Longitudinal Trends in Patient-Reported Outcomes in the First Year After Lumpectomy Versus Mastectomy.

BACKGROUND: It is unclear how patient-reported outcomes (PROs) change longitudinally after breast cancer surgery. We sought to compare trends in PROs among patients who underwent lumpectomy versus mastectomy over the first year after surgery. PATIENTS AND METHODS: Newly diagnosed stage 0-III female patients with breast cancer who underwent lumpectomy or mastectomy at an academic breast center between June 2019 and March 2023 were invited to participate in a longitudinal PRO study. Enrolled patients received the BREAST-Q™ module, a validated tool measuring domains, such as satisfaction with breasts, psychosocial well-being, physical well-being, and sexual well-being. Scores for each domain were compared between the lumpectomy and mastectomy groups over the first year after surgery. Linear mixed models were used to estimate the change in PRO scores over time. RESULTS: The cohort included 203 who underwent lumpectomy and 144 who underwent mastectomy. Patients who underwent lumpectomy were older, more likely to receive adjuvant radiation and endocrine therapy, and less likely to receive adjuvant chemotherapy. Patients who underwent lumpectomy demonstrated greater increases in scores over time for satisfaction with breasts, psychosocial well-being, and sexual well-being compared with patients who underwent mastectomy, after adjusting for the abovementioned covariates and receipt of reconstruction. The lumpectomy group had a larger decline in physical well-being over time compared with the mastectomy group. CONCLUSIONS: Patients who underwent lumpectomy demonstrated greater satisfaction with their breasts, psychosocial well-being, and sexual well-being but worse physical well-being over the first year after surgery compared with patients who underwent mastectomy. These results may help inform early-stage breast cancer patients making decisions about their surgical care.

Breast Cancer Surgery: A Qualitative Exploration of Concerns Over Time.

INTRODUCTION: As outcomes for breast cancer patients improve, addressing the side effects and distress of treatment can optimize survivorship. Although distress in breast cancer is well known in literature, there is a lack of information on how these concerns change through the phases of the cancer care continuum. Therefore, this study investigates the longitudinal trajectory of worry in patients with nonmetastatic breast cancer. METHODS: Female patients with newly diagnosed stage I-III breast cancer comprised a mixed-methods, longitudinal study at a cancer center from June 2019 to June 2023. Patients completed an open-ended survey regarding their top three concerns. Responses were obtained before surgery and two weeks, three, six, nine months, and one year postoperatively. Responses were qualitatively coded and analyzed to determine themes of cancer-related distress. RESULTS: Participants (n = 262) were aged an average 57.53 y (±12.54), 65.8% had stage I disease at diagnosis, and 91.1% were White. Responses revealed that patients' top three sources of concerns varied by treatment phase. Overall, patients were worried about their cancer diagnosis and the risk of recurrence. Preoperatively, patients were worried about treatment timeline, while postoperative concerns transitioned to physical appearance and surgical side effects. CONCLUSIONS: Breast cancer patients consistently reported worries about cancer diagnosis, recurrence, and metastasis as well as the side effects and fear of treatments. However, patient worry appeared to be intrinsically linked with their treatment phase. Therefore, support and interventions should be catered to reflect the changing patterns of patients' sources of distress to optimize breast cancer patients' quality of life.

Exploration of Patient Retention in Seeking a Second Opinion: A Retrospective Cohort Study.

INTRODUCTION: It is common for cancer patients to seek a second opinion for a variety of reasons. Understanding what drives patients to choose to receive treatment with their second opinion provider may uncover opportunities to improve the second opinion process. Therefore, we sought to identify the patient, disease, and treatment characteristics that were associated with second opinion retention rates in patients seeking a second surgical opinion for breast, colon, and pancreatic cancer. METHODS: We conducted a retrospective cohort study to evaluate patients who sought a second opinion within a large academic health-care system for breast, colon, and pancreatic cancer. Electronic medical records were reviewed for second opinions. Patient demographics and characteristics were collected and compared between the retained group and the nonretained groups. RESULTS: A total of 237 patients obtained second opinions for breast, colorectal, and pancreatic cancer. Patients that were offered a different treatment plan at their second opinion were more likely to be retained for systemic therapy (P = 0.009) for pancreatic cancer and any treatment for colon cancer (P = 0.003). Seeing a radiation oncologist (P = 0.007) or a plastic surgeon (P = 0.02) during the multidisciplinary consultation increased retention rates for breast cancer. CONCLUSIONS: Surgeons can better identify patients that are more likely to be retained after a second opinion by the individual patient characteristics and treatment factors. Understanding the factors that lead to retention for these three cancer types may help physicians provide the best possible resources for most patients presenting for second opinion evaluations.

Clinical implications of receptor conversions in breast cancer patients who have undergone neoadjuvant chemotherapy.

PURPOSE: In this study, we aimed to determine the incidence of receptor conversions after neoadjuvant chemotherapy (NAC) for breast cancer and assess the rate at which receptor conversion leads to changes in adjuvant therapy regimens. METHODS: We performed a retrospective review of female breast cancer patients treated with NAC at an academic breast center between January 2017 and October 2021. Patients with residual disease on surgical pathology and complete receptor status information for both pre-NAC and post-NAC specimens were included. Incidence of receptor conversions, defined as a change in at least one hormone receptor (HR) or HER2 status compared to preoperative specimens, was tabulated, and adjuvant therapy modalities were reviewed. Factors associated with receptor conversion were analyzed using chi-square tests and a binary logistic regression. RESULTS: Of the 240 patients with residual disease after NAC, 126 (52.5%) had receptor testing repeated. After NAC, 37 specimens (29%) had a receptor conversion. Receptor conversion resulted in the addition or removal of an adjuvant therapy in 8 patients (6%), indicating a number needed to screen of 16. Prior history of cancer, receipt of initial biopsy at an outside site, HR-positive tumors, and a pathologic stage of II or lower were factors associated with receptor conversions. CONCLUSION: HR and HER2 expression profiles frequently change after NAC and drive adjustments in adjuvant therapy regimens. Repeat testing of HR and HER2 expression should be considered in patients who receive NAC, especially in patients with early stage, HR-positive tumors whose initial biopsies were performed externally.

Postoperative Outcomes After Staged Versus Coordinated Breast Surgery and Bilateral Salpingo-Oophorectomy.

BACKGROUND: The objective of this study was to compare postoperative complication rates and healthcare charges between patients who underwent coordinated versus staged breast surgery and bilateral salpingo-oophorectomy (BSO). PATIENTS AND METHODS: The MarketScan administrative database was used to identify adult female patients with invasive breast cancer or BRCA1/BRCA2 mutations who underwent BSO and breast surgery (lumpectomy or mastectomy with or without reconstruction) between 2010 and 2015. Patients were assigned to the coordinated group if a breast operation and BSO were performed simultaneously or assigned to the staged group if BSO was performed separately. Primary outcomes were (1) incidence of 90-day postoperative complications and (2) 2-year aggregate perioperative healthcare charges. Fisher's exact tests, Wilcoxon rank-sum tests, and multivariable regression analyses were performed. RESULTS: Of the 4228 patients who underwent breast surgery and BSO, 412 (9.7%) were in the coordinated group and 3816 (90.3%) were in the staged group. The coordinated group had a higher incidence of postoperative complications (24.0% vs. 17.7%, p < 0.01), higher risk-adjusted odds of postoperative complications [odds ratio (OR) 1.37, 95% confidence interval (CI) 1.06-1.76, p = 0.02], and similar aggregate healthcare charges before (median charges: $106,500 vs. $101,555, p = 0.96) and after risk-adjustment [incidence rate ratio (IRR) 1.00, 95% CI 0.93-1.07; p = 0.95]. In a subgroup analysis, incidence of postoperative complications (12.9% for coordinated operations vs. 11.7% for staged operation, p = 0.73) was similar in patients whose breast operation was a lumpectomy. CONCLUSIONS: While costs were similar, coordinating breast surgery with BSO was associated with more complications in patients who underwent mastectomy, but not in patients who underwent lumpectomy. These data should inform shared decision-making in high-risk patients.

Financial Toxicity of Breast Cancer Care: The Patient Perspective Through Surveys and Interviews.

INTRODUCTION: Although the economic burden of cancer care is an emerging concern in the United States, the potential financial toxicity of breast cancer care at the patient level remains poorly understood. This study aims to characterize the scope of the contributors to financial distress on breast cancer patients and the resources utilized to address them. METHODS: Adult female patients diagnosed with invasive breast cancer or ductal carcinoma in situ between 2014 and 2019 at a single institution were retrospectively evaluated. Those who enrolled in copay assistance or indicated financial concerns on an intake distress screen were provided a web-based survey assessing financial changes, resources used, and financial engagement with providers. Semi-structured interviews further explored sources of financial distress and were analyzed by two researchers using grounded theory methodology. RESULTS: Sixty-eight patients completed the online survey, 15 of the 68 also participated in semi-structured phone interviews. On the online survey 74% of participants endorsed a financial distress score ≥5 on a scale of 0-10. Seventy-four percent changed their budget, 72% used their savings, and 60% cut down on spending. However, only 40% used resources such as financial counseling or financial assistance. Interviews revealed three major contributors to financial distress: (1) unexpected medical and nonmedical expenses, (2) lost revenue from missed work, and (3) altered budgeting. CONCLUSIONS: Many breast cancer patients experience significant financial distress without access to the resources they need. This study highlights the need for financial transparency, supportive financial services counseling at the time of diagnosis, throughout treatment and beyond.

Access to Results of Patient Reported Outcome Surveys Does Not Improve Survey Response Rates.

INTRODUCTION: In this embedded substudy of a longitudinal, randomized controlled trial, we sought to evaluate the effects of patient engagement and results feedback on longitudinal patient-reported outcome (PRO) survey completion rates. METHODS: Newly diagnosed stage 0-III breast cancer patients seen at an academic breast center between June 2019 and December 2021 were invited to participate in a longitudinal PRO study. Participants were emailed the BREAST-Q survey, a validated PRO scale, preoperatively and at regular intervals during their postoperative course. Patients were randomized into the intervention group, who received survey results upon completion, or the control group, who received no feedback. The primary endpoint was postoperative survey completion rate. An intention to treat analysis was performed and a quasi-Poisson regression was used to compare rates of longitudinal survey completion between the two groups. RESULTS: Of the 253 patients offered the preoperative survey, 115 were in the intervention group and 138 were in the control group. Postoperative survey completion rate was 54% for the intervention group and 47% for the control group. There was no significant difference in longitudinal postoperative survey completion rate between the two groups (rate ratio 1.10; 95% confidence interval [CI] 0.93-1.31). CONCLUSIONS: In this prospective randomized controlled study, patients did not complete surveys at a higher rate when their survey results were shared with them, suggesting that viewing these results without appropriate clinical context does not generate significant enhancement in patient engagement. Effective interventions to improve survey response rate must be identified to better evaluate PROs.

Toward a Politics of Care: Southeast Asian Refugee Organizing, Kinship, Care, and Reunion.

From a critical refugee studies orientation, our article redefines care within the context of myriad forms of state violence impacting Southeast Asian post-war refugee communities. Research reveals how harm is compounded at every step of Southeast Asian refugee journeys: war, forced displacement, resettlement, family separation, inherited health conditions, and generational trauma. How do we reckon with refugee trauma without conceding to it as an unchangeable fact of our lives? What knowledge might we gain by attending to the everyday work of survival in refugee communities? To answer these questions, the authors conceptualize care through (a) abolitionist organizing, (b) queer kinship and affective labor, (c) historiographic caretaking, and (d) refugee reunion.

Patient Perceptions of Changes in Breast Cancer Care and Well-Being During COVID-19: A Mixed Methods Study.

BACKGROUND: Widespread healthcare restructuring due to the COVID-19 pandemic led to modifications in the timing and delivery of care for breast cancer patients. Our study explores patient concerns relating to COVID-19, breast cancer, and changes to breast cancer care. PATIENTS AND METHODS: Breast cancer patients who presented for surgical consultation at an academic, multidisciplinary clinic completed the electronically distributed validated COVID-19 Impact and Healthcare Related Quality of Life questionnaire between August 2020 and February 2021. This questionnaire uses Likert score responses to assess COVID-specific concerns within domains, including distress and financial hardship. Scale scores were determined by averaging items within each domain, and scores > 2 indicated greater disruption. Semistructured interviews were conducted with patients who indicated interest in participating in the questionnaire. RESULTS: Of 381 patients recruited, 133 patients completed the questionnaire and 20 patients completed interviews. Sixty-three percent of survey participants reported attending a telemedicine appointment for their cancer care, and the majority (67%) were satisfied with their experience. Half of the participants (50%) reported fear about how the COVID-19 pandemic will impact their cancer care or recovery, and 66% reported anxiety about contracting COVID-19. Twenty-two percent of participants reported decreased income due to COVID-19. Patient interviews revealed tangible changes to care and provided in-depth information on the advantages and disadvantages of telehealth. CONCLUSIONS: Breast cancer patients report anxiety about COVID-19 infection and potential care modifications. Our study identifies impacts on patients' care and quality of life. Further investigation will inform interventions to improve psychosocial outcomes for patients and the telehealth experience.

No One-Size-Fits-All: Sexual Health Education Preferences in Patients with Breast Cancer.

BACKGROUND: Using explanatory mixed methods, we characterize the education that patients with breast cancer received about potential sexual health effects of treatment and explore preferences in format, content, and timing of education. PATIENTS AND METHODS: Adult patients with stage 0-IV breast cancer seen at an academic breast center during December 2020 were emailed questionnaires assessing sexual health symptoms experienced during treatment. Patients interested in further study involvement were invited to participate in semistructured interviews. These interviews explored sexual health education provided by the oncology team and patient preferences in content, format, and timing of education delivery. RESULTS: Eighty-seven (32%) patients completed the questionnaire. Most patients reported decreased sexual desire (69%), vaginal dryness (63%), and less energy for sexual activity (62%) during/after treatment. Sixteen patients participated in interviews. Few women reported receiving information about potential sexual effects of breast cancer treatment; patients who did reported a focus on menopausal symptoms or fertility rather than sexual function. Regarding preferences in format, patients were in favor of multiple options being offered rather than a one-size-fits-all approach, with particular emphasis on in-person options and support groups. Patients desired education early and often throughout breast cancer treatment, not only about sexual side effects but also on mitigation strategies, sexual function, dating and partner intimacy, and body image changes. CONCLUSION: Few patients received information about the sexual health effects of breast cancer treatment, though many experienced symptoms. Potential adverse effects should be discussed early and addressed often throughout treatment, with attention to strategies to prevent and alleviate symptoms and improve overall sexual health.

U.S. Vietnamese parents' HPV vaccine decision-making for their adolescents: an exploration of practice-, provider-, and patient-level influences.

U.S. Vietnamese have high cervical cancer incidence and low human papillomavirus (HPV) vaccine initiation. Using the P3 model, we explored practice-, provider-, and patient-level determinants of U.S. Vietnamese parents' HPV vaccine decision-making for their adolescents. We conducted a cross-sectional, online survey (04/2020-12/2020) with U.S. Vietnamese parents who had ≥ 1 adolescent ages 9-18. We assessed HPV vaccination outcomes (initiation, willingness to initiate, completion) and provider recommendation. Modified Poisson regressions were used to identify practice-, provider- and patient-level correlates of outcomes. The sample (n = 408) was 44 years old on average; 83% were female and 85% had a Bachelor's degree. Around half of adolescents were female (51%) and 13-18 year old (54%). Only 41 and 23% of parents had initiated and completed the HPV vaccine series for their child, respectively. Initiation was associated with receiving provider recommendation (either low- or high-quality), while willingness to initiate was associated with receiving high-quality recommendation. Both initiation and willingness to initiate was negatively associated with parental perception that their child was too young for a "sexually transmitted infection (STI)-preventing vaccine." Provider recommendation was associated with higher parental U.S. acculturation and the child being older and female. Provider-facing interventions should promote high-quality, age-based, gender-neutral HPV vaccine recommendation. These and population- and individual-facing interventions should recognize the need for additional parental education, particularly related to misconceptions regarding STI prevention.

Choosing Between Mastectomy and Breast-Conserving Therapy: Is Patient Distress an Influencing Factor?

BACKGROUND: Breast-conserving therapy (BCT) offers oncologic outcomes similar to those of mastectomy, yet many patients, when provided the option, choose mastectomy. This study aimed to evaluate the relationship between patient-reported distress and surgical decisions and to determine factors predictive of choosing BCT versus mastectomy. METHODS: Patients with newly diagnosed breast cancer deemed candidates for BCT who completed a distress screen at their initial visit to an academic institution between 2016 and 2019 were retrospectively reviewed. This screening tool captures distress in emotional, social, health, and practical domains on a scale of 0 to 10. The distress scores were compared against surgical decisions using nonparametric Wilcoxon rank-sum tests. Patient factors associated with surgical choice were analyzed using chi-square, Fisher's exact, and Student's t tests. A two-sided p value lower than 0.05 was considered significant. RESULTS: Of 506 patients deemed eligible for BCT, 430 (85%) chose BCT and 76 (15%) pursued mastectomy. The distress levels did not differ significantly between the surgical options. The patients who underwent mastectomy were on the average younger (50.7 vs 60.4 years; p < 0.0001), presented with palpable masses (p < 0.0001), had stage 0, 2, or 3 versus stage 1 disease (p < 0.0001), sought consultation for second opinions (19.7% vs 8.6%; p = 0.0032), received neoadjuvant chemotherapy (31.6% vs 16.3%; p = 0.0016), or had deleterious gene mutations (21.1% vs 5.1%; p < 0.0001). CONCLUSIONS: Distress was not associated with the pursuit of surgical treatment. Rather, younger age, search for a second opinion, and a palpable mass present at presentation were associated with more aggressive surgical decisions. Understanding factors that influence surgical decision-making is critical in guiding informed decisions that reflect patient values.

Early Trajectories of Patient Reported Outcomes in Breast Cancer Patients Undergoing Lumpectomy Versus Mastectomy.

PURPOSE: This study was designed to: (1) characterize longitudinal patient-reported outcomes (PROs) between breast cancer patients undergoing lumpectomy and mastectomy and (2) compare return to baseline scores at 3 months and 6 months postoperatively. METHODS: Newly diagnosed breast cancer patients seen at an academic breast center between June 2019 and February 2021 were invited to participate in longitudinal PRO surveys at their initial clinic visit. If willing to participate, patients were emailed the validated BREAST-Q™ questionnaire at the initial clinic visit (baseline), 2 weeks after surgery, and then every 3 months for the first year. We used linear mixed models to estimate the differences in slopes over time between lumpectomy and mastectomy for each PRO measure. Pearson's Chi-square tests with Yates' continuity correction were used to compare proportions of patients who return to baseline PRO scores. P < 0.05 was considered significant. RESULTS: Of 164 patients invited to participate, 100 (61%) completed a baseline survey and were included in analyses. Mastectomy patients had significantly greater decreases in breast satisfaction (P = 0.002), psychosocial well-being (P < 0.0001), and sexual well-being (P < 0.0001) over time compared with lumpectomy patients. Both surgical groups reported a decrease in physical well-being, although the decline was more significant in lumpectomy patients (P = 0.005). At 3 months and 6 months after surgery, significantly larger proportions of lumpectomy patients returned to their baseline breast satisfaction, psychosocial well-being, and physical well-being compared with mastectomy patients. CONCLUSIONS: Understanding how outcomes important to patients change over the care continuum can provide opportunities for early intervention and may prevent debilitating long-term morbidities of treatment.

Longitudinal Risk Management for Patients with Increased Risk for Breast Cancer.

INTRODUCTION: This study aims to characterize longitudinal care management and evaluate the relationship between various patient factors and the likelihood of choosing risk-reducing behaviors in women with increased risk of developing breast cancer. METHODS: A retrospective study was conducted to evaluate all adult female patients who had at least one clinic visit with a surgical provider for discussion of breast cancer risk assessment between January, 2017 to July, 2020 at an academic center. Patients with prior history of breast cancer were excluded. Patient details and strategies pursued at clinic visits were recorded. A time-to-event analysis was performed, and hazard ratios were determined to characterize associations between patient characteristics and time to pursuing risk-reducing care management. RESULTS: There were 283 participants with at least one follow-up visit and 48 (17.0%) ultimately changed their initial strategy to either chemoprevention or prophylactic mastectomy. Patients with gene mutations were 6 times more likely to engage in risk-reducing management compared to those without (hazard ratio (HR) 5.99, P < 0.001). Those with histories of high-risk proliferative changes (HR 7.62, P < 0.001) and hysterectomy (HR 2.99, P = 0.019) were also more likely to engage in risk-reducing management. Age, race, and increased predicted risk of developing breast cancer (estimated by various calculators) were not associated with increased likelihood of engaging in risk-reducing strategies. CONCLUSION: Known gene mutations, history of high-risk proliferative changes, and prior hysterectomy were factors associated with women who were more likely to engage in risk-reducing strategies. These findings, when paired with patient reported outcome measures, may help guide shared decision-making.

Hepatitis B Testing Among Vietnamese in Metropolitan Atlanta: The Role of Healthcare-Related and Acculturation-Related Factors.

BACKGROUND: Compared to other racial/ethnic groups, U.S. Vietnamese have higher Hepatitis B infection prevalence, which is a major liver cancer risk factor. Increased testing could reduce this disparity. It is critical to understand subgroups of U.S. Vietnamese least likely to have been tested for Hepatitis B and design appropriate interventions. We examined healthcare- and acculturation-related factors influencing Hepatitis B testing among U.S. Vietnamese. METHODS: Survey data of 100 U.S. Vietnamese attending health fairs/programs hosted by community-based organizations (2017-2018) were analyzed. Healthcare-related predictors included insurance and past 2-year checkup. Acculturation-related predictors included Vancouver Acculturation Index, percentage of lifetime in the U.S., and Vietnamese and English fluency. We conducted a multiple logistic regression controlling for age, sex, education, and household income. RESULTS: The sample was an average 37.5 years old and 61.6% female. Insurance coverage was reported by 83.0%. Average percentage of lifetime in the U.S. was 56.8%. Seventy percent reported having received Hepatitis B testing. Hepatitis B testing was associated with health insurance (aOR = 2.61, 95% CI = [1.05-6.47], p = .04) but not any acculturation-related predictors CONCLUSION: Improving insurance coverage and options can be a strategy to increase Hepatitis B testing among U.S. Vietnamese. More education regarding Hepatitis B (e.g., via community-based, culturally-appropriate, lay health worker-led programs) is needed to ensure that individuals are aware of their testing status and pursue appropriate healthcare decisions.

Reassessing Opioid Use in Breast Surgery.

BACKGROUND: This study aims to assess multimodal pain management and opioid prescribing practices in patients undergoing breast surgery. METHODS: A retrospective review of patients undergoing breast surgery at an academic medical center between April 1, 2018 and September 30, 2019, was performed. Patients with a history of recent opioid use or conditions precluding use of nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen (APAP) were excluded. Opioid-sparing pain regimens were assessed. Opioids prescribed on discharge were recorded as oral morphine equivalents (OMEs) and concordance with the Opioid Prescribing Engagement Network (OPEN) determined. RESULTS: The total study population consisted of 518 patients. 358 patients underwent minor outpatient procedures (sentinel lymph node biopsy, lumpectomy, and excisional biopsy), 10-40% of whom were appropriately prescribed as per the OPEN. Perioperatively, 53.9% of patients received APAP, 24.6% NSAIDs, 20.4% gabapentin, and 0.3% blocks; intraoperatively, 95.8% received local anesthetic and 25.7% ketorolac. For mastectomy without reconstruction, 63-88% of prescriptions were concordant with the OPEN. For mastectomy with reconstruction, discharge opioids ranged from 25 to 400 OMEs with a mean of 134.4 OMEs; 25% of patients received a refill. Of all patients undergoing mastectomy ± reconstruction, 62.5% received APAP, 18.8% NSAIDs, 38.8% pregabalin, and 20.6% locoregional block perioperatively; 37.5% received local anesthetic and 15.6% ketorolac intraoperatively. Of 143 inpatient stays, 89% received APAP, 38% NSAID, and 29% benzodiazepines; 29 patients received no opioids inpatient but were still prescribed 25-200 OMEs on discharge. CONCLUSIONS: There is need for a multidisciplinary approach to pain management with the use of enhanced recovery after surgery protocols as potential means to standardize perioperative regimens and mitigate opioid overprescription.

Inhibition of Mast Cell-Derived Histamine Decreases Human Cholangiocarcinoma Growth and Differentiation via c-Kit/Stem Cell Factor-Dependent Signaling.

The tumor microenvironment of cholangiocarcinoma (CCA) is composed of numerous cells, including mast cells (MCs). MCs release histamine, which increases CCA progression and angiogenesis. Cholangiocytes secrete stem cell factor, which functions via the MC growth factor receptor c-Kit. Here, we show that cholangiocytes express histidine decarboxylase and its inhibition reduces CCA growth. MC recruitment in the tumor microenvironment increased CCA growth. MC infiltration and MC markers were detected by toluidine blue staining and real-time PCR in human biopsies and in tumors from athymic mice treated with saline, histamine, histidine decarboxylase inhibitor, or cromolyn sodium. Tumor growth, angiogenesis, and epithelial-mesenchymal transition (EMT)/extracellular matrix (ECM) markers were measured in mice treated with cromolyn sodium. In vitro, human CCA cells were treated with MC supernatant fluids before evaluating angiogenesis and EMT/ECM expression. Migration assays were performed with CCA cells treated with the stem cell factor inhibitor. MC supernatant fluids increased CCA histidine decarboxylase, vascular endothelial growth factor, and MC/EMT/ECM expression that decreased with pretreatment of cromolyn sodium. MCs were found in human biopsies. In mice treated with cromolyn sodium, MC infiltration and tumor growth decreased. Inhibition of CCA stem cell factor blocked MC migration and MC/EMT/ECM in CCA. MCs migrate into CCA tumor microenvironment via c-Kit/stem cell factor and increase tumor progression, angiogenesis, EMT switch, and ECM degradation.

Inhibition of mast cell-derived histamine secretion by cromolyn sodium treatment decreases biliary hyperplasia in cholestatic rodents.

Cholangiopathies are characterized by dysregulation of the balance between biliary growth and loss. We have shown that histamine (HA) stimulates biliary growth via autocrine mechanisms. To evaluate the paracrine effects of mast cell (MC) stabilization on biliary proliferation, sham or BDL rats were treated by IP-implanted osmotic pumps filled with saline or cromolyn sodium (24 mg/kg BW/day (inhibits MC histamine release)) for 1 week. Serum, liver blocks and cholangiocytes were collected. Histidine decarboxylase (HDC) expression was measured using real-time PCR in cholangiocytes. Intrahepatic bile duct mass (IBDM) was evaluated by IHC for CK-19. MC number was determined using toluidine blue staining and correlated to IBDM. Proliferation was evaluated by PCNA expression in liver sections and purified cholangiocytes. We assessed apoptosis using real-time PCR and IHC for BAX. Expression of MC stem factor receptor, c-kit, and the proteases chymase and tryptase were measured by real-time PCR. HA levels were measured in serum by EIA. In vitro, MCs and cholangiocytes were treated with 0.1% BSA (basal) or cromolyn (25 µM) for up to 48 h prior to assessing HDC expression, HA levels and chymase and tryptase expression. Supernatants from MCs treated with or without cromolyn were added to cholangiocytes before measuring (i) proliferation by MTT assays, (ii) HDC gene expression by real-time PCR and (iii) HA release by EIA. In vivo, cromolyn treatment decreased BDL-induced: (i) IBDM, MC number, and biliary proliferation; (ii) HDC and MC marker expression; and (iii) HA levels. Cromolyn treatment increased cholangiocyte apoptosis. In vitro, cromolyn decreased HA release and chymase and tryptase expression in MCs but not in cholangiocytes. Cromolyn-treated MC supernatants decreased biliary proliferation and HA release. These studies provide evidence that MC histamine is key to biliary proliferation and may be a therapeutic target for the treatment of cholangiopathies.