The Combined Effect of Immune Checkpoint Inhibitors and Tyrosine Kinase Inhibitors on Thyroid Function.

Background: Recent successes with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the treatment of solid malignancies have paved the way for a new era of combined therapy. A common side effect seen with each of these classes of treatment is thyroid dysfunction, with rates estimated at 30-40% for TKI and 10-20% for ICI. However, little is known about the effect of combined ICI+TKI therapy on thyroid function. Therefore, this study evaluated the incidence, clinical features, and risk factors for developing thyroid abnormalities during ICI+TKI therapy and the relationship to cancer outcomes. Methods: We conducted a retrospective cohort study of patients treated with combination ICI+TKI cancer therapy at City of Hope Comprehensive Cancer Center from 2017 to 2023 who had pretreatment normal thyrotropin (TSH) levels. Primary analyses assessed the frequency, timing, and severity of thyroid function test abnormalities during ICI+TKI cancer therapy, and the requirement for thyroid hormone replacement. Secondary analyses evaluated risk factors for the development of thyroid dysfunction, including sex and drug regimen, and the association with cancer progression-free survival or overall survival. Univariable and multivariable models were used. Results: There were 106 patients who received ICI+TKI therapy with a median age of 63.5 years and a median follow-up of 12.8 months (interquartile range [IQR] 5.9-20.9). Notably, 63.2% (67/106) developed thyroid function abnormalities during ICI+TKI therapy, including 11 (10.4%) with hyperthyroidism, 42 (39.6%) with subclinical hypothyroidism (SCHypo), and 14 (13.2%) with overt hypothyroidism. The onset of thyroid dysfunction occurred at a median of 7 weeks (IQR 3.1-9.0) after start of ICI+TKI treatment for hyperthyroidism, 8.0 weeks (IQR 3.0-19.0) for SCHypo, and 8.1 weeks (IQR 5.9-9.1) for overt or worsening hypothyroidism. Hyperthyroidism resolved to hypothyroidism or normal TSH without intervention in all subjects, suggesting thyroiditis, and hypothyroidism was readily treated with thyroid hormone replacement. Conclusions: Thyroid dysfunction is a frequent adverse event in individuals treated with combination ICI+TKI therapy, with our data suggesting a rapid onset and higher incidence than previously seen with ICI or TKI therapy alone. Therefore, close monitoring of thyroid function during initial therapy and multidisciplinary care with endocrinology are recommended to facilitate early detection and initiation of thyroid hormone replacement in these patients.

Safety and efficacy of immune checkpoint inhibitor cancer therapy in patients with preexisting type 1 diabetes mellitus.

Introduction: Immune checkpoint inhibitors (ICI) produce dramatic tumor shrinkage and durable responses in many advanced malignancies, but their use is limited by the development of immune-related adverse events (IRAEs) that occur in up to 60% of patients and often affect endocrine organs. Concern for more severe IRAEs in patients with preexisting autoimmune diseases, including type 1 diabetes mellitus (T1DM), has led to the exclusion of such individuals from clinical trials of ICI therapy. As a result, little is known about the safety and efficacy of ICI in this population. Here, we report safety and treatments outcomes in ICI-treated patients with preexisting T1DM. Methods: This retrospective case-controlled study evaluated adult patients with T1DM who received ICI therapy for solid malignancies from 2015 to 2021 at four academic medical centers. Patients with prior ICI therapy, bone marrow transplantation, or pregnancy were excluded. We collected data on demographics, cancer diagnosis and treatment, IRAE incidence and severity, and diabetes management. Controls were matched 2:1 by age, sex, cancer diagnosis, and ICI therapy class. Results: Of 12,142 cancer patients treated with ICI therapy, we identified 11 with a preexisting confirmed diagnosis of T1DM prior to starting ICI therapy. Mean age was 50.6 years, 63.6% were women, and most received anti-PD1/PDL1 monotherapy (10/11) compared with combination therapy (1/11). Grade 3/4 IRAEs were seen in 3/11 subjects with preexisting T1DM and were hepatitis, myositis, and myasthenia gravis. All three cases had interruption of ICI therapy and administration of adjunct therapies, including steroids, IVIG, or mycophenolate mofetil with resolution of the IRAE. The odds of all-grade IRAEs and of severe IRAEs were comparable between cases and controls matched for age, sex, cancer type, and ICI therapy [OR 0.83 (95% CI 0.2-3.56), p = 0.81, and OR 1.69 (0.31-9.36), p = 0.55, respectively]. Overall survival was not different between patients with T1DM and controls (p = 0.54). No patients had hospitalizations for diabetes-related complications during therapy. Discussion: These data suggest that ICI monotherapy can successfully be used in patients with preexisting T1DM, with IRAE rates comparable with individuals without preexisting T1DM. Larger, prospective studies of these potentially life-saving ICI therapies that include patients with preexisting autoimmunity are warranted.

