Thyroid Immune-Related Adverse Events in Patients with Cancer Treated with anti-PD1/anti-CTLA4 Immune Checkpoint Inhibitor Combination: Clinical Course and Outcomes

ObjectiveThyroid immune-related adverse events (irAEs) have been reported to have prognostic significance among patients with cancer treated with anti-programmed cell death-1 (PD1) and anti-programmed death-ligand 1 monotherapies. We evaluated the clinical course and predictors of thyroid irAEs in relation to outcomes of patients with advanced cancer treated with combination anti-PD1/anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4).MethodsWe conducted a regional study and identified patients with advanced cancer who received ≥1 cycle of combination anti-PD1/anti-CTLA4 between 2015 and 2019 in Hong Kong. Thyroid function tests (TFTs) were monitored every 3 weeks. Thyroid irAE was defined by ≥2 abnormal TFTs after initiation of combination anti-PD1/anti-CTLA4 in the absence of other causes.ResultsOne hundred and three patients were included (median age: 59 years; 71.8% men). About 45% had prior anti-PD1 exposure. Upon median follow-up of 6.8 months, 17 patients (16.5%) developed thyroid irAEs, where 6 initially presented with thyrotoxicosis (overt, n = 4; subclinical, n = 2) and 11 with hypothyroidism (overt, n = 2; subclinical, n = 9). Eventually, 10 patients (58.8%) required continuous thyroxine replacement. Systemic steroid was not required in all cases. Prior anti-PD1 exposure (odds ratio, 3.67; 95% CI, 1.19–11.4; P = .024) independently predicted thyroid irAEs. Multivariable Cox regression analysis revealed that occurrence of thyroid irAEs was independently associated with better overall survival (adjusted hazard ratio, 0.34; 95% CI, 0.17–0.71; P = .004).ConclusionThyroid irAEs are common in routine clinical practice among patients with advanced cancer treated with anti-PD1/anti-CTLA4 combination and might have potential prognostic significance. Regular TFT monitoring is advised for timely treatment of thyroid irAEs to prevent potential morbidities.     

Immunomodulator Clarithromycin Enhances Mucosal and Systemic Immune Responses and Reduces Re-Infection Rate in Pediatric Patients with Influenza Treated with Antiviral Neuraminidase Inhibitors: A Retrospective Analysis

Background/Aims

Treatment with antiviral neuraminidase inhibitors suppresses influenza viral replication and antigen production, resulting in marked attenuation of mucosal immunity and mild suppression of systemic immunity in mice. This study investigated the effects of immunomodulator clarithromycin (CAM) supplementation on mucosal and systemic immunity in pediatric patients with influenza treated with neuraminidase inhibitors.

Methods

A retrospective, non-randomized case series study was conducted among five treatment groups of 195 children aged 5.9±3.3 years infected with influenza A in 2008/2009 season. The five treatment groups were oseltamivir (OSV), zanamivir (ZNV), OSV+CAM, ZNV+CAM and untreated groups. Anti-viral secretory IgA (S-IgA) levels in nasal washes and IgG levels in sera were measured. The re-infection rate was analyzed among the same five treatment groups in the 2009/2010 season.

Results

Treatment of influenza with OSV and ZNV for 5 days attenuated the induction of anti-viral S-IgA in nasal washes and anti-viral IgG in serum, compared with the untreated group. The combination of CAM plus OSV or ZNV boosted and restored the production of mucosal S-IgA and systemic IgG. The re-infection rates in the subsequent season were significantly higher in the OSV and ZNV groups than the untreated, while CAM+OSV and CAM+ZNV tended to reduce such rate.

Conclusions

CAM restored the attenuated anti-viral mucosal and systemic immunity and reduced the re-infection rate in the subsequent year in pediatric patients with influenza treated with OSV and ZNV.     

