Implications of tumor-infiltrating lymphocytes in early-stage triple-negative breast cancer: clinical oncologist perspectives.

Breast cancer (BC) is the most common neoplasm in women worldwide and one of the leading causes of female death. The triple-negative subtype, characterized by the absence of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2), tends to occur in younger patients, be more aggressive and less differentiated. Furthermore, this subtype is considered the most immunogenic and associated with higher levels of tumor cell infiltration, mainly lymphocytes. Tumor-infiltrating lymphocytes (TILs) play a crucial role in the interaction of the host's immune system and cancer cells. The microenvironment is critical in tumor development and progression. Assessment of infiltrating lymphocytes can provide valuable information about the immune response and, given the lack of biomarkers to guide treatment decisions and predict outcomes in triple-negative tumors and can be considered as a potential biomarker. Some evidence suggests that higher levels of these lymphocytes are associated with better responses to systemic treatment, longer progression-free survival and overall survival (OS). However, treatment escalation or de-escalation strategies for triple-negative BC (TNBC) currently do not consider the presence or density of TILs for therapeutic decisions. TILs appear to be useful predictive and prognostic indicators. Further clinical studies are needed to confirm these relationships and integrate TILs as a biomarker consistently into clinical practice. This article summarizes key concepts relating to the role of the immune infiltrate in BC, along with the current status and future prospects regarding TILs as a predictive and prognostic biomarker.

Chronic Lymphocytic Thyroiditis with Oncocytic Metaplasia Influences PD-L1 Expression in Papillary Thyroid Carcinoma.

BACKGROUND: Despite the increasing recognition of PD-L1 as predictor of immunotherapeutic response in various malignancies, its role and prognostic significance in thyroid cancer remain underexplored and subject to debate. This study begins to address this gap by comprehensively analyzing PD-L1 expression in papillary thyroid carcinoma (PTC) and investigating its correlation with key clinicopathological variables. METHODS: We conducted immunohistochemistry (IHC) to assess PD-L1 expression in whole-tissue sections from 121 primary papillary thyroid carcinoma (PTC) cases. We then analyzed the correlations between PD-L1 expression and various clinicopathological variables. RESULTS: PD-L1 expression was detected in 33.1% of papillary thyroid carcinomas (PTCs), predominantly exhibiting weak to moderate intensity. Notably, this study found no significant correlation between PD-L1 expression and various clinicopathological variables. The lack of association with traditional factors such as age, sex, histological subtype, and tumor size suggests the complex and multifaceted nature of PD-L1 regulation in PTC. Multivariate logistic regression analysis identified chronic lymphocytic thyroiditis with oncocytic metaplasia as the sole independent predictor of PD-L1 expression (P = 0.014), underlining the potential influence of the tumor microenvironment on immune checkpoint expression in PTC. CONCLUSIONS: Our study underscores the intricate interplay between chronic lymphocytic thyroiditis with oncocytic metaplasia and PD-L1 expression in papillary thyroid carcinoma. The observed link suggests a potential avenue for therapeutic intervention using anti-PD-1/PD-L1 therapies in surgery-refractory PTC. Understanding the dynamics of immune checkpoint regulation in the context of the tumor microenvironment is crucial for devising effective treatment strategies. Future research endeavors should delve deeper into the molecular mechanisms underlying this interaction and explore its implications for patient outcomes. As the field of immunotherapy continues to evolve, our findings contribute valuable insights into the complex immunological landscape of thyroid cancer.

Trop-2 Is Highly Expressed in Early Luminal-Like Breast Cancer.

Trop-2, a transmembrane glycoprotein, has been identified in human epithelial cells as a contributor to tumor growth and unfavorable prognosis in breast cancer (BC). Our study aimed to assess the expression of Trop-2 protein via immunohistochemistry (IHC) and correlate it with clinicopathological features in early luminal-like BC. We conducted a cross-sectional study evaluating Trop-2 protein expression in tissue microarrays using IHC. The expression was evaluated by the H-score and the following categorization was used: H-Score 0 to <100 as low, H-Score 100 to 200 as intermediate, and H-Score >200 to 300 as high. The study included 84 patients with a median age of 57, of whom 70% had invasive ductal carcinomas, 75% were classified as T2, and 47.6% had no affected lymph nodes. Trop-2 expression was high in 56% of patients and intermediate in 38%. None of the patients had an H-Score of zero. No correlation was observed between Trop-2 expression and clinicopathological features, including age, histological subtype, grade, Ki67, tumor size, nodal status, lymphovascular invasion, tumor subtype, and pathological staging. We demonstrated that Trop-2 is highly expressed in early luminal-like BC and is not influenced by clinicopathological features.

