for crop tolerance.

MAIN CONCLUSION: Saline and wet environments stress most plants, reducing growth and yield. Halophytes adapt with ion regulation, energy maintenance, and antioxidants. Understanding these mechanisms aids in breeding resilient crops for climate change. Waterlogging and salinity are two abiotic stresses that have a major negative impact on crop growth and yield. These conditions cause osmotic, ionic, and oxidative stress, as well as energy deprivation, thus impairing plant growth and development. Although few crop species can tolerate the combination of salinity and waterlogging, halophytes are plant species that exhibit high tolerance to these conditions due to their morphological, anatomical, and metabolic adaptations. In this review, we discuss the main mechanisms employed by plants exposed to saline waterlogging, intending to understand the mechanistic basis of their ion homeostasis. We summarize the knowledge of transporters and channels involved in ion accumulation and exclusion, and how they are modulated to prevent cytosolic toxicity. In addition, we discuss how reactive oxygen species production and cell signaling enhance ion transport and aerenchyma formation, and how plants exposed to saline waterlogging can control oxidative stress. We also address the morphological and anatomical modifications that plants undergo in response to combined stress, including aerenchyma formation, root porosity, and other traits that help to mitigate stress. Furthermore, we discuss the peculiarities of halophyte plants and their features that can be leveraged to improve crop yields in areas prone to saline waterlogging. This review provides valuable insights into the mechanisms of plant adaptation to saline waterlogging thus paving the path for future research on crop breeding and management strategies.

Inherited ARPC5 mutations cause an actinopathy impairing cell motility and disrupting cytokine signaling.

We describe the first cases of germline biallelic null mutations in ARPC5, part of the Arp2/3 actin nucleator complex, in two unrelated patients presenting with recurrent and severe infections, early-onset autoimmunity, inflammation, and dysmorphisms. This defect compromises multiple cell lineages and functions, and when protein expression is reestablished in-vitro, the Arp2/3 complex conformation and functions are rescued. As part of the pathophysiological evaluation, we also show that interleukin (IL)-6 signaling is distinctively impacted in this syndrome. Disruption of IL-6 classical but not trans-signaling highlights their differential roles in the disease and offers perspectives for therapeutic molecular targets.

Metastatic Differentiated Thyroid Cancer Survival Is Unaffected by Mode of Preparation for 131I Administration.

Context: Recombinant human thyrotropin (rhTSH) is currently not Food and Drug Administration approved for the treatment of high-risk patients with differentiated thyroid cancer (DTC). Objective: The goal of our study was to compare the outcomes in higher-risk patients with metastatic DTC prepared for radioiodine (RAI) therapy with rhTSH vs thyroid hormone withdrawal (THW). Methods: A retrospective chart review was performed of patients with metastatic DTC in follow-up at MedStar Washington Hospital Center and MedStar Georgetown University Hospital from 2009 to 2017. Patients were divided according to their preparation for RAI therapy, with assessment of progression-free survival (PFS) and overall survival (OS). Results: Fifty-five patients with distant metastases (16 men, 39 women) were prepared for RAI therapy exclusively either with rhTSH (n = 27) or with THW (n = 28). There were no statistically significant differences between the groups regarding clinicopathological features and history of RAI therapies. The median follow-up time for patients with rhTSH-aided therapies was 4.2 years (range, 3.3-5.5 years) and for patients with THW-aided therapies was 6.8 years (range, 4.2-11.6 years) (P = .002). Multivariate analysis showed that the method of thyrotropin stimulation was not associated with a difference in PFS or OS. Conclusion: As has been shown previously for low-risk DTC, this study indicates that the mode of preparation for RAI therapy does not appear to influence the outcomes of patients with metastatic DTC. PFS and OS were similar for patients with THW-aided or rhTSH-aided RAI therapies.

Nodular regenerative hyperplasia in X-linked agammaglobulinemia: An underestimated and severe complication.

