Immune effector monocyte-neutrophil cooperation induced by the primary tumor prevents metastatic progression of breast cancer.

Metastatic behavior varies significantly among breast cancers. Mechanisms explaining why the majority of breast cancer patients never develop metastatic outgrowth are largely lacking but could underlie the development of novel immunotherapeutic target molecules. Here we show interplay between nonmetastatic primary breast cancer and innate immune response, acting together to control metastatic progression. The primary tumor systemically recruits IFNγ-producing immune effector monocytes to the lung. IFNγ up-regulates Tmem173/STING in neutrophils and enhances their killing capacity. The immune effector monocytes and tumoricidal neutrophils target disseminated tumor cells in the lungs, preventing metastatic outgrowth. Importantly, our findings could underlie the development of immunotherapeutic target molecules that augment the function of immune effector monocytes and neutrophils.

Mobile health applications: awareness, attitudes, and practices among medical students in Malaysia.

BACKGROUND: The popularity of mobile health (mHealth) applications (or apps) in the field of health and medical education is rapidly increasing, especially since the COVID-19 pandemic. We aimed to assess awareness, attitudes, practices, and factors associated with the mHealth app usage among medical students. METHODS: We conducted a cross-sectional study involving medical students at a government university in Sarawak, Malaysia, from February to April 2021. Validated questionnaires were administered to all consenting students. These questionnaires included questions on basic demographic information as well as awareness, attitude toward, and practices with mHealth apps concerned with medical education, health and fitness, and COVID-19 management. RESULTS: Respondents had favorable attitudes toward mHealth apps (medical education [61.8%], health and fitness [76.3%], and COVID-19 management [82.7%]). Respondents' mean attitude scores were four out of five for all three app categories. However, respondents used COVID-19 management apps more frequently (73.5%) than those for medical education (35.7%) and fitness (39.0%). Usage of all three app categories was significantly associated with the respondent's awareness and attitude. Respondents in the top 20% in term of household income and study duration were more likely to use medical education apps. The number of respondents who used COVID-19 apps was higher in the top 20% household income group than in the other income groups. The most common barrier to the use of apps was uncertainty regarding the most suitable apps to choose. CONCLUSION: Our study highlighted a discrepancy between awareness of mHealth apps and positive attitudes toward them and their use. Recognition of barriers to using mHealth apps by relevant authorities may be necessary to increase the usage of these apps.

LGR5 in breast cancer and ductal carcinoma in situ: a diagnostic and prognostic biomarker and a therapeutic target.

BACKGROUND: Novel biomarkers are required to discern between breast tumors that should be targeted for treatment from those that would never become clinically apparent and/or life threatening for patients. Moreover, therapeutics that specifically target breast cancer (BC) cells with tumor-initiating capacity to prevent recurrence are an unmet need. We investigated the clinical importance of LGR5 in BC and ductal carcinoma in situ (DCIS) to explore LGR5 as a biomarker and a therapeutic target. METHODS: We stained BC (n = 401) and DCIS (n = 119) tissue microarrays with an antibody against LGR5. We examined an LGR5 knockdown ER- cell line that was orthotopically transplanted and used for in vitro colony assays. We also determined the tumor-initiating role of Lgr5 in lineage-tracing experiments. Lastly, we transplanted ER- patient-derived xenografts into mice that were subsequently treated with a LGR5 antibody drug conjugate (anti-LGR5-ADC). RESULTS: LGR5 expression correlated with small tumor size, lower grade, lymph node negativity, and ER-positivity. ER+ patients with LGR5high tumors rarely had recurrence, while high-grade ER- patients with LGR5high expression recurred and died due to BC more often. Intriguingly, all the DCIS patients who later died of BC had LGR5-positive tumors. Colony assays and xenograft experiments substantiated a role for LGR5 in ER- tumor initiation and subsequent growth, which was further validated by lineage-tracing experiments in ER- /triple-negative BC mouse models. Importantly, by utilizing LGR5high patient-derived xenografts, we showed that anti-LGR5-ADC should be considered as a therapeutic for high-grade ER- BC. CONCLUSION: LGR5 has distinct roles in ER- vs. ER+ BC with potential clinical applicability as a biomarker to identify patients in need of therapy and could serve as a therapeutic target for high-grade ER- BC.