Active Surveillance of Differentiated Thyroid Cancer Metastatic Cervical Lymph Nodes: A Retrospective Single-Center Cohort Study.

Background: The most frequent site of recurrence of differentiated thyroid cancer (DTC) is cervical lymph nodes (LNs), which often necessitates repeated surgical interventions and morbidity in a generally indolent disease. Data on active surveillance (AS) of small cervical nodal metastasis are still scarce, particularly in real-world clinical settings. In this study, we evaluated the DTC outcomes of AS of metastatic cervical LNs and explored factors associated with disease progression. Methods: We conducted a retrospective cohort study, including DTC patients with biopsy-proven metastatic cervical LNs, who were followed on AS in a tertiary care, university-based institution in Brazil. The inclusion criteria were cervical metastasis ≤2.0 cm and an AS duration of at least 6 months. We excluded lesions with aggressive histology, those in close proximity to or invading local structures. The primary outcome was disease progression (enlargement ≥3 mm in any diameter or a new cervical metastasis). Results: Data from 40 patients were analyzed. Most were female (77.5%) and had papillary thyroid cancer (97.5%). The mean age was 47.0 (± standard deviation 15.8) years. The 8th edition of the tumor, node, metastasis stage (TNM8) staging for DTC was as follows: 29 in stage I (74.4%), 8 in stage II (20.5%), and 2 in stage IV (5.0%). The median maximum LN diameter was 0.9 (interquartile range [IQR], 0.8-1.3) cm, and the median AS follow-up duration was 27.5 (IQR, 16.5-47.3) months. Disease progression occurred in 14 (35%) patients: 7 (17.5%) due to enlargement ≥3 mm, and 7 (17.5%) had new cervical metastasis. The cervical progression-free survival was 51.0 (confidence interval, 47.0-55.0) months. No demographic, oncological, or biochemical factors were associated with disease progression. Of the 14 patients with disease progression, 8 were referred for surgery. No permanent surgical complications were reported. Of the six patients who remained on AS despite disease progression, five showed no further progression during subsequent follow-up (range 6-40 months). Conclusions: We observed that most small metastatic cervical LNs remained stable and were safely managed with AS. Nevertheless, these observations are limited by the retrospective design, small sample size, and short follow-up. Further prospective and long-term studies are warranted.

Age-related variation in malignant cytology rates of thyroid nodules: insights from a retrospective observational study assessing the ACR TI-RADS.

OBJECTIVE: The influence of age on the malignant cytology rate of thyroid nodules remains uncertain. The American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) is currently used to guide subsequent investigations of thyroid nodules, regardless of clinical variables. This study aimed to investigate the impact of age on the malignant cytology rates of thyroid nodules and the diagnostic performance of ACR TI-RADS across different age groups. DESIGN: A retrospective, single-center, observational study. METHODS: Patients aged ≥ 20 years with thyroid nodules, who underwent fine-needle aspiration biopsy between 2012 and 2019 were evaluated. Ultrasound images were used to obtain the TI-RADS data. Malignancy was determined based on suspicious for malignancy (Bethesda V) and malignant (Bethesda VI) cytology results or malignancy in cell block analysis. RESULTS: A total of 1023 nodules from 921 patients (88.2% female) were analyzed. The median age was 58.5 (interquartile range [IQR], 41.1-66.6) years, and the median nodule size was 2.4 (IQR, 1.7-3.6) cm. Stratification by age revealed a decreasing prevalence of malignant cytology across subgroups of 20-39, 40-59, and ≥60 years (10.7%, 8.5%, and 3.7%, respectively; P = .002). After adjusting for sex, multinodularity, nodule size, and ACR TI-RADS category, we observed that each year of age reduced the OR for malignant cytology by 3.0% (95% CI: 0.7%-5.3%; P = .011). When comparing the subgroups of 20-39 and ≥60 years, the malignant cytology rate decreased by half in TI-RADS 4 (from 21.4% to 10.4%) and two-thirds in TI-RADS 5 (from 64.7% to 22.6%). CONCLUSIONS: Our study demonstrated that as patient age increased, the rate of malignant cytology in thyroid nodules decreased. Moreover, age significantly influences the malignancy rates of thyroid nodules classified according to the ACR TI-RADS.