BACKGROUND: Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary immunodeficiency but data in XLA are limited. OBJECTIVES: This study sought to describe NRH prevalence, associated features, and impact in patients with XLA. METHODS: Medical records of all patients with XLA referred to the National Institutes of Health between October 1994 and June 2019 were reviewed. Liver biopsies were performed when clinically indicated. Patients were stratified into NRH+ or NRH- groups, according to their NRH biopsy status. Fisher exact test and Mann-Whitney test were used for statistical comparisons. RESULTS: Records of 21 patients with XLA were reviewed, with a cumulative follow-up of 129 patient-years. Eight patients underwent ≥1 liver biopsy of whom 6 (29% of the National Institutes of Health XLA cohort) were NRH+. The median age at NRH diagnosis was 20 years (range, 17-31). Among patients who had liver biopsies, alkaline phosphatase levels were only increased in patients who were NRH+ (P = .04). Persistently low platelet count (<100,000 per µL for >6 months), mildly to highly elevated hepatic venous pressure gradient and either hepatomegaly and/or splenomegaly were present in all patients who were NRH+. In opposition, persistently low platelet counts were not seen in patients who were NRH-, and hepatosplenomegaly was observed in only 1 patient who was NRH-. Hepatic venous pressure gradient was normal in the only patient tested who was NRH-. All-cause mortality was higher among patients who were NRH+ (5 of 6, 83%) than in the rest of the cohort (1 of 15, 7% among patients who were NRH- and who were classified as unknown; P = .002). CONCLUSIONS: NRH is an underreported, frequent, and severe complication in XLA, which is associated with increased morbidity and mortality.

T and B cell abnormalities, pneumocystis pneumonia, and chronic lymphocytic leukemia associated with an AIOLOS defect in patients.

AIOLOS/IKZF3 is a member of the IKAROS family of transcription factors. IKAROS/IKZF1 mutations have been previously associated with different forms of primary immunodeficiency. Here we describe a novel combined immunodeficiency due to an IKZF3 mutation in a family presenting with T and B cell involvement, Pneumocystis jirovecii pneumonia, and/or chronic lymphocytic leukemia. Patients carrying the AIOLOS p.N160S heterozygous variant displayed impaired humoral responses, abnormal B cell development (high percentage of CD21low B cells and negative CD23 expression), and abrogated CD40 responses. Naive T cells were increased, T cell differentiation was abnormal, and CD40L expression was dysregulated. In vitro studies demonstrated that the mutant protein failed DNA binding and pericentromeric targeting. The mutant was fully penetrant and had a dominant-negative effect over WT AIOLOS but not WT IKAROS. The human immunophenotype was recapitulated in a murine model carrying the corresponding human mutation. As demonstrated here, AIOLOS plays a key role in T and B cell development in humans, and the particular gene variant described is strongly associated with immunodeficiency and likely malignancy.

Biotin Interference in Assays for Thyroid Hormones, Thyrotropin and Thyroglobulin.

Background: Biotin has been reported to interfere with several commonly used laboratory assays resulting in misleading values and possible erroneous diagnosis and treatment. This report describes a prospective study of possible biotin interference in thyroid-related laboratory assays, with a comparison of different commonly used assay platforms. Materials and Methods: Thirteen adult subjects (mean age 45 ± 13 years old) were administered biotin 10 mg/day for eight days. Blood specimens were collected at three time points on day 1 and on day 8 (baseline, two, and five hours after biotin ingestion). Thyrotropin (TSH), free triiodothyronine (fT3), free thyroxine (fT4), total triiodothyronine (TT3), total thyroxine (TT4), thyroxine binding globulin (TBG), and thyroglobulin (Tg) levels were analyzed with four different platforms: Abbott Architect, Roche Cobas 6000, Siemens IMMULITE 2000, and liquid chromatography with tandem mass spectrometry (LC-MS/MS). TSH, fT3, fT4, TT3, and TT4 were measured with Abbott Architect and Roche Cobas 6000. fT3, fT4, TT3, and TT4 were also measured by LC-MS/MS. Tg was measured by Siemens IMMULITE 2000. TBG was assessed with Siemens IMMULITE 2000. Results: Significant changes in TSH, fT4, and TT3 measurements were observed after biotin exposure when the Roche Cobas 6000 platform was used. Biotin intake resulted in a falsely lower Tg level when measurements were performed with Siemens IMMULITE 2000. At the time points examined, maximal biotin interference was observed two hours after biotin exposure both on day 1 and day 8. Conclusions: A daily dose of 10 mg was shown to interfere with specific assays for TSH, fT4, TT3, and Tg. Physicians must be aware of the potential risk of erroneous test results in subjects taking biotin supplements. Altered test results for TSH and Tg can be particularly problematic in patients requiring careful titration of levothyroxine therapy such as those with thyroid cancer.