Iodine contrast exposure and incident COVID-19 infection.

Background: Iodine and particularly its oxidated forms have long been recognized for its effective antiseptic properties. Limited in vitro and in vivo data suggest that iodine exposure may rapidly inactivate, reduce transmission, and reduce infectivity of SARS-CoV-2. We hypothesized that iodine exposure may be associated with decreased incident COVID-19 infection. Methods: A retrospective population-level cohort analysis was performed of the U.S. Veterans Health Administration between 1 March 2020 and 31 December 2020, before the widespread availability of vaccines against SARS-CoV-2. Multivariable logistic regression models estimated the adjusted odds ratios (OR) and 95% confidence intervals (CI) of the associations between iodinated contrast exposure and incident COVID-19 infection, adjusting for age, sex, race/ethnicity, place of residence, socioeconomic status, and insurance status. Results: 530,942 COVID-19 tests from 333,841 Veterans (mean ± SD age, 62.7 ± 15.2 years; 90.2% men; 61.9% non-Hispanic Whites) were analyzed, of whom 9% had received iodinated contrast ≤60 days of a COVID-19 test. Iodine exposure was associated with decreased incident COVID-19 test positivity (OR, 0.75 95% CI, 0.71-0.78). In stratified analyses, the associations between iodinated contrast use and decreased COVID-19 infection risk did not differ by age, sex, and race/ethnicity. Conclusion: Iodine exposure may be protective against incident COVID-19 infection. Weighed against the risks of supraphysiologic iodine intake, dietary, and supplemental iodine nutrition not to exceed its Tolerable Upper Limit may confer an antimicrobial benefit against SARS-CoV-2. A safe but antimicrobial level of iodine supplementation may be considered in susceptible individuals, particularly in geographic regions where effective COVID-19 vaccines are not yet readily available.

The Current Status of Preclinical Endocrine Education in U.S. Medical Schools.

OBJECTIVE: To characterize the current landscape of preclinical medical endocrine education in U.S. allopathic medical schools. METHODS: U.S. endocrine curriculum directors were asked to voluntarily complete a 16-question email survey surveying the status of endocrine preclinical education at their medical school. RESULTS: Sixty-nine of 155 (45%) endocrine block director respondents completed the online survey between July 2021 and September 2021. A larger incoming class, a longer duration of the endocrine curriculum, and the offering of a separate endocrine curriculum (ie apart from the teaching of other organ systems) were each independently associated with an increased number of faculty teaching the course. Schools that used a gland-/organ-based curriculum only and those that used a combination of gland-/organ-based curriculum with topic-based curriculum differed significantly in their use of large lectures, small groups, and several curriculum components, including point of care glucose testing, continuous glucose monitoring, and insulin pumps. CONCLUSION: This survey study reports the current landscape of preclinical endocrine education in the United States and describes opportunities to improve interest in pursuing endocrinology as a career.

Driving Factors to Pursue Endocrinology Training Fellowship: Empirical Survey Data and Future Strategies.