Prognosis of Differentiated Thyroid Carcinoma in Patients with Graves Disease: A Systematic Review and Meta-Analysis

Objective: It is still controversial whether differentiated thyroid carcinoma (DTC) in patients with Graves disease (GD) can be more aggressive than non-Graves DTC. We conducted a systematic review and meta-analysis to examine the association between GD and prognosis in patients with DTC.Methods: We comprehensively searched the databases of MEDLINE and EMBASE from inception to March 2019. We included published studies that compared the risk of mortality and prognosis between DTC patients with GD and those with non-GD. Data from each study were combined using the random-effects model.Results: Twenty-five studies from February 1988 to May 2018 were included (987 DTC patients with GD and 2,064 non-Graves DTC patients). The DTC patients with GD had a significantly higher risk of associated multifocality/multicentricity (odds ratio, 1.45; 95% confidence interval, 1.04 to 2.02; I², 6.5%; P =.381) and distant metastasis at the time of cancer diagnosis (odds ratio, 2.19; 95% confidence interval, 1.08 to 4.47; I², 0.0%; P =.497), but this was not associated with DTC-related mortality and recurrence/persistence during follow-up.Conclusion: Our meta-analysis demonstrates a statistically significant increased risk of multifocality/multicentricity and distant metastasis at the time of cancer diagnosis in DTC patients with GD than those without GD.Abbreviations: CI = confidence interval; DTC = differentiated thyroid carcinoma; GD = Graves disease; LN = lymph node; OR = odds ratio; PTC = papillary thyroid carcinoma; TC = thyroid carcinoma; TSAb = thyroid-stimulating antibody; TSH = thyroid-stimulating hormone     

免疫检查点抑制剂联合抗血管生成二线治疗晚期食管癌患者疗效及肿瘤标志物表达、预后生存期的影响

摘要 目的：研究信迪利单抗与阿帕替尼在晚期食管癌二线治疗中的应用效果。方法：根据随机数字表法将2019年1月～2022年1月本院收治的70例食管癌患者分为对照组与观察组,每组各35例,对照组给予阿帕替尼治疗,观察组给予信迪利单抗与阿帕替尼联合治疗,观察两组患者的客观缓解率（ORR）、疾病控制率（DCR）,并在治疗前后利用酶联免疫吸附法检测其糖类抗原50（CA-50）、糖类抗原199（CA199）、癌胚抗原（CEA）、鳞癌抗原（SCC）水平;随后通过随访记录两组患者的预后生存期,并建立多因素Logistic模型分析影响患者达到中位OS、PFS的独立危险因素。结果：与对照组比较,观察组ORR、DCR率较高（P＜0.05）。与对照组相比,治疗后观察组血清CA50、CA199、CEA、SCC水平较低（P＜0.05）。与对照组比较,观察组中位OS、PFS较长（P＜0.05）。多因素Logistic分析结果显示,治疗方法、CA50、CA199、CEA、SCC是影响食管癌预后生存期的独立危险因素（P＜0.05）。结论：利用免疫检查点抑制剂与抗血管生成药物对晚期食管癌患者开展二线治疗,不仅能降低血清中的肿瘤标志物浓度,还能延长患者的预后生存期,治疗效果较为显著。     

Color-Flow Doppler Sonography in Patients with Subclinical Thyroid Dysfunction

ObjectiveTo assess the value of color-flow Doppler sonography (CFDS) in evaluating intrathyroidal blood flow and velocity in patients with subclinical thyroid dysfunction.MethodsIn this prospective study, patients with subclinical hypothyroidism, patients with subclinical hyperthyroidism, and euthyroid patients without known thyroid autoimmune disease who served as controls were included. Subclinical thyroid dysfunction was defined as normal serum free thyroxine (FT₄) and free triiodothyronine (FT₃) in the presence of high (subclinical hypothyroidism), or lowsuppressed (subclinical hyperthyroidism) serum thyrotropin (TSH) levels. Serum FT₄, FT₃, TSH, and antibodies to thyroid peroxidase and thyroglobulin were measured in all participants. In addition, TSH receptor antibody levels were determined in patients with subclinical hyperthyroidism. All participants underwent conventional sonography and CFDS. Mean peak systolic velocity (PSV) and resistive index were obtained from multiple extranodular thyroid parenchyma samplings and inferior thyroid artery measurements.ResultsThe study population included 27 patients with subclinical hypothyroidism, 15 patients with subclinical hyperthyroidism, and 20 euthyroid patients. Patients with subclinical hypothyroidism had significantly higher mean intrathyroidal PSV values than control patients (19.9 ± 5.6 cm/s vs 15.7 ± 4.4 cm/s; P = .008), whereas patients with subclinical hyperthyroidism had significantly higher mean PSV values than control patients at the inferior thyroid artery level (29.7 ± 10.7 cm/s vs 21.9 ± 6.8 cm/s; P = .014). Compared with control patients, a greater proportion of patients with subclinical hypothyroidism and patients with subclinical hyperthyroidism had marked CFDS patterns (78% vs 15% [P <.001] and 53% vs 15%; [P <.001], respectively). A significant association was found between positivity for thyroid autoantibodies and intense CFDS patterns. No correlation was found between TSH or thyroid hormone levels and CFDS pattern or blood flow velocity.ConclusionWe have demonstrated that significantly increased thyroid blood flow velocity and vascularity are already present in patients with mild thyroid dysfunction.(Endocr Pract. 2010;16:376-381)     