Germline IKZF1 mutations and their impact on immunity: IKAROS-associated diseases and pathophysiology.

Introduction: The transcription factor IKAROS and IKAROS family members are critical for the development of lymphocyte and other blood cell lineages. Germline heterozygous IKZF1 mutations have been described in primary immunodeficiency as well as in human hematologic malignancies, affecting both B and T cells. Depending on the allelic variants of IKZF1 mutations (haploinsufficiency and dominant negative) clinical phenotypes vary from bacterial, viral, or fungal infection to autoimmune disease and malignancy.Areas covered: In this review, the authors provide an overview of genotype-phenotype correlation and clinical manifestations in patients with IKZF1 mutations. The importance of accurate diagnosis and monitoring immunological changes is also discussed for the management of these complex and rare diseases. IKZF1/IKAROS, immunodeficiency, and CVID were used as the search terms in PubMed and Google Scholar.Expert opinion: Over the past 5 years both genetic and molecular studies have unveiled surprisingly diverse roles of IKZF1 mutations in primary immunodeficiency. While an increasing number of novel IKZF1 variants are being reported, limited, and complex laboratory testing is necessary to verify the mutation's pathogenicity. Therefore, the combination of understanding mechanistic concepts and clinical and immunological follow-up is necessary to increase our knowledge of IKAROS-associated diseases.

Do Molecular Profiles of Primary Versus Metastatic Radioiodine Refractory Differentiated Thyroid Cancer Differ?

Management of metastatic radioiodine refractory differentiated thyroid cancer (DTC) can be a therapeutic challenge. Generally, little is known about the paired molecular profile of the primary tumor and the metastases and whether they harbor the same genetic abnormalities. The present study compared the molecular profile of paired tumor specimens (primary tumor/metastatic sites) from patients with radioiodine refractory DTC in order to gain insight into a possible basis for resistance to radioiodine. Twelve patients with radioiodine refractory metastases were studied; median age at diagnosis of 61 years (range, 25-82). Nine patients had papillary TC (PTC), one had follicular TC (FTC), and two had Hürthle cell TC (HTC). Distant metastases were present in the lungs (n = 10), bones (n = 4), and liver (n = 1). The molecular profiling of paired tumors was performed with a panel of 592 genes for Next Generation Sequencing, RNA-sequencing, and immunohistochemistry. Digital microfluidic PCR was used to investigate TERT promoter mutations. The genetic landscape of all paired sites comprised BRAF, NRAS, HRAS, TP53, ATM, MUTYH, POLE, and NTRK genes, including BRAF and NTRK fusions. BRAF V600E was the most common point mutation in the paired specimens (5/12). TERT promoter mutation C228T was detected in one case. PD-L1 expression at metastatic sites was highly positive (95%) for one patient with HTC. All specimens were stable for microsatellite instability testing, and the tumor mutation burden was low to intermediate. Therefore, the molecular profile of DTC primary and metastatic lesions can show heterogeneity, which may help explain some altered responses to therapeutic intervention.

IKAROS-Associated Diseases in 2020: Genotypes, Phenotypes, and Outcomes in Primary Immune Deficiency/Inborn Errors of Immunity.