Radioiodine associated de novo Graves' opthalmopathy in an Asian cohort.

Radioactive iodine in the treatment of Graves' disease has been associated with the development of de novo Graves' ophthalmopathy (GO). In this report, we describe five individuals who required extensive ophthalmic treatment for post-RAI de novo GO.

Risk of sudden sensorineural hearing loss in patients with systemic lupus erythematosus: a population-based cohort study.

Sudden sensorineural hearing loss (SSHL) may be a manifestation of systemic vascular involvement in systemic lupus erythematosus (SLE) and may have an important impact on the health of patients with SLE. To investigate the risk of developing SSHL in patients with SLE, we conducted a population-based, retrospective cohort study from the Taiwan National Health Insurance Research Database. A total of 7168 patients diagnosed with SLE and 35840 control subjects without SLE were selected from claims made from 2001 to 2006. The incidence of SSHL was assessed and determined at the end of 2010. The incidence of SSHL was 2.22-fold higher in the SLE group than in the non-SLE group (6.52 vs. 2.93 per 10000 person-years), with an adjusted hazard ratio (HR) of 2.253 (95% confidence interval, CI=1.407-3.608) calculated using a Cox proportional hazard regression model. Age was an independent risk factor for SSHL, with adjusted HRs of 2.103 for individuals aged≥35 years compared with those 0-34 years. In the 0-34 age range, the incidence of developing SSHL was 4.27-fold (95% CI=2.11-8.67) higher in the SLE group compared with the non-SLE group. In female patients, the incidence of developing SSHL was 2.19-fold (95% CI=1.73-3.50) higher in the SLE group than in the non-SLE group. Systemic lupus erythematosus was significantly associated with an increased risk of developing SSHL. Scheduled auditory examinations for patients with SLE to assess the presence of chronic hearing impairment are advised to enable the early detection of SSHL.

MMP9 modulates the metastatic cascade and immune landscape for breast cancer anti-metastatic therapy.

Metastasis, the main cause of cancer-related death, has traditionally been viewed as a late-occurring process during cancer progression. Using the MMTV-PyMT luminal B breast cancer model, we demonstrate that the lung metastatic niche is established early during tumorigenesis. We found that matrix metalloproteinase 9 (MMP9) is an important component of the metastatic niche early in tumorigenesis and promotes circulating tumor cells to colonize the lungs. Blocking active MMP9, using a monoclonal antibody specific to the active form of gelatinases, inhibited endogenous and experimental lung metastases in the MMTV-PyMT model. Mechanistically, inhibiting MMP9 attenuated migration, invasion, and colony formation and promoted CD8+ T cell infiltration and activation. Interestingly, primary tumor burden was unaffected, suggesting that inhibiting active MMP9 is primarily effective during the early metastatic cascade. These findings suggest that the early metastatic circuit can be disrupted by inhibiting active MMP9 and warrant further studies of MMP9-targeted anti-metastatic breast cancer therapy.

Higher risk of developing sudden sensorineural hearing loss in patients with chronic otitis media.

IMPORTANCE: Several sources have suggested an association between chronic sensory hearing impairment and chronic otitis media (COM). However, to our knowledge, no studies have evaluated the risk of sudden sensorineural hearing loss (SSNHL) in patients with COM (COM-positive). OBJECTIVE: To examine the risk of developing SSNHL in COM-positive patients. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study; we compared 10 248 patients with newly diagnosed COM from January 1, 2001, through December 31, 2008, with 30 744 age- and sex-matched controls using data from Taiwan's National Health Insurance Research Database. METHODS: We followed each patient and evaluated the incidence of SSNHL. MAIN OUTCOMES AND MEASURES: The incidence of SSNHL at the end of 2011. RESULTS: The incidence of SSNHL was 3 times higher in the COM-positive cohort than in the COM-negative cohort (14.47 vs 4.83 per 10 000 person-years). Cox proportional hazard regressions showed that the adjusted hazard ratio (AHR) was 3.02 (95% CI, 2.30-3.98). A stratified analysis showed that the highest risk of developing SSNHL was in the first follow-up year (incidence rate ratio [IRR], 3.87; 95% CI, 1.93-7.79). Thereafter, the risk declined during years 1 to 5 and then peaked (IRR, 3.01; 95% CI, 1.89-4.79). Patients who needed surgery had a higher incidence of SSNHL (AHR, 2.69; 95% CI, 1.62-4.48) compared with patients who needed only medication and observation. CONCLUSIONS AND RELEVANCE: Chronic otitis media was significantly associated with a higher risk of developing SSNHL.