Using an ultrasonography risk stratification system to enhance the thyroid fine needle aspiration performance.

PURPOUSE: The American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) is a risk stratification system for thyroid nodules based on their ultrasonography (US) characteristics. Here, we aimed to assess TI-RADS on fine needle aspiration biopsy (FNAB) recommendations and performance in thyroid nodules. METHODS: We performed a retrospective study in a single center. All patients with thyroid nodules who underwent FNAB between 2012 and 2019 were included. TI-RADS data were extracted from medical records. Malignancy rates were defined based on cytological exams. RESULTS: A total of 1,044 nodules (938 patients) were evaluated. TI-RADS classification was as follows: 13 TI-RADS 1, 524 TI-RADS 2, 273 TI-RADS 3, 148 TI-RADS 4, and 85 TI-RADS 5. TI-RADS classification showed a sensitivity of 75% (95 %CI: 63-84.7), a negative predictive value of 97.6% (95 %CI: 96.5-98.5), and accuracy of 73.1% (95 %CI: 70.3-75.8). According to TI-RADS FNAB criteria, only 314 (30%) nodules would have undergone FNAB. Of them, 157 (50%) were classified as benign (Bethesda II), 45 (14.3%) as undetermined (Bethesda III or IV), and 51 (16.2%) as malignant (Bethesda V or VI). Of the remaining 729 nodules that did not meet FNAB criteria, 17 (2.3%) had Bethesda V or VI and underwent surgery. Of them, four (23%) were <1 cm in size (microcarcinomas), and eight (47.0%) remain in follow-up according to the TI-RADS criteria. Seven malignant cases would be missed (0.9%). CONCLUSION: ACR TI-RADS allows a significant decrease in the number of FNAB, increasing its diagnostic accuracy.

Frequency of the common germline MUTYH mutations p.G396D and p.Y179C in patients diagnosed with colorectal cancer in Southern Brazil.

INTRODUCTION: MUTYH-associated polyposis (MAP) is an autosomal recessive cancer predisposition syndrome associated with the development of colorectal tumors and colonic polyps at an early age. MAP syndrome is associated to germline biallelic mutations in the MUTYH gene which lead to deficient DNA repair through the base-excision repair system and accumulation of G:C→T:A transversions. Occurrence of such mutations in oncogenes and tumor suppressor genes drives colorectal carcinogenesis and is associated with the development of colonic polyps. Two common mutations, p.Y179C and p.G396D, are present in approximately 70-80% of MAP in European families with identified MUTYH germline mutations. The aim of this study was to assess the frequency of the germline MUTYH mutations p.Y179C and p.G396D in Brazilian patients with MAP and other hereditary colorectal cancer (CRC) phenotypes, as well as in sporadic CRC cases. MATERIALS AND METHODS: A total of 75 patients were included. Samples were screened for the MUTYH germline mutations p.Y179C and p.G396D by allelic discrimination assays using allele-specific TaqMan® probes. In all mutation-positive cases, results were confirmed by sequencing. RESULTS AND CONCLUSIONS: Biallelic germline MUTYH mutations were identified in 4 of 60 (6.6%) patients with a phenotype of hereditary colorectal cancer. Germline MUTYH mutation screening should be considered in the differential diagnosis of hereditary colorectal syndromes, and not only in MAP, but also in familial adenomatous polyposis and Bethesda criteria-positive families. Additional mutation screening studies of the MUTYH gene in a larger number of Brazilian patients will be necessary to confirm these results and determine the validity and applicability of MUTYH mutation screening in our population.

Basal-like immunophenotype markers and prognosis in early breast cancer.