OBJECTIVE: There is a current and anticipated labor shortage of endocrinologists in the United States. Over the past decade, the number of applications to endocrinology fellowship programs has plateaued despite increased available positions, and interest in endocrinology has declined relative to other internal medicine subspecialty fields. The examination of driving factors for pursuit of endocrinology as a subspecialty career is needed. METHODS: A 12-question online survey was developed to identify the primary reasons for current endocrinology fellows/trainees to pursue the field. This survey was sent to 152 U.S. endocrinology fellowship program directors for completion by their fellows between July and August 2021. RESULTS: A total of 176 of 629 fellows (28.0%) completed the survey. The majority (57.4%) had decided to pursue endocrinology as a career during residency, while 27.3% had decided during medical school. The endocrinology rotation during residency was ranked by 79 fellows (44.9%) as the most influential factor, followed by having positive experiences with a clinical mentor (27.3%). Endocrinology exposure during medical school was sparse, with only 2.8% noting the availability of an endocrinology student interest group, while 59.7% reported inadequate endocrinology exposure during their medical school curriculum. CONCLUSION: The majority of current endocrinology fellows/trainees report that exposure to the field during medical school was limited, and that their endocrinology elective and mentorship experiences during residency were the most influential factors for pursuing endocrinology as a subspecialty. Improved integration of endocrinology experiences between medical school and residency may enhance career interest in endocrinology.

Optimal Thyroid Hormone Replacement Dose in Immune Checkpoint Inhibitor-Associated Hypothyroidism Is Distinct from Hashimoto's Thyroiditis.

Background: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many advanced cancers but are recognized to cause treatment-limiting immune-related adverse events (IrAE). ICI-associated thyroiditis is the most common endocrine IrAE and usually resolves to permanent hypothyroidism. Optimal thyroid hormone replacement in these patients remains unclear. We report the levothyroxine (LT4) dose needed to achieve stable euthyroid state in patients with hypothyroidism from ICI-associated thyroiditis, with comparison to patients with Hashimoto's thyroiditis (HT) and athyreotic state. Methods: We conducted a retrospective study of adults with ICI-associated hypothyroidism treated with LT4 at an academic medical center. Patient data were collected from the electronic medical record. Cases had ICI exposure followed first by hyperthyroidism and then subsequent hypothyroidism. Controls were HT (positive thyroid autoantibodies, requiring LT4) and athyreotic (total thyroidectomy or radioiodine ablation, requiring LT4) patients. Patients with central hypothyroidism, thyroid cancer, pregnancy, gastrointestinal stromal tumors, and use of L-triiodothyronine were excluded. Our primary outcome compared LT4 dose needed to achieve euthyroid state (thyrotropin 0.3-4.7 mIU/L over >6 consecutive weeks) for ICI-associated hypothyroidism, HT, and athyreotic patients, considering the impact of age and possible interfering medications by linear regression modeling. Secondary analysis considered the impact of endocrine specialty care on the time to euthyroid state. Results: One hundred three patients with ICI-associated thyroiditis were identified. Sixty-six of the 103 patients achieved euthyroid state; 2 with intrinsic thyroid gland function recovery and 64 on LT4. The mean LT4 dose achieving stable euthyroid state was 1.45 ± standard deviation (SD) 0.47 mcg/[kg·day] in ICI-associated hypothyroidism, 1.25 ± SD 0.49 mcg/[kg·day] in HT, and 1.54 ± SD 0.38 mcg/[kg·day] in athyreotic patients, using actual body weight. The difference in dose between ICI-associated hypothyroidism and HT was statistically significant (p = 0.0093). Dosing differences were not explained by age or use of interfering medications. Conclusions: ICI-associated thyroiditis represents an increasingly recognized cause of hypothyroidism. Our study demonstrates that patients with ICI-associated hypothyroidism have different thyroid hormone dosing requirements than patients with HT. Based on our findings and prior reports, we recommend that in patients with ICI-associated thyroiditis LT4 therapy be started at an initial weight-based dose of 1.45 mcg/[kg·day] once serum free thyroxine levels fall below the reference range.