Effect of metformin on the incidence of head and neck cancer in diabetics.

BACKGROUND: The purpose of this study was to examine the effect of metformin on head and neck cancer in patients with diabetes. METHODS: We compared 66,600 patients, all with diabetes and all newly diagnosed with head and neck cancer in 2002. Half were being treated with metformin for diabetes (Met(+) ) and half were not (Met(-) : controls). All were matched for comorbidities (obesity, coronary artery disease, hyperlipidemia, and hypertension), sex, and age. The risk of head and neck cancer at the end of 2011 was determined. RESULTS: The incidence of head and neck cancer was 34% lower in the Met(+) cohort than in the Met(-) cohort (adjusted hazard ratio [HR] = 0.66; 95% confidence interval [CI] = 0.55-0.79). The risks for oropharyngeal cancer (adjusted HR = 0.66; 95% CI = 0.17-0.74) and nasopharyngeal carcinoma (NPC; adjusted HR = 0.50; 95% CI = 0.31-0.80) were significantly lower in the Met(+) cohort than in the Met(-) cohort. CONCLUSION: Metformin is associated with a lower risk of developing head and neck cancer in patients with diabetes.

Risk of head and neck cancer in patients with diabetes mellitus: a retrospective cohort study in Taiwan.

IMPORTANCE: An increasing body of evidence suggests that certain types of cancers are more common in people with diabetes mellitus (DM). However, the risk of head and neck cancer (HNC) in patients with DM has seldom been explored. OBJECTIVE: To examine the risk of HNC in patients with DM. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study using Taiwan's Longitudinal Health Insurance Research Database, we compared 89,089 patients newly diagnosed as having DM and controls without DM-related medical claims matched for comorbidities (obesity, coronary artery disease, hyperlipidemia, and hypertension), sex, and age. Patients were assessed from the index date until the end of follow-up on December 31, 2011, or until the patient was censored because of death. MAIN OUTCOMES AND MEASURES: The incidence of HNC at the end of 2011. RESULTS: The incidence of HNC was 1.47 times higher in patients newly diagnosed as having DM than was the risk of a first malignant tumor in the control group (adjusted hazard ratio [AHR], 1.48; 95% CI, 1.31-1.67). The risks of oral cancer (AHR, 1.74; 95% CI, 1.47-2.06), oropharyngeal cancer (AHR, 1.53; 95% CI, 1.01-2.31), and nasopharyngeal carcinoma (AHR, 1.40; 95% CI, 1.03-1.89) were significantly higher in patients with DM than in controls. CONCLUSIONS AND RELEVANCE: Diabetes is associated with an increased risk of developing HNC. The risks of developing oral cavity cancer, oropharyngeal cancer, and nasopharyngeal carcinoma were significantly higher in patients with DM.

Galectin-1 overexpression in nasopharyngeal carcinoma: effect on survival.

CONCLUSIONS: Galectin-1 overexpression is significantly correlated with the survival rate of patients with nasopharyngeal carcinoma (NPC). Immunohistochemical analysis of galectin-1 expression might be useful for identifying patients with a high risk of distant metastasis and for prompting timely adjuvant systemic therapy for patients with aggressive NPC. OBJECTIVES: We examined the effect of galectin-1 on the survival rate of patients with NPC. METHODS: A total of 124 patients diagnosed between 1998 and 2002 with NPC without distant metastasis were enrolled in this single-center historical prospective cohort study. Immunohistochemical analysis was used to correlate the galectin-1 expression score in the cytoplasm and the survival rate of patients with NPC. RESULTS: Patients with NPC who overexpressed galectin-1 in cytoplasm showed more aggressive tumor growth and significantly shorter disease-specific survival (DSS) (p = 0.0037) and distant metastasis-free survival (DMFS) (p = 0.0006) than patients with NPC who did not overexpress galectin-1. Multivariate analysis showed that galectin-1 overexpression remained prognostically independent for DSS (p = 0.031, hazard ratio = 1.821), and DMFS (p = 0.005, hazard ratio = 2.417), together with the advanced III-IV stages.