Innate Immune Signalling Genetics of Pain,Cognitive Dysfunction and Sickness Symptoms in Cancer Pain Patients Treated with Transdermal Fentanyl

Common adverse symptoms of cancer and chemotherapy are a major health burden; chief among these is pain, with opioids including transdermal fentanyl the mainstay of treatment. Innate immune activation has been implicated generally in pain, opioid analgesia, cognitive dysfunction, and sickness type symptoms reported by cancer patients. We aimed to determine if genetic polymorphisms in neuroimmune activation pathways alter the serum fentanyl concentration-response relationships for pain control, cognitive dysfunction, and other adverse symptoms, in cancer pain patients. Cancer pain patients (468) receiving transdermal fentanyl were genotyped for 31 single nucleotide polymorphisms in 19 genes: CASP1, BDNF, CRP, LY96, IL6, IL1B, TGFB1, TNF, IL10, IL2, TLR2, TLR4, MYD88, IL6R, OPRM1, ARRB2, COMT, STAT6 and ABCB1. Lasso and backward stepwise generalised linear regression were used to identify non-genetic and genetic predictors, respectively, of pain control (average Brief Pain Inventory < 4), cognitive dysfunction (Mini-Mental State Examination ≤ 23), sickness response and opioid adverse event complaint. Serum fentanyl concentrations did not predict between-patient variability in these outcomes, nor did genetic factors predict pain control, sickness response or opioid adverse event complaint. Carriers of the MYD88 rs6853 variant were half as likely to have cognitive dysfunction (11/111) than wild-type patients (69/325), with a relative risk of 0.45 (95% CI: 0.27 to 0.76) when accounting for major non-genetic predictors (age, Karnofsky functional score). This supports the involvement of innate immune signalling in cognitive dysfunction, and identifies MyD88 signalling pathways as a potential focus for predicting and reducing the burden of cognitive dysfunction in cancer pain patients.     

女性甲状腺癌的病理与预后分析

目的:探讨女性甲状腺癌的病理特点以及预后影响因素。方法:收集2005年1月至2009年8月,齐齐哈尔和平医院收治的女性甲状腺癌患者148例,回顾分析其临床病理特点以及预后影响因素。结果:病理检查显示131例(88.5%)甲状腺乳头状癌(PTC),6例(4.1%)为滤泡状癌(FTC),3例(2.0%)为髓样癌(MTC),6例(4.1%)为未分化癌(ATC);病理分期Ⅰ-Ⅱ期占45.3%,Ⅲ-Ⅳ期占54.7%;27例(18.24%)为周围组织侵犯,9例(6.1%)为远处转移,10例(6.76%)对侧甲状腺转移,56例(37.84%)颈部淋巴结转移;1年、3年、5年生存率依次为97.3%、93.2%、83.8%;年龄、病理床分期、病理类型、淋巴结转移、远处转移以及周围组织侵犯均是影响临床预后的重要因素(P0.05)。结论:女性甲状腺癌存在病理分期晚、病理分型差、淋巴结转移、远处转移及局部侵犯率高等不良预后因素,早期影像学检查对临床治疗具有指导意义。     

Systemic Immune-Inflammation Index and Circulating T-Cell Immune Index Predict Outcomes in High-Risk Acral Melanoma Patients Treated with High-Dose Interferon

High-dose interferon alfa-2b (IFN-α-2b) improves the survival of patients with high-risk melanoma. We aimed to identify baseline peripheral blood biomarkers to predict the outcome of acral melanoma patients treated with IFN-α-2b. Pretreatment baseline parameters and clinical data were assessed in 226 patients with acral melanoma. Relapse-free survival (RFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and multivariate Cox regression analyses were applied after adjusting for stage, lactate dehydrogenase (LDH), and ulceration. Univariate analysis showed that neutrophil-to-lymphocyte ratio ≥2.35, platelet-to-lymphocyte ratio ≥129, systemic immune-inflammation index (SII) ≥615 × 10⁹/l, and elevated LDH were significantly associated with poor RFS and OS. The SII is calculated as follows: platelet count × neutrophil count/lymphocyte count. On multivariate analysis, the SII was associated with RFS [hazard ratio (HR)=1.661, 95% confidence interval (CI): 1.066-2.586, P=.025] and OS (HR=2.071, 95% CI: 1.204-3.564, P=.009). Additionally, we developed a novel circulating T-cell immune index (CTII) calculated as follows: cytotoxic T lymphocytes/(CD4⁺ regulatory T cells × CD8⁺ regulatory T cells). On univariate analysis, the CTII was associated with OS (HR=1.73, 95% CI: 1.01-2.94, P=.044). The SII and CTII might serve as prognostic indicators in acral melanoma patients treated with IFN-α-2b. The indexes are easily obtainable via routine tests in clinical practice.     

Natural Killer T Cells in Advanced Melanoma Patients Treated with Tremelimumab

A significant barrier to effective immune clearance of cancer is loss of antitumor cytotoxic T cell activity. Antibodies to block pro-apoptotic/downmodulatory signals to T cells are currently being tested. Because invariant natural killer T cells (iNKT) can regulate the balance of Th1/Th2 cellular immune responses, we characterized the frequencies of circulating iNKT cell subsets in 21 patients with melanoma who received the anti-CTLA4 monoclonal antibody tremelimumab alone and 8 patients who received the antibody in combination with MART-1_26–35 peptide-pulsed dendritic cells (MART-1/DC). Blood T cell phenotypes and functionality were characterized by flow cytometry before and after treatment. iNKT cells exhibited the central memory phenotype and showed polyfunctional cytokine production. In the combination treatment group, high frequencies of pro-inflammatory Th1 iNKT CD8⁺ cells correlated with positive clinical responses. These results indicate that iNKT cells play a critical role in regulating effective antitumor T cell activity.     

Thyroid Function in Patients Treated with Radioactive Iodine for Thyrotoxicosis

A series of 105 patients treated at least two years earlier with radioactive iodine for thyrotoxicosis have been surveyed. Eighty-five patients (81%) were euthyroid clinically and on the basis of routine thyroid function tests. Of the euthyroid patients 46 (54%) had normal thyroid-stimulating hormone (TSH) levels and 39 (46%) had raised TSH levels. There was no difference in serum triiodothyronine levels between these two groups but the serum protein bound iodine and serum thyroxine, though still well within the normal range, were significantly lower in the group with raised TSH levels. The serum cholesterol was also significantly higher in this latter group.Most of the euthyroid patients were seen again a year later. None had become hypothyroid and neither those with normal nor those with raised TSH levels showed any evidence of a decline in the level of serum thyroxine.It is concluded that raised serum TSH levels in patients treated with iodine-131 are not necessarily indicative of hypothyroidism. There is no indication that patients who have this abnormality become overtly hypothyroid over a 12-month follow up.     

Pituitary Dysfunction in Patients with Intracranial Germ Cell Tumors Treated with Radiotherapy

Objective:To evaluate the endocrine abnormalities in intracranial germ cell tumors (iGCTs) treated with radio-therapy (RT), and to discuss the effects of RT on pituitary functions.Methods: Seventy-seven patients diagnosed with iGCTs who had received RT and endocrine follow-up in Huashan Hospital between January 2010 and July 2017 were retrospectively analyzed, consisting of 49 germinomas and 28 NGGCTs. The median follow-up period was 50.0 months. Fifty-one patients had radiologically proved suprasellar/sellar lesions.Results: The male to female ratio was 62/15. The median endocrine follow-up period was 19 (4, 42) months. The median age at the last endocrine visit was 18 (16, 20) years old. The 5-year overall and recurrence-free survival were both 98.7%. The overall prevalence of central adrenal insufficiency (CAI), central hypothyroidism (CHT), central hypogonadism (CHG), hyperprolactinemia, and central diabetes insipidus (CDI) was 57.3%, 56%, 56.6%, 35.3%, and 52.1%, respectively, after RT. Patients having suprasellar/sellar lesions showed significantly higher post-therapeutic prevalence of hypopituitarism than those who didn’t. Compared to that before RT, CAI, CHT, and CHG weren’t significantly improved while the levels of prolactin and the prevalence of CDI declined significantly (P =.03 and.001). The radiation doses to pituitary and hypothalamus between those with and without CAI, CHT, and CHG weren’t significantly different.Conclusion: The prevalence of hypopituitarism was high in iGCTs, especially in those with suprasellar/sellar involvement. The levels of prolactin and the prevalence of CDI declined significantly after RT. The hypopituitarism in iGCTs was mainly induced by tumor effects, and RT showed no additional damage to pituitary functions in our study.Abbreviations: AFP = alpha-fetoprotein; CAI = central adrenal insufficiency; CDI = central diabetes insipidus; CHG = central hypogonadism; CHT = central hypothyroidism; CT = computed tomography; DA = dopamine; GH = growth hormone; βHCG = beta-human chorionic gonadotropin; HPA = hypothalamus-pituitary-adrenal; HPG = hypothalamus-pituitary-gonadal; HPL = hyperprolactinemia; HPT = hypothalamus-pituitary-thyroid; iGCT = intracranial germ cell tumor; IGF-1 = insulin-like growth factor 1; NGGCT = nongerminomatous germ cell tumors; OS = overall survival; PFS = progression-free survival; PRL = hypothalamus-pituitary-prolactin; RT = radiotherapy     

Absence of Cardiac Valve Dysfunction in Obese Patients Treated with Sibutramine

BACH, DAVID S., AILA M. RISSANEN, CARL M. MENDEL, GILLIAN SHEPHERD, STEVEN R. WEINSTEIN, FINIAN KELLY, TIMOTHY B. SEATON, BABABHAI PATEL, TUULA A. PEKKARINEN, AND WILLIAM F. ARMSTRONG. Absence of cardiac valve dysfunction in obese patients treated with sibutramine. Obes Res. Objective: Serotonin-releasing agents prescribed as weight-loss medications have been implicated as a cause of acquired aortic and mitral valve abnormalities. Sibutramine hydrochloride (MERIDIA®) is a serotonin and norepi-nephrine reuptake inhibitor with proven efficacy of weight reduction. The purpose of this study was to determine the incidence of cardiac valve disease in sibutramine-treated patients. Research Methods and Procedures: Obese patients with type 2 diabetes mellitus enrolled in an ongoing double-blind, placebo-controlled, parallel-arm, 12-month study of sibutramine (followed by a 12-month open label extension) underwent transthoracic echocardiographic imaging and color Doppler interrogation for assessment of cardiac valve anatomy and function. Results: A total of 210 patients were evaluated. Of these, 133 were receiving sibutramine (72 in the double-blind period), and 77 were receiving placebo. The mean ± Standard Deviation age was 54±9 years, and the mean duration of treatment was 229±117 days (approximately 7. 6 months). The prevalence of left-sided cardiac valve dysfunction was low and similar for the two treatment groups (sibutramine 31133, or 2. 3%; placebo 2/77, or 2. 6%). All five cases were cases of aortic insufficiency; four were mild, one was severe (in a placebo patient). All three sibutramine cases were patients over age 50; two had a history of systemic hypertension. Conclusion: The prevalence of left-sided cardiac valve dysfunction was not higher than background in obese patients treated with sibutramine for an average of 7. 6 months.     

Keeping Tumors in Check: A Mechanistic Review of Clinical Response and Resistance to Immune Checkpoint Blockade in Cancer

Immune checkpoints are a diverse set of inhibitory signals to the immune system that play a functional role in adaptive immune response and self-tolerance. Dysregulation of these pathways is a vital mechanism in the avoidance of immune destruction by tumor cells. Immune checkpoint blockade (ICB) refers to targeted strategies to disrupt the tumor co-opted immune suppression to enhance anti-tumor immunity. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) are two immune checkpoints that have the widest range of antibody-based therapies. These therapies have gone from promising approaches to Food and Drug Administration-approved first- and second-line agents for a number of immunogenic cancers. The burgeoning investigations of ICB efficacy in blood and solid cancers have underscored the importance of identifying the predictors of response and resistance to ICB. Identification of response correlates is made complicated by the observations of mixed reactions, or different responses in multiple lesions from the same patient, and delayed responses that can occur over a year after the induction therapy. Factors that can influence response and resistance in ICB can illuminate underlying molecular mechanisms of immune activation and suppression. These same response predictors can guide the identification of patients who would benefit from ICB, reduce off-target immune-relate adverse events, and facilitate the use of combinatorial therapies to increase efficacy. Here we review the underlying principles of immune checkpoint therapy and results of single-agent ICB clinical trials, and summarize the predictors of response and resistance.     

Immune Dysfunction in Children with CHARGE Syndrome: A Cross-Sectional Study

CHARGE syndrome is a variable, multiple congenital malformation syndrome. Patients with CHARGE syndrome have frequent infections that are presumed to be due to anatomical anomalies of the craniofacial region and upper airway, and cranial nerve problems resulting in swallowing difficulties and aspiration. The possible contribution of immunological abnormalities to these infections has not been systematically studied even though immune deficiencies have been described in patients with 22q11.2 deletion syndrome, a condition which shares remarkable clinical overlap with CHARGE syndrome. We assessed the frequency and nature of immune dysfunction in 24 children with genetically proven CHARGE syndrome. All patients, or their parents, completed a questionnaire on infectious history. Their immune system was extensively assessed through full blood counts, immunoglobulin levels, lymphocyte subpopulations, peripheral B- and T-cell differentiation, T-receptor excision circle (TREC) analysis, T-cell function, and vaccination responses. All CHARGE patients had a history of infections (often frequent), mainly otitis media and pneumonia, leading to frequent use of antibiotics and to hospital admissions. Decreased T-cell numbers were found in 12 (50%) patients, presumably caused by insufficient thymic output since TREC amounts were also diminished in CHARGE patients. Despite normal peripheral B-cell differentiation and immunoglobulin production in all patients, 83% of patients had insufficient antibody titers to one or more early childhood vaccinations. Based on our results, we recommend immunological evaluation of CHARGE patients with recurrent infections.     

Better Prognosis in Newborns with Trisomy 13 Who Received Intensive Treatments: A Retrospective Study of 16 Patients

Intensive treatment for newborns with trisomy 13 is controversial because of their lethal prognosis. We report the better life prognosis of patients with trisomy 13 who received intensive treatment. At our hospital, we provided an intensive management to such patients including resuscitation and surgical procedures as required. Herein, we present the results of a retrospective study (1989-2010) of 16 trisomy 13 cases who received an intensive treatment. None was diagnosed to have trisomy 13 before birth; 9 were delivered by C-section and oxygen was administered to all patients during postpartum resuscitation. Mechanical ventilation was used in 9 patients after tracheal intubation and tracheotomy was performed in 2 patients when withdrawing of extubation was difficult. Regarding prognosis, 9 patients died, 3 were referred to another hospital, and 4 were discharged from the hospital. Four and 7 patients died within 7 and 30 days after birth, respectively. Nine patients survived for >1 month, 7 for >180 days, and 5 for >3 years. Median survival for 16 patients was 733 days. The patients who received intensive treatments survived longer compared to the previous data. This study provides useful information concerning genetic counseling, especially from an ethical point of view, before providing intensive management to newborns with trisomy 13.