IKAROS, encoded by IKZF1, is a zinc finger transcription factor and a critical regulator of hematopoiesis. Mutations in IKZF1 have been implicated in immune deficiency, autoimmunity, and malignancy in humans. Somatic IKZF1 loss-of-function mutations and deletions have been shown to increase predisposition to the development of B cell acute lymphoblastic leukemia (B-ALL) and associated with poor prognosis. In the last 4 years, germline heterozygous IKZF1 mutations have been reported in primary immune deficiency/inborn errors of immunity. These allelic variants, acting by either haploinsufficiency or dominant negative mechanisms affecting particular functions of IKAROS, are associated with common variable immunodeficiency, combined immunodeficiency, or primarily hematologic phenotypes in affected patients. In this review, we provide an overview of genetic, clinical, and immunological manifestations in patients with IKZF1 mutations, and the molecular and cellular mechanisms that contribute to their disease as a consequence of IKAROS dysfunction.

N-Glycan Modification in Covid-19 Pathophysiology: In vitro Structural Changes with Limited Functional Effects.

In 2014, we reported two siblings with a rare congenital disorder of glycosylation due to mutations in mannosyl-oligosaccharide glucosidase (MOGS). The glycan alteration derived from this disease resulted in an in vitro infection resistance to particular enveloped, N-glycosylation-dependent viruses as influenza and HIV. As part of the global effort to find safe and effective antiviral therapies for Covid-19, we assessed the in vitro activity of the FDA-approved α-glucosidase inhibitor miglustat against SARS-CoV-2. Expression plasmids encoding SARS-CoV-2 spike (S) and human ACE2 glycoproteins (GP) were tested to evaluate N-glycan modifications induced by α-glucosidase inhibition. Immunoprecipitation was used to assess binding between these two GP. Cell-to-cell fusion was assessed by immunofluorescence of cocultures of SARS-CoV-2 S and ACE2-expressing cells. Miglustat effect on immune response was tested by measuring cytokine release from PBMC exposed to purified SARS-CoV-2 S. In our overexpression system, miglustat successfully and specifically modified N-glycans in both SARS-CoV-2 S and its main receptor ACE2. Binding between these two GP was not affected by glycan modifications. A surrogate marker for viral cytopathic effect, measured as receptor-dependent SARS-CoV-2 S-driven cell-to-cell fusion, was not disrupted by miglustat treatment. This observation was further confirmed in MOGS-null transfected cells. Miglustat produced no statistically significant effects on cytokine production following SARS-CoV-2 S glycoprotein stimulation of PBMC. Our work shows that despite clear N-glycan alteration in the presence of miglustat, the functions of the Covid-19-related glycoproteins studied were not affected, making it unlikely that miglustat can change the natural course of the disease.

IKAROS Family Zinc Finger 1-Associated Diseases in Primary Immunodeficiency Patients.

Ikaros zinc finger 1 (IKZF1 or Ikaros) is a hematopoietic zinc finger DNA-binding transcription factor that acts as a critical regulator of lymphocyte and myeloid differentiation. Loss-of-function germline heterozygous mutations in IKZF1 affecting DNA-binding were described as causative of 2 distinct primary immunodeficiency (PID)/inborn error of immunity diseases. Mutations acting by haploinsufficiency present with a common variable immune deficiency-like phenotype mainly characterized by increased susceptibility to infections. Mutations acting in a dominant negative fashion present with a combined immunodeficiency phenotype with high prevalence of Pneumocystis jirovecii pneumonia. Pathophysiology and manifestations of IKAROS-associated diseases in patients with PID are reviewed here.

A Novel Risk Stratification System for Thyroid Nodules With Indeterminate Cytology-A Pilot Cohort Study.