Risk of developing sudden sensorineural hearing loss in patients with nasopharyngeal carcinoma: a population-based cohort study.

BACKGROUND: The purpose of this study was to explore the risk of developing of sudden sensorineural hearing loss (SSHL) in patients with nasopharyngeal carcinoma (NPC). METHODS: A population-based, retrospective cohort study using the Taiwan National Health Insurance Research Database was conducted. From 2001 to 2006, 9121 patients with newly diagnosed NPC and 45,605 comparison subjects without NPC were selected. The incidence of SSHL at the end of 2009 was determined. RESULTS: The incidence of SSHL was 6.53-fold higher in the NPC group compared to the non-NPC group (p < .001). Using Cox proportional hazard regressions, the risk of developing SSHL increased with an adjusted hazard ratio (HR) of 6.747 (95% confidence interval [CI] = 5.366-8.484) in patients with NPC compared with patients without NPC. CONCLUSION: NPC was significantly associated with an increased risk of developing SSHL. The risk of developing SSHL increased over follow-up time.

Risk of second primary malignancies after nasopharyngeal carcinoma: a population-based cohort study in Taiwan.

BACKGROUND: The purpose of this study was to examine the risk of second primary malignancy (SPM) after nasopharyngeal carcinoma (NPC). METHODS: We compared the incidence of SPM in patients diagnosed with NPC at the end of 2009 using the data extracted from the Taiwan Longitudinal Health Insurance Database between 2001 and 2008 (n = 10,299), with age-matched controls (1:10; n = 102,990). RESULTS: We found a 55% increased risk of SPM in patients diagnosed with NPC, compared to the risk of first malignancy in the age-matched controls (incidence rate ratio [IRR] = 1.55; p < .0001). Although the diagnosis of SPM was negatively correlated with the survival of patients with NPC (p = .0011), primary NPC did not display any synergic effect on the survival of patients with SPM, compared to age-matched controls with a newly diagnosed malignancy (p = .8986). CONCLUSION: NPC is associated with an increased risk of developing an SPM.

Increased risk of sudden sensorineural hearing loss in patients with human immunodeficiency virus aged 18 to 35 years: a population-based cohort study.

IMPORTANCE: No case series or cohort studies to date in the English literature have evaluated sudden sensorineural hearing loss (SSHL) in patients with human immunodeficiency virus (HIV). OBJECTIVE: To investigate the risk of developing SSHL in patients with HIV. DESIGN AND SETTING: Retrospective cohort population-based study using data from the Taiwan National Health Insurance Research Database. PARTICIPANTS: In total, 8760 patients with HIV and 43,800 control subjects without HIV were selected from insurance claims between January 1, 2001, and December 31, 2006. MAIN OUTCOME MEASURE: The incidence of SSHL was assessed and determined at the end of 2009. RESULTS: Among patients aged 18 to 35 years, the incidence of SSHL was 2.17-fold higher in the HIV group than in the control group (4.32 vs 1.99 per 10,000 person-years, P = .03). The risk of developing SSHL increased with HIV infection; an adjusted hazard ratio of 2.169 (95% CI, 1.071-4.391) was calculated using a Cox proportional hazards regression model. Among male patients, the incidence of developing SSHL was 2.23-fold higher (95% CI, 1.06-4.69) in the HIV group than in the control group. The incidence of SSHL did not differ significantly between the HIV group and the control group for patients 36 years or older. CONCLUSION AND RELEVANCE: Human immunodeficiency virus infection is significantly associated with an increased risk of developing SSHL in patients aged 18 to 35 years, particularly among male patients.

Increased risk of getting sudden sensorineural hearing loss in patients with chronic kidney disease: a population-based cohort study.