AIMS AND BACKGROUND: Basal-like breast cancer is a distinct group of tumors with heterogeneous behavior, and not all have a poor prognosis. The present study analyzed the prevalence and prognosis of early basal-like breast cancer. METHODS AND STUDY DESIGN: A total of 112 patients with stage I and II breast cancer were retrospectively analyzed using immunohistochemical stains for estrogen receptor, progesterone receptor, HER2, cytokeratin 5/6 and epidermal growth factor receptor. Basal-like tumors were defined as being estrogen receptor, progesterone receptor and HER2 negative and cytokeratin 5/6 and/or epidermal growth factor receptor positive. RESULTS: Of the 112 cases, respectively 13 (11.6%) were basal-like, 77 (68.8%) luminal A or B, 13 (11.6%) HER2 positive and 9 (8%) undefined. In basal-like tumors, epidermal growth factor receptor and cytokeratin 5/6 expression was positive in 5 patients (38.5%) and 12 patients (92%), respectively. There was no significant correlation between basal-like breast cancer and age (P = 0.207), lymph node status (P = 1.0) or clinical stage (P = 0.53). Among all tested biomarkers, positivity was found in 81 (72.3%) for estrogen receptor, 13 (11.6%) for HER2, 11 (9.8%) for epidermal growth factor receptor and 36 (32.1%) for cytokeratin 5/6. Epidermal growth factor receptor expression was significantly correlated with estrogen receptor-negative (P = 0.01) and HER2-positive (P = 0.02) tumors. During a median follow-up of 81 months, there were 26 (23%) disease relapses and 12 (10.7%) deaths. No significant difference relating to disease-free survival and overall survival was noted between basal-like breast cancer and subtypes luminal A and B, HER2 positive and undefined. CONCLUSIONS: The addition of cytokeratin 5/6 and epidermal growth factor receptor defines a small subgroup of patients with basal-like tumors. In a population with early breast cancer, basal-like tumors did not have a prognosis different from the other subtypes. Neither was there a significant association with clinicopathological features. The high frequency of epidermal growth factor receptor positivity in estrogen receptor-negative and HER2-positive tumors represents a potential target in clinical trials.

Decreased expression of the thyroid hormone-inactivating enzyme type 3 deiodinase is associated with lower survival rates in breast cancer.

Thyroid hormones (THs) are critical regulators of cellular processes, while changes in their levels impact all the hallmarks of cancer. Disturbed expression of type 3 deiodinase (DIO3), the main TH-inactivating enzyme, occurs in several human neoplasms and has been associated with adverse outcomes. Here, we investigated the patterns of DIO3 expression and its prognostic significance in breast cancer. DIO3 expression was evaluated by immunohistochemistry in a primary cohort of patients with breast cancer and validated in a second cohort using RNA sequencing data from the TCGA database. DNA methylation data were obtained from the same database. DIO3 expression was present in normal and tumoral breast tissue. Low levels of DIO3 expression were associated with increased mortality in the primary cohort. Accordingly, low DIO3 mRNA levels were associated with an increased risk of death in a multivariate model in the validation cohort. DNA methylation analysis revealed that the DIO3 gene promoter is hypermethylated in tumors when compared to normal tissue. In conclusion, DIO3 is expressed in normal and tumoral breast tissue, while decreased expression relates to poor overall survival in breast cancer patients. Finally, loss of DIO3 expression is associated with hypermethylation of the gene promoter and might have therapeutic implications.

The tissue expression pattern of CA 19.9 is associated with oncological features in medullary thyroid carcinoma.

PURPOSE: Elevated serum levels of carbohydrate antigen 19.9 (CA19.9), a well-established tumor marker in pancreatic neoplasms, has been proposed as a prognostic marker of tumor aggressiveness in medullary thyroid carcinoma (MTC). A hypothesis of C-cell dedifferentiation has been raised. Here, we evaluated the expression of CA19.9 and CD133, a stem cell marker, in MTC tissues. METHODS: MTC samples from patients attending a university-based hospital were evaluated for CA19.9 and CD133 expression by immunohistochemistry. Clinical data were retrieved from medical records. RESULTS: Tumor specimens from 70 MTC patients (57.1% hereditary) were evaluated. The age at diagnosis was 36.1 ± 16.3 years, and 58.6% were female; 53% of patients had cervical and 20% distant metastases. CA19.9 staining was detected in 87% of the samples, but no association was observed with biochemical markers, tumor size, local or distant metastases (All P > 0.05). Remarkable, CA19.9 expression was higher in the metastasis than in primary tumor samples (P = 0.0002). CD133 was expressed in 90.5% samples, but no correlation was found with CA19.9. Interestingly, we identified three distinct expression patterns to CA19.9: individual, focal, and diffuse cells. Sporadic MTC was associated with the individual cell pattern (70.6%), while the hereditary form with the focal expression pattern (63.9%; P = 0.04). Remarkably, the diffuse pattern was associated with larger tumor size and distant metastases (P = 0.032). CONCLUSIONS: The majority of samples stained for CA19.9, suggesting it is an MTC cell-intrinsic feature. Three distinct expression patterns were identified, which were associated with the hereditary or sporadic form, larger tumor size, and presence of metastases.