Systemic light-chain amyloidosis incidentally diagnosed after subtotal parathyroidectomy and thyroid lobectomy.

A 74-year-old woman with a history of primary hyperparathyroidism, thyroid nodules, atrial fibrillation and pacemaker placement for sick sinus syndrome presented with fatigue, constipation and persistent lower extremity oedema. She underwent subtotal parathyroidectomy and left thyroid lobectomy. Histopathology revealed amyloidosis affecting the thyroidand parathyroids confirmed by Congo Red Staining with Mayo Clinic subtyping of light chain kappa-type amyloidosis. She was found to have combined systolic and diastolic cardiac dysfunction, carpal tunnel neuropathy and pre-diabetes suggestive of systemic amyloidosis with involvement of the heart, nerves and pancreas. Congo red stain was positive for amyloidosis on bone marrow biopsy suggestive of a diagnosis of systemic amyloidosis. She was treated with daratumumab with good clinical response. This case illustrates the necessity of considering systemic amyloidosis in patients with incidentally discovered diffuse amyloid deposits on biopsy of an endocrine organ, as endocrine effects are a rare but likely underdiagnosed consequence of systemic amyloidosis.

Hypoglycemic episodes predict length of stay in patients with acute burns.

Hypoglycemic episodes are associated with worse hospital outcomes. All adult patients admitted to our burn center from 2015 to 2019 were retrospectively reviewed. Patient demographics and burn characteristics were recorded. The primary outcome was mortality, and secondary outcomes were total length-of-stay and intensive care unit length-of-stay. All patients experiencing at least one hypoglycemic episode were compared to patients who did not experience hypoglycemia. There were 914 patients with acute burns admitted during the study period, 33 of which (4%) experienced hypoglycemic episodes. Of these, 17 patients (52%) experienced a single hypoglycemic episode, while the remainder experienced multiple hypoglycemic episodes. Patients with one or more hypoglycemic events were matched to non-hypoglycemic controls using propensity matching. Patients that experienced hypoglycemia had significantly less TBSA involvement (5% vs. 13%,median, p < 0.0002), higher prevalence of diabetes (48% vs. 18%, p < 0.0001), higher mortality (18% vs. 7%, p = 0.01), longer total length-of-stay (22 vs. 8 days, median, p < 0.0001), and longer ICU length-of-stay (12 vs. 0 days, median, p < 0.0001). A single hypoglycemic episode was associated with prolonged total (IRR = 1.91, p < 0.0001) and ICU length-of-stay (IRR = 3.86, p < 0.0001). Hypoglycemia was not associated with higher mortality in the survival analysis (p = 0.46).

Subclinical Hyperthyroidism: A Review of the Clinical Literature.

Subclinical hyperthyroidism (SCHyper) is a biochemical diagnosis characterized by a decreased serum thyroid-stimulating hormone (TSH) and normal serum thyroxine (T4) and triiodothyronine (T3) concentrations. Because SCHyper can be resolved, it is recommended to repeat serum TSH, T3, and T4 concentrations in 3 to 6 months before confirming a diagnosis of SCHyper to consider treatment. Proposed grading systems distinguish between mild (TSH, 0.1-0.4 mIU/L) and severe SCHyper (TSH, <0.1 mIU/L) and are used alongside patients' age and the presence of risk factors and symptoms to guide treatment. Appropriate evaluation includes an investigation of the underlying cause and assessment of an individual's risk factors to determine the necessity and type of treatment that may be recommended. SCHyper may be associated with increased risks of cardiovascular-related adverse outcomes, bone loss, and in some studies, cognitive decline. Treatment may include observation without therapy, initiation of antithyroid medications, or pursuit of radioiodine therapy or thyroid surgery. Considerations for treatment include the SCHyper etiology, anticipated long-term natural history of the condition, potential benefits of correcting the thyroid dysfunction, and risks and benefits of each treatment option. The purpose of this overview is to provide a guide for clinicians in evaluating and managing SCHyper in the routine clinical practice.

The supralaryngeal articulation of stress and accent in Greek.