OBJECTIVES/HYPOTHESIS: To examine the risk of getting Sudden Sensorineural Hearing Loss (SSHL) among patients with chronic kidney disease (CKD). STUDY DESIGN: A retrospective cohort study. METHODS: Population-based representative insurance claims data were used to examine the risk of getting SSHL among patients with chronic kidney disease. Data extracted from the Taiwan National Health Insurance Research Database yielded 37,421 patients with newly diagnosed renal insufficiency and 37,421 subjects without renal insufficiency from between 2000 and 2004. RESULTS: The incidence of SSHL at the end of 2009 was determined. The incidence of SSHL was 1.57 times higher in the CKD-carrying group compared to the incidence in the non-CKD group (10.24 vs. 6.52 per 10,000 person-years), with adjusted hazard ratio (HR) of 1.46 (95% CI = 1.194-1.787) using Cox proportional hazard regressions. Age was an independent risk factor of getting SSHL, with adjusted HRs of 2.01, 3.178, and 2.285 for age ranges of 35 ≈ 49, 50 ≈ 64 and ≥ 65 compared with age range of 0 ≈ 35. Diabetes Mellitus was another independent risk factor with HR of 1.31 (95% CI = 1.003-1.711). CONCLUSIONS: Present results suggested a significant association between CKD and increased risk of getting SSHL. Comorbidity of diabetes in patients with CKD appeared to be associated with increased risk of getting SSHL, especially for the patients who are 35 years of age and older.

Sudden sensorineural hearing loss is correlated with an increased risk of acute myocardial infarction: a population-based cohort study.

OBJECTIVES/HYPOTHESIS: Previous studies have indicated that hypercholesterolemia and a high burden of cardiovascular risk factors are associated with the development of sudden sensorineural hearing loss (SSHL). The purpose of this study was to test the hypothesis that SSHL is a risk factor for the development of myocardial infarction (MI). STUDY DESIGN: A retrospective cohort study. METHODS: Using the Taiwan Longitudinal Health Insurance Database, we compared patients diagnosed with SSHL between January 1, 2001, and December 31, 2006, (N = 44,830) with age-matched controls (1:1) (N = 44,830). We followed up on each patient until the end of 2009 to evaluate the incidence of MI for a minimum period of 3 years after their initial SSHL diagnosis. RESULTS: We found that after adjusting for potential confounds with an adjusted hazard ratio (HR) of 1.254 (95% confidence interval, 1.092-1.440, P < 0.05), patients with SSHL were more likely to suffer MI than the control population. When stratified by patient age, the incidence of MI was 1.62-fold and 1.28-fold higher for SSHL-diagnosed patients aged between 50 and 64 years and those aged ≥ 65 years (P = 0.0064 and P = 0.0001), respectively, than in the non-SSHL group. CONCLUSIONS: SSHL may confer an independent risk of MI. This observation may prompt the early detection and timely treatment of patients at a high risk of MI.

Cancer survival in patients with HIV/AIDS in the era of highly active antiretroviral therapy in Taiwan: a population-based cohort study.

OBJECTIVES: HIV-related immunosuppression has been associated with the development of AIDS-defining malignancies. We examined the overall survival of HIV-infected patients who developed cancer. DESIGN: A retrospective cohort study. METHODS: Using the Taiwan Longitudinal Health Insurance Database, we compared patients diagnosed with HIV (n=9918) between January 1, 2002, and December 31, 2007 with age-matched controls (n=99,180). Each patient was followed until the end of 2009 (least 2 years after the initial HIV diagnosis) to evaluate the incidence of malignancies. RESULTS: The risk of overall malignancies in the HIV-infected cohort was 1.88 times higher than the risk of a first malignancy in the age-matched non-HIV infected cohort (incidence rate ratio [IRR])=2.05, p<0.0001). The diagnosis of a malignancy was negatively correlated with survival in the HIV-infected cohort (p<0.0011), and HIV infection had a synergistic effect on the survival of patients with malignancies compared with the non-HIV infected cohort, all of who had been newly diagnosed with cancer (p<0.0001). However, the difference in the risk of developing nasopharyngeal carcinoma (NPC), a highly prevalent malignancy in Taiwan, between the two cohorts was not significant (IRR=0.22, 95% CI=0.03-1.65). CONCLUSIONS: The risk of cancer in HIV-infected patients in Taiwan has increased significantly in the era of highly active antiretroviral therapy. A history of HIV significantly affected the survival of the patients in our study cohort after they developed cancer. Evidence level: 2B.