Background: Thyroid ultrasound (US), fine needle aspiration biopsy (FNAB), and molecular testing have been widely used to stratify the risk of malignancy in thyroid nodules. The goal of this study was to investigate a novel diagnostic approach for cytologically indeterminate thyroid nodules (ITN) based upon a combination of US features and genetic alterations. Methods: We performed a pilot cohort study of patients with ITN (Bethesda III/IV), who underwent surgical treatment. Based on standardized sonographic patterns established by the American Thyroid Association (ATA), each ITN received an US score (XUS), ranging between 0 and 0.9 according to its risk of thyroid cancer (TC). DNA and RNA were extracted from pathologic material, available for all patients, and subjected to Oncomine™ Comprehensive Assay v2 (OCAv2) next-generation sequencing. Each genetic alteration was annotated based on its strength of association with TC and its sum served as the genomic classifier score (XGC). The total risk score (TRS) was the sum of XUS and XGC. ROC curves were generated to assess the diagnostic accuracy of XUS, XGC, and TRS. Results: The study cohort consisted of 50 patients (39 females and 11 males), aged 47.5 ± 14.8 years. Three patients were excluded due to molecular testing failure. Among the remaining 47 patients, 28 (59.6%) were diagnosed with TC. BRAFV600E was the most common mutation in papillary TC, PAX8-PPARG fusion was present in NIFTP, pathogenic variants of SLX4, ATM, and NRAS were found in Hürthle cell TC and RET mutations in medullary TC. The diagnostic accuracy of XGC and TRS was significantly higher compared with XUS (88 vs. 62.5%, p < 0.001; 85.2 vs. 62.5%, p < 0.001, respectively). However, this increased accuracy was due to significantly better sensitivity (80.7 vs. 34.6%, p < 0.001; 84.6 vs. 34.6%, p < 0.001, respectively) without improved specificity (94.7 vs. 90%, p = 0.55; 85.7 vs. 90%, p = 0.63, respectively). Conclusion: Molecular testing might not be necessary in ITN with high-risk US pattern (XUS = 0.9), as specificity of TC diagnosis based on Xus alone is sufficient and not improved with molecular testing. OCAv2 is useful in guiding the management of ITN with low-to-intermediate risk US features (XUS < 0.9), as it increases the accuracy of TC diagnosis.

Nationwide Survey on Implementation of 2011 Nuclear Regulatory Commission Policy on Release of Patients After 131I Therapy for Thyroid Cancer.

The objective of this nationwide survey was to evaluate whether there has been a change in the practice regarding hospital release of differentiated thyroid cancer patients treated with 131I since the publication of Nuclear Regulatory Commission Regulatory Issue Summary 2011-01 addressing patient release. Methods: A survey was emailed to approximately 25,000 members of ThyCa: Thyroid Cancer Survivors' Association, Inc., and was available online from March to August 2018. Responses were included from adult patients regarding their most recent 131I therapy received between 2011 and 2018 ("after 2011"). Responses to this survey were compared with those of a similar previous survey for 131I therapies received between 1997 and 2009 ("before 2009"). Results: Of the 2,136 responses, 1,111 met the inclusion criteria. A similar percentage (∼98%) of patients were given oral or written radiation safety instructions (RSIs) after 2011 and before 2009, with a shift away from nuclear medicine physicians providing instructions after 2011 (43%) in comparison with before 2009 (54%; P < 0.001). More patients were able to discuss and individualize the RSIs after 2011 (67%) than before 2009 (29%; P < 0.001). However, 2% of patients do not recall ever receiving RSIs after 2011. After 2011, more patients were treated as outpatients (87%) than before 2009 (66%; P < 0.001). For outpatients, more patients were discharged within 30 min after receiving 131I therapy after 2011 (78%) than before 2009 (72%; P = 0.002). The same percentage (0.6%) of patients traveled more than 2 h with at least 2 occupants in the vehicle within approximately 1 m of the patient after 2011 and before 2009. Immediately after therapy, a similar percentage of patients stayed in a nonprivate residence after 2011 (4%) and before 2009 (5%; P = 0.28). Of the 27 outpatients released within 30 min to nonprivate residences, 2 patients received 5.55-11.1 GBq (150-299 mCi) of 131I. Conclusion: This survey suggests that since publication of the Nuclear Regulatory Commission Regulatory Issue Summary 2011-01 on patient release after radioiodine therapy, there have been improvements in some radiation safety practices on release of outpatients, as well as improvements in patient compliance on travel and lodging.

PI3K pathway defects leading to immunodeficiency and immune dysregulation.

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is involved in a broad range of cellular processes, including growth, metabolism, differentiation, proliferation, motility, and survival. The PI3Kδ enzyme complex is primarily present in the immune system and comprises a catalytic (p110δ) and regulatory (p85α) subunit. Dynamic regulation of PI3Kδ activity is required to ensure normal function and differentiation of immune cells. In the last decade, discovery of germline mutations in genes involved in the PI3Kδ pathway (PIK3CD, PIK3R1, or phosphatase and tensin homolog [PTEN]) proved that both overactivation and underactivation (gain of function and loss of function, respectively) of PI3Kδ lead to impaired and dysregulated immunity. Although a small group of patients reported to underactivate PI3Kδ show predominantly humoral defects and autoimmune features, more than 200 patients have been described with overactivation of PI3Kδ, presenting with a much more complex phenotype of combined immunodeficiency and immune dysregulation. The clinical and immunologic characterization, as well as current pathophysiologic understanding and specific therapies for PI3K pathway defects leading to immunodeficiency and immune dysregulation, are reviewed here.

Improved Survival After Multimodal Approach with 131I Treatment in Patients with Bone Metastases Secondary to Differentiated Thyroid Cancer.

Background: The objective of this study was to evaluate the overall survival (OS) of radioiodine (131I) treatments alone or combined with non-131I treatments in patients with bone metastases (BM) of differentiated thyroid cancer (DTC). Methods: This was a retrospective study of patients who were evaluated between 2001 and 2018 at MedStar Washington Hospital Center and who had DTC, BM, and at least one 131I treatment after the diagnosis of BM. The OS was analyzed by Kaplan-Meier survival curves and was compared by log-rank test between two groups: patients who received 131I treatments alone and those who received treatments combining 131I with non-131I treatments (CombTx). Non-131I treatments include surgery, radiofrequency ablation, cryotherapy, arterial embolization, external beam radiation, Cyberknife, systemic targeted therapy, and anti-resorptive medication. Results: A total of 77 patients met the above criteria and were followed up to 41 years. Thirty percent (23/77) of patients received 131I treatment alone, and 70% (54/77) received CombTx. For 131I treatment alone, the median survival was 3.9 years, and the 1-, 2-, 3-, 5-, and 10-year OS rates were 86%, 81%, 61%, 35%, and 23%, respectively. For CombTx, the median survival was 7.7 years, and the 1-, 2-, 3-, 5-, and 10-year OS rates were 96%, 92%, 86%, 69%, and 30%, respectively. Patients who had undergone initial 131I therapy within six months post thyroidectomy demonstrated a better median survival after BM diagnosis than those whose initial 131I therapy was six months or more after thyroidectomy (6.5 vs. 0.5 years; p < 0.001). Patients who received external beam radiation therapy demonstrated a better median survival than those who did not (7.8 vs. 4.4 years; p = 0.016). Patients who received denosumab demonstrated a better median survival than those who did not (7.7 vs. 5.2 years; p = 0.03). Patients who were <55 years of age at the initial diagnosis of DTC or at the initial diagnosis of BM had a better median OS than those diagnosed at ≥55 years of age (both p = 0.01). In the multivariate analysis, only age at initial diagnosis of DTC and initial 131I therapy within six months post thyroidectomy, and multiple 131I treatments were independent prognostic factors. Conclusions: In patients with DTC with BM, 131I treatment in combination with one or more non-131I direct and systemic treatments was associated with a significant increase in OS compared with those patients who were treated by 131I treatment alone.