It is well reported that articulatory movements comprising prominence units are longer, larger and faster than their non-prominent counterparts. However, it is unclear whether these effects arise at the level of lexical stress or accent or both, reflecting a hierarchy of prominence, i.e., being stronger when induced by accent as opposed to stress. It is also uncertain whether prominence-induced kinematic effects are invariant across positions of stress within the word, types of focus the accent denotes, and positions of words in the phrase. We conduct an electromagnetic articulography (EMA) study to assess the supralaryngeal kinematic correlates of prominence in Greek across three stress positions (antepenultimate, penultimate, ultimate; i.e., all possible stress positions in Greek), two accentual conditions (accented and de-accented) and two phrasal positions (phrase-medial and phrase-final). Focus type is also considered, with the accentual conditions coming from two types of focus (broad and narrow), while the de-accented conditions are by default unfocused. Our results indicate that stressed syllables involve longer, larger and faster gestures than their unstressed counterparts, regardless of the position of stress within the word. Notably, variation in velocity is accounted for by variation in displacement. Presence of accent does not further expand the stressed gestures, although it is related to minimal kinematic changes across the whole word, the exact profile of which depends on stress position. With the exception of final vowel duration, focus type is not systematically encoded in these kinematic effects. Finally, interactions are detected between the kinematic profile of prominence and that of boundaries. Implications of our findings for the hierarchy of prominence and cross-linguistic differences are discussed, and a gestural account of prominence and boundaries is put forward.

Additive Effects of Arsenic and Aristolochic Acid in Chemical Carcinogenesis of Upper Urinary Tract Urothelium.

BACKGROUND: Aristolochic acids (AA) and arsenic are chemical carcinogens associated with urothelial carcinogenesis. Here we investigate the combined effects of AA and arsenic toward the risk of developing upper tract urothelial carcinoma (UTUC). METHODS: Hospital-based (n = 89) and population-based (2,921 cases and 11,684 controls) Taiwanese UTUC cohorts were used to investigate the association between exposure to AA and/or arsenic and the risk of developing UTUC. In the hospital cohort, AA exposure was evaluated by measuring aristolactam-DNA adducts in the renal cortex and by identifying A>T TP53 mutations in tumors. In the population cohort, AA exposure was determined from prescription health insurance records. Arsenic levels were graded from 0 to 3 based on concentrations in well water and the presence of arseniasis-related diseases. RESULTS: In the hospital cohort, 43, 26, and 20 patients resided in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Aristolactam-DNA adducts were present in >90% of these patients, indicating widespread AA exposure. A>T mutations in TP53 were detected in 28%, 44%, and 22% of patients residing in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Population studies revealed that individuals who consumed more AA-containing herbs had a higher risk of developing UTUC in both arseniasis-endemic and nonendemic areas. Logistic regression showed an additive effect of AA and arsenic exposure on the risk of developing UTUC. CONCLUSIONS: Exposure to both AA and arsenic acts additively to increase the UTUC risk in Taiwan. IMPACT: This is the first study to investigate the combined effect of AA and arsenic exposure on UTUC.

The Three-Dimensional Microenvironment of the Mitral Valve: Insights into the Effects of Physiological Loads.

INTRODUCTION: In the mitral valve (MV), numerous pathological factors, especially those resulting from changes in external loading, have been shown to affect MV structure and composition. Such changes are driven by the MV interstitial cell (MVIC) population via protein synthesis and enzymatic degradation of extracellular matrix (ECM) components. METHODS: While cell phenotype, ECM composition and regulation, and tissue level changes in MVIC shape under stress have been studied, a detailed understanding of the three-dimensional (3D) microstructural mechanisms are lacking. As a first step in addressing this challenge, we applied focused ion beam scanning electron microscopy (FIB-SEM) to reveal novel details of the MV microenvironment in 3D. RESULTS: We demonstrated that collagen is organized into large fibers consisting of an average of 605 ± 113 fibrils, with a mean diameter of 61.2 ± 9.8 nm. In contrast, elastin was organized into two distinct structural subtypes: (1) sheet-like lamellar elastin, and (2) circumferentially oriented elastin struts, based on both the aspect ratio and transmural tilt. MVICs were observed to have a large cytoplasmic volume, as evidenced by the large mean surface area to volume ratio 3.68 ± 0.35, which increased under physiological loading conditions to 4.98 ± 1.17. CONCLUSIONS: Our findings suggest that each MVIC mechanically interacted only with the nearest 3-4 collagen fibers. This key observation suggests that in developing multiscale MV models, each MVIC can be considered a mechanically integral part of the local fiber ensemble and is unlikely to be influenced by more distant structures.

Pudendal nerve entrapment leading to avoidant/restrictive food intake disorder (ARFID): A case report.

Avoidant/restrictive food intake disorder (ARFID) is a diagnosis in diagnostic and statistical manual of mental disorders-5 (DSM-5) manifested by persistent failure to meet nutritional and/or energy needs. Pudendal nerve entrapment (PNE) often causes pelvic discomfort in addition to constipation and painful bowel movements. Current literature on ARFID is sparse and focuses on the pediatric and adolescent population. No association between PNE and ARFID has been described. We present a case of ARFID in an adult male with PNE resulting from subsequent scarring from testicular cancer surgery. The patient's gastrointestinal symptoms due to PNE caused significant food avoidance and restriction subsequently leading to severe malnourishment. Clinicians should be aware that distressing gastrointestinal symptoms arising from a secondary disease process such as PNE might lead to dietary restriction and food aversion. More research is needed for proper screening, detection, and treatment of ARFID. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2017; 50:84-87).

Cytomegalovirus Infection in Pediatric Solid Organ Transplant Recipients: a Focus on Prevention.

Solid organ transplantation is a life-saving procedure that has changed the prognosis for infants and children with end-stage organ disease. Cytomegalovirus (CMV) is one of the most common infections that occur after organ transplantation in pediatric patients, yet the standard of care for CMV prevention remains unclear. We review the literature regarding CMV disease effects, risk factors, diagnostics, prevention strategies, and antiviral treatment in pediatric solid organ transplantation. This discussion focuses on the current prevention strategies: prophylaxis, preemptive, and hybrid therapy, as well as novel strategies that may help better prevent the CMV disease in the pediatric solid organ transplant population.

Functional differences and interactions between the Escherichia coli type III secretion system effectors NleH1 and NleH2.

The human pathogens enterohemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC), as well as the related mouse pathogen Citrobacter rodentium, utilize a type III secretion system (T3SS) to inject multiple effector proteins into host cells. The E. coli O157:H7 strain EDL933 carries two copies of non-locus of enterocyte effacement (LEE)-encoded protein H, designated NleH1 and NleH2, both of which bind to the human ribosomal protein S3 (RPS3), a subunit of NF-κB transcriptional complexes. In this study, we describe significant functional differences between NleH1 and NleH2 in their ability to regulate the host NF-κB pathway. We show that the EHEC and EPEC NleH effectors are functionally equivalent in their ability to affect RPS3 nuclear translocation. NleH1, but not NleH2, inhibited NF-κB activity without altering the kinetics of IκBα phosphorylation/degradation. We also determined that the class I PSD-95/Disc Large/ZO-1 (PDZ)-binding domain of NleH was important for its activity in the NF-κB pathway. In addition to binding RPS3, we found that NleH1 and NleH2 are able to bind to each other in vitro and in vivo, suggesting an additional mechanism by which the E. coli NleH effectors may regulate the extent and duration of NF-κB activation after their T3SS-dependent translocation. We also performed mouse infection experiments and established that mouse mortality and Citrobacter colonization were reduced in mice infected with ΔnleH. Complementing ΔnleH with NleH1 restored Citrobacter virulence and colonization to wild-type levels, whereas complementing with NleH2 reduced them. Taken together, our data show that NleH1 and NleH2 have pronounced functional differences in their ability to alter host transcriptional responses to bacterial infection.