Antireflux surgery leads to durable improvement in laryngopharyngeal reflux symptoms.

BACKGROUND: Laryngopharyngeal reflux (LPR) symptoms are often present in patients with Gastroesophageal reflux disease (GERD). Whereas antireflux surgery (ARS) provides predictably excellent results in patients with typical GERD, those with atypical symptoms have variable outcomes. The goal of this study was to characterize the response of LPR symptoms to antireflux surgery. METHODS: Patients who underwent ARS between January 2009 and May 2020 were prospectively identified from a single institutional database. Patient-reported information on LPR symptoms was collected at standardized time points (preoperative and 2 weeks, 8 weeks, and 1 year postoperatively) using a validated Reflux Symptom Index (RSI) questionnaire. Patients were grouped by preoperative RSI score: ≤ 13 (normal) and > 13 (abnormal). Baseline characteristics were compared between groups using chi-square test or t-test. A mixed effects model was used to evaluate improvement in RSI scores. RESULTS: One hundred and seventy-six patients fulfilled inclusion criteria (mean age 57.8 years, 70% female, mean BMI 29.4). Patients with a preoperative RSI ≤ 13 (n = 61) and RSI > 13 (n = 115) were similar in age, BMI, primary reason for evaluation, DeMeester score, presence of esophagitis, and hiatal hernia (p > 0.05). The RSI > 13 group had more female patients (80 vs 52%, p = < 0.001), higher mean GERD-HRQL score, lower rates of PPI use, and normal esophageal motility. The RSI of all patients improved from a mean preoperative value of 19.2 to 7.8 (2 weeks), 6.1 (8 weeks), and 10.9 (1 year). Those with the highest preoperative scores (RSI > 30) had the best response to ARS. When analyzing individual symptoms, the most likely to improve included heartburn, hoarseness, and choking. CONCLUSIONS: In our study population, patients with LPR symptoms achieved a rapid and durable response to antireflux surgery. Those with higher preoperative RSI scores experienced the greatest improvement. Our data suggest that antireflux surgery is a viable treatment option for this patient population.

Factors Influencing Management and Outcome in Patients with Occult Breast Cancer with Axillary Lymph Node Involvement: Analysis of the National Cancer Database.

BACKGROUND: Occult breast cancer (OBC) is rare and optimal local-regional (LR) management has not been defined. Using a patient registry database, we examine factors associated with treatment and outcomes in OBC. METHODS: Female patients with cT0 N1/2 M0 BC were selected from the National Cancer Database (2004-2013) and categorized into four treatment groups: MAST = mastectomy with axillary lymph node dissection (ALND) ± radiation (RT); RT + ALND = RT with ALND, no breast surgery; ALND = ALND alone; OBS = no breast surgery, RT, or ALND. Patient characteristics and overall survival (OS) were compared between groups, and multivariable analysis was used to identify factors associated with treatment and OS. RESULTS: Among 2.03 million BC cases, 1853 females (0.09%) with cT0 N1/2 M0 disease were identified and 1231 patients were categorized into a treatment group: MAST = 592, RT + ALND = 342, ALND = 106, OBS = 191. On logistic regression, care at an academic center was associated with a higher likelihood of RT + ALND compared with MAST (odds ratio 2.03, 95% confidence interval [CI] 1.50-2.74, p < 0.001). Patients treated with RT + ALND had significantly better OS on univariate survival analysis compared with patients treated with MAST (hazard ratio [HR] 0.475, 95% CI 0.306-0.736, p = 0.001). RT + ALND was independently associated with OS on multivariable survival analysis (HR 0.509, 95% CI 0.321-0.808, p = 0.004), after adjusting for covariates. CONCLUSIONS: Patients with OBC were more likely to undergo RT + ALND if they received care at an academic center. Patients treated with RT + ALND had significantly better OS compared with patients treated with MAST, after adjusting for covariates. This supports the use of RT + ALND as LR treatment for patients with OBC.

Pharmacologic regulation of AMPK in breast cancer affects cytoskeletal properties involved with microtentacle formation and re-attachment.

The presence of tumor cells in the circulation is associated with a higher risk of metastasis in patients with breast cancer. Circulating breast tumor cells use tubulin-based structures known as microtentacles (McTNs) to re-attach to endothelial cells and arrest in distant organs. McTN formation is dependent on the opposing cytoskeletal forces of stable microtubules and the actin network. AMP-activated protein kinase (AMPK) is a cellular metabolic regulator that can alter actin and microtubule organization in epithelial cells. We report that AMPK can regulate the cytoskeleton of breast cancer cells in both attached and suspended conditions. We tested the effects of AMPK on microtubule stability and the actin-severing protein, cofilin. AMPK inhibition with compound c increased both microtubule stability and cofilin activation, which also resulted in higher McTN formation and re-attachment. Conversely, AMPK activation with A-769662 decreased microtubule stability and cofilin activation with concurrent decreases in McTN formation and cell re-attachment. This data shows for the first time that AMPK shifts the balance of cytoskeletal forces in suspended breast cancer cells, which affect their ability to form McTNs and re-attach. These results support a model where AMPK activators may be used therapeutically to reduce the metastatic efficiency of breast tumor cells.

The combinatorial activation of the PI3K and Ras/MAPK pathways is sufficient for aggressive tumor formation, while individual pathway activation supports cell persistence.

A high proportion of human tumors maintain activation of both the PI3K and Ras/MAPK pathways. In basal-like breast cancer (BBC), PTEN expression is decreased/lost in over 50% of cases, leading to aberrant activation of the PI3K pathway. Additionally, BBC cell lines and tumor models have been shown to exhibit an oncogenic Ras-like gene transcriptional signature, indicating activation of the Ras/MAPK pathway. To directly test how the PI3K and Ras/MAPK pathways contribute to tumorigenesis, we deleted PTEN and activated KRas within non-tumorigenic MCF-10A breast cells. Neither individual mutation was sufficient to promote tumorigenesis, but the combination promoted robust tumor growth in mice. However, in vivo bioluminescence reveals that each mutation has the ability to promote a persistent phenotype. Inherent in the concept of tumor cell dormancy, a stage in which residual disease is present but remains asymptomatic, viable cells with each individual mutation can persist in vivo during a period of latency. The persistent cells were excised from the mice and showed increased levels of the cell cycle arrest proteins p21 and p27 compared to the aggressively growing PTEN-/-KRAS(G12V) cells. Additionally, when these persistent cells were placed into growth-promoting conditions, they were able to re-enter the cell cycle and proliferate. These results highlight the potential for either PTEN loss or KRAS activation to promote cell survival in vivo, and the unique ability of the combined mutations to yield rapid tumor growth. This could have important implications in determining recurrence risk and disease progression in tumor subtypes where these mutations are common.