ESR1 Mutations Are Not a Common Mechanism of Endocrine Resistance in Patients With Estrogen Receptor-Positive Breast Cancer Treated With Neoadjuvant Aromatase Inhibitor Therapy.

Introduction: Mutations in the ESR1 gene (ESR1m) are important mechanisms of resistance to endocrine therapy in estrogen receptor-positive (ER+) metastatic breast cancer and have been studied as a potential therapeutic target, as well as a predictive and prognostic biomarker. Nonetheless, the role of ESR1m as a possible mechanism of primary endocrine resistance, as well as whether it also occurs in tumors that are resistant to ET administered in early-stage disease as (neo)adjuvant, has not been adequately studied. In this study, we evaluated the prevalence of ESR1m in tumor samples from patients with ER+ breast cancer resistant to neoadjuvant aromatase inhibitor therapy. Methods: We followed a prospective cohort of patients with ER+ HER2- stages II and III breast cancer treated with neoadjuvant endocrine therapy (NET). Tumor samples from patients with a pattern of primary endocrine resistance [defined as a Preoperative Endocrine Prognostic Index (PEPI) score of ≥4] were identified and analyzed for the presence of ESR1m. Results: One hundred twenty-seven patients were included in the cohort, of which 100 (79%) had completed NET and underwent surgery. Among these patients, the PEPI score ranged from 0 to 3 in 70% (70/100), whereas 30% (30/100) had a PEPI score of 4 or more. Twenty-three of these patients were included in the analysis. ESR1 mutations were not identified in any of the 23 patients with early-stage ER+ breast cancer resistant to NET. Discussion: Growing evidence supports the notion that there are different mechanisms for primary and secondary endocrine resistance. Our study suggests that ESR1 mutations do not evolve rapidly and do not represent a common mechanism of primary endocrine resistance in the neoadjuvant setting. Therefore, ESR1m should be considered a mechanism of acquired endocrine resistance in the context of advanced disease. Further research should be conducted to identify factors associated with intrinsic resistance to ET.

Prevention of postmolar gestational trophoblastic neoplasia using prophylactic single bolus dose of actinomycin D in high-risk hydatidiform mole: a simple, effective, secure and low-cost approach without adverse effects on compliance to general follow-up or subsequent treatment.

OBJECTIVE: To evaluate the efficacy of actinomycin D (Act-D) as prophylactic chemotherapy (P-Chem) to reduce postmolar gestational trophoblastic neoplasia (GTN) in patients with high-risk hydatidiform mole (Hr-HM). METHODS: From 1987 to 2006, 265 Hr-HM were selected in a retrospective analysis of a nonrandomized clinical trial of 1090 patients with gestational trophoblastic disease (GTD) followed up at a Trophoblastic Disease Center (TDC) in southern Brazil. From 1996 to 2006, 163 received a single bolus dose of Act-D at time of uterine evacuation (Hr-HM-chem group); 102 with the same risk factors did not get P-Chem (Hr-HM-control group). Variables were: number of patients with postmolar GTN who required chemotherapy during follow-up, postmolar GTN morbidity, compliance and operational costs. RESULTS: Postmolar GTN was diagnosed in 18.4% of the Hr-HM-chem patients (95% CI: 12.7-24.7) and in 34.3% of the Hr-HM-control patients (95% CI: 25.1-43.5). Postmolar GTN was 46% lower in P-Chem (RR=0.54; 95% CI: 0.35-0.82; NNT=7). P-Chem adverse effects were occasional and minor. When disease progressed to postmolar GTN, severity was the same, but costs were lower for the Hr-HM-chem group. Compliance with follow-up was high and similar in both groups. CONCLUSIONS: Follow-up of patients with Hr-HM showed that a single bolus dose of prophylactic Act-D reduced the incidence of postmolar GTN. Compliance and postmolar GTN morbidity were not affected. Treatment costs and emotional complications were reduced. This prophylactic approach can be adopted before uterine evacuation in any TDC that treats Hr-HM patients that present with undelivered moles.

MnSOD gene polymorphism association with steroid-dependent cancer.

Oxidative stress enhances carcinogenesis due to DNA damage. Manganese superoxide dismutase (MnSOD) Val16Ala polymorphism has been recently associated with breast and prostate cancer. The role of oxidative stress in male breast cancer is poorly investigated due to the low prevalence of this neoplasia. We studied the relationship between prostate cancer (PC), male (MBC) and female breast cancer (FBC) and this polymorphism in a case-control study. Human genetic polymorphism Val16Ala of MnSOD was obtained from blood and paraffin-embedded tumor samples. The polymorphism was determined in 11 cases of MBC, 51 cases of PC, 89 cases of FBC and 372 age-adjusted healthy controls by polymerase chain reaction-restriction fragment length polymorphism techniques using restriction enzyme Hae III. Chi-square or Fisher test were used to compare the MnSOD frequency distribution. The observed genotypic frequencies of all samples were AA = 9.6% (n = 50), VV = 25.4% (n = 133) and AV = 64% (n = 340), all at Hardy-Weinberg equilibrium. Breast and prostate cancer risk was elevated in male and female patients with the Ala/Ala genotype compared to controls (p = 0.006, odds ratio = 2.5, 95% confidence interval 1.393-4.541). Even though the frequency of the Ala allele was low (9.6%) in the studied population, these data support the hypothesis that MnSOD and oxidative stress play a significant role in breast cancer risk both in males and females and also brings new information on the role of this polymorphism in prostate cancer. This is the first study which provides some evidence that genetic polymorphism in the MnSOD gene may be associated with an increased risk of male breast cancer. Studies with a larger sample size are needed to confirm the findings.

A model to optimize public health care and downstage breast cancer in limited-resource populations in southern Brazil. (Porto Alegre Breast Health Intervention Cohort).

BACKGROUND: Breast cancer (BC) is a major public health problem, with rising incidence in many regions of the globe. Although mortality has recently dropped in developed countries, death rates are still increasing in some developing countries, as seen in Brazil. Among the reasons for this phenomenon are the lack of structured screening programs, a long waiting period between diagnosis and treatment, and lack of access to health services for a large proportion of the Brazilian population. METHODS AND DESIGN: Since 2004, an intervention study in a cohort of women in Southern Brazil, denominated Porto Alegre Breast Health Intervention Cohort, is being conducted in order to test the effectiveness and cost-effectiveness of a model for BC early detection and treatment. In this study, over 4,000 women from underserved communities aged 40 to 69 years are being screened annually with mammography and clinical breast examination performed by a multidisciplinary team, which also involves nutritional counseling and genetic cancer risk assessment. Risk factors for BC development are also being evaluated. Active search of participants by lay community health workers is one of the major features of our program. The accrual of new participants was concluded in 2006 and the study will last for 10 years. The main goal of the study is to demonstrate significant downstaging of BC in an underserved population through proper screening, attaining a higher rate of early-stage BC diagnoses than usually seen in women diagnosed in the Brazilian Public Health System. Preliminary results show a very high BC incidence in this population (117 cases per 100,000 women per year), despite a low prevalence of classical risk factors. DISCUSSION: This study will allow us to test a model of BC early diagnosis and treatment and evaluate its cost-effectiveness in a developing country where the mortality associated with this disease is very high. Also, it might contribute to the evaluation of risk factors in a population with a different ethnic background from that studied in developed countries. If our model is proven effective, it may be replicated in other parts of the globe where BC is also a major public health problem.

Association of ESR1 Mutations and Visceral Metastasis in Patients with Estrogen Receptor-Positive Advanced Breast Cancer from Brazil.

Mutations in the ESR1 gene (ESR1m) are important mechanisms of resistance to endocrine therapy in estrogen receptor-positive advanced breast cancer and have been recognized as a prognostic and predictive biomarker as well as a potential therapeutic target. However, the prevalence of ESR1m in real-world patients has not been adequately described. Therefore, we sought to evaluate the prevalence of ESR1m in metastatic samples from Brazilian patients with estrogen receptor-positive (ER+) advanced breast cancer previously treated with endocrine therapy. The presence of ESR1m was evaluated in formalin-fixed paraffin-embedded (FFPE) breast cancer tissue using real-time quantitative polymerase chain reaction (RT-qPCR). Mutations in codons 380, 537, and 538 of the ESR1 gene were analyzed. Out of 77 breast cancer samples, 11 (14.3%) showed mutations in the ESR1 gene. ESR1m were detected in a variety of organs, and the D538G substitution was the most common mutation. In visceral metastasis, ESR1m were detected in 25% (8/32) of the samples, whereas in nonvisceral metastasis, ESR1m were detected in 6.7% (3/45) of the samples. The odds of a sample with visceral metastasis having an ESR1 mutation is 4.66 times the odds of a sample of nonvisceral metastasis having an ESR1 mutation (95% CI: 1.13-19.27; p value = 0.0333). Our study indicates that the prevalence of ESR1m in samples from Brazilian patients with metastatic ER+ breast cancer is similar to that described in patients included in clinical trials. We observed an association of ESR1m with visceral metastasis.

Cisplatin, Fluorouracil in Bolus Injection, and Leucovorin in First-Line Therapy for Advanced Gastric Cancer as an Alternative to Protocols With Infusional Fluorouracil.

PURPOSE: Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer death worldwide. Platinum agents and fluoropyrimidines are the main compounds used in the first-line setting for advanced GC. Given the activity of fluorouracil (FU) bolus, the PFL protocol, a chemotherapy regimen combining cisplatin, FU bolus, and leucovorin, was incorporated at the Brazilian National Cancer Institute, because this schedule does not require hospitalization or infusion pumps. This study aims to evaluate the outcomes of PFL in the first-line setting for patients with advanced GC. MATERIALS AND METHODS: This was a retrospective cohort study evaluating patients with advanced GC treated in the first-line setting with cisplatin 80 mg/m2 on day 1 and FU bolus 400 mg/m2 plus leucovorin 20 mg/m2 on days 1, 8, 15, and 22 every 4 weeks, from January 2008 to December 2014. RESULTS: A total of 109 patients were enrolled. The median number of cycles received per patient was four (one to 11). Complete responses were achieved in 6.4% and partial responses in 14.7%. Median progression-free survival was 6.3 months (95% CI, 5.08 to 7.58 months) and median overall survival was 8.3 months (95% CI, 6.79 to 9.87 months). Thirty-four (31.2%) patients were alive in 1 year. Grade 3 and 4 adverse events were experienced by 26.6% and 3.7% of patients, respectively, with dose reduction necessary in 9.1%. CONCLUSION: PFL is active in advanced GC and could be an alternative for FU continuous infusion protocols in institutions with limited resources and/or low budget, which is the reality in many nations all over the world.

Neoadjuvant Multikinase Inhibitor in Patients With Locally Advanced Unresectable Thyroid Carcinoma.

Background: Papillary thyroid carcinoma (PTC) is the most common and less aggressive thyroid cancer, but some patients may display locally advanced disease. Therapeutic options are limited in these cases, particularly for those patients with unresectable tumors. Neoadjuvant therapy is not part of the recommended work up. Methods: Report a case of an unresectable grossly locally invasive PTC successfully managed with neoadjuvant therapy and provide a systematic review (SR) using the terms "Neoadjuvant therapy" AND "Thyroid carcinoma." Results: A 32-year-old man with a 7.8 cm (in the largest dimension) PTC was referred to total thyroidectomy, but tumor resection was not feasible due to extensive local invasion (trachea, esophagus, and adjacent structures). Sorafenib, a multikinase inhibitor (MKI), was initiated; a 70% tumor reduction was observed after 6 months, allowing new surgical intervention and complete resection. Radioactive iodine (RAI) was administered as adjuvant therapy, and whole body scan (WBS) shows uptake on thyroid bed. One-year post-surgery the patient is asymptomatic with a status of disease defined as an incomplete biochemical response. The SR retrieved 123 studies on neoadjuvant therapy use in thyroid carcinoma; of them, 6 were extracted: 4 case reports and 2 observational studies. MKIs were used as neoadjuvant therapy in three clinical cases with 70-84% of tumor reduction allowing surgery. Conclusion: Our findings, along with other reports, suggest that MKIs is an effective neoadjuvant therapy and should be considered as a therapeutic strategy for unresectable grossly locally invasive thyroid carcinomas.

The Challenge of Evaluating Adnexal Masses in Patients With Breast Cancer.

This narrative literature review addresses the problem of an adnexal mass discovered during the course of breast cancer (BC) care, which may represent a benign condition, a metastatic process, or a primary ovarian cancer (OC), clinical scenarios associated with distinct physiopathology and prognosis. Furthermore, the coexistence of BC and OC in the same patient may be owing to a hereditary disorder, deserving specific management strategies and counseling. The initial detection and evaluation of an adnexal mass in a patient with BC requires a high index of suspicion, and the initial workup should include a thorough medical history and physical examination, measurement of tumor markers, complete blood count, and imaging tests. Transvaginal ultrasonography remains the standard tool, and findings suggestive of malignancy include bilateral tumors, thick septations, predominance of a solid component, Doppler flow to the solid component, and ascites. From the pathology point of view, features that are suggestive of metastatic disease include bilaterality, mild ovarian enlargement, vascular emboli, no omental deposits, and the absence of transition from benign to malignant epithelium. Although there is a considerable overlap in OC and BC immunohistochemical profiles, BC usually stain positive for GCDFP-15 and negative for vimentine, PAX8, and WT1, and OC often stain positive for CK7, PAX8, WT1, and to mesothelin. Genetic counselling should always be indicated in this clinical scenario. In conclusion, diagnostic spectrum of an ovarian mass in a patient with BC is broad, and a systematic multi-professional strategy is necessary to conduct these challenging cases.

Impact of Serum TSH and Anti-Thyroglobulin Antibody Levels on Lymph Node Fine-Needle Aspiration Thyroglobulin Measurements in Differentiated Thyroid Cancer Patients.

BACKGROUND: Thyroglobulin measurements in the washout of fine needle aspiration (FNA-Tg) are an excellent tool to detect lymph node (LN) metastases of differentiated thyroid carcinoma (DTC). Nevertheless, how to define the best cutoffs and the influence of potential confounders are still being discussed. OBJECTIVE: To evaluate the accuracy of FNA-Tg measurement to detect DTC metastases and the influence of thyroid status and anti-thyroglobulin antibodies (TgAb). METHODS: One hundred thirty-eight patients with DTC and suspicious cervical LN were included. Patients underwent ultrasound (US)-guided FNA for cytological examination and FNA-Tg measurements. Final diagnoses were confirmed by histological examination or clinical and US follow-up for at least 1 year. RESULTS: Data from 119 subjects with suspicious LN were evaluated. The median value of FNA-Tg in patients with metastatic LN (n = 65) was 3,263.0 ng/mL (838.55-12,507.5), while patients without LN metastasis (n = 54) showed levels of 0.2 ng/mL (0.2-0.2). According to the ROC curve analysis, the best cutoff value to predict metastasis was 4.41 ng/mL for FNA-Tg, with a sensitivity of 98% and specificity of 96%. There were no differences in the median of FNA-Tg measurements between those on (TSH 0.16 mUI/mL) and those off levothyroxine (TSH 99.41 mUI/mL) therapy (47.94 vs. 581.15 ng/mL, respectively; p = 0.79). Interestingly, the values of FNA-Tg in patients with LN metastasis (n = 65) did not differ between patients with positive and those with negative TgAb (88.8 vs. 3,263.0 ng/mL, respectively; p = 0.57). CONCLUSION: US-guided FNA-Tg proved to be a useful examination in the follow-up of patients with DTC, independently of TSH status and the presence of TgAb.

Serum TSH levels as a predictor of malignancy in thyroid nodules: A prospective study.

BACKGROUND: The role of serum TSH concentrations as a predictor of malignancy of thyroid nodule remains unclear. OBJECTIVE: To prospectively evaluate the usefulness of serum TSH levels as a predictor of malignancy in thyroid nodules. METHODS: Patients with thyroid nodule(s) who underwent fine-needle aspiration biopsy under ultrasonographic guidance in a tertiary, university-based hospital were consecutively evaluated. Patients with known thyroid cancer and/or patients receiving thyroid medication were excluded. Serum TSH levels were measured by two differents methodologies, chemiluminescent (CLIA) and electrochemiluminscent immunoassay (ECLIA). Anatomopathological exam of tissue samples obtained at thyroidectomy was considered the gold standard for the diagnosis of thyroid cancer. RESULTS: A total of 615 patients participated in the study. The mean age was 55.9±14.7 years, and 544(88.5%) were female. The median TSH values were 1.48 and 1.55 µU/mL, using CLIA and ECLIA, respectively. One-hundred-sixty patients underwent thyroidectomy and the final diagnoses were malignant in 47(29.4%) patients. TSH levels were higher in patients with malignant than in those with benign nodules in both TSH assays: 2.25 vs. 1.50; P = 0.04 (CLIA) and 2.33 vs. 1.27; P = 0.03 (ECLIA). Further analysis using binary logistic regression identified elevated TSH levels, a family history of thyroid cancer, the presence of microcalcifications, and solitary nodule on US as independent risk factors for malignancy in patients with thyroid nodules. Additional analyses using TSH levels as a categorical variable, defined by ROC curve analysis, showed that the risk of malignancy was approximately 3-fold higher in patients with TSH levels ≥2.26 µU/mL than in patients with lower TSH levels (P = 0.00). CONCLUSIONS: Higher serum TSH levels are associated with an increased risk of thyroid cancer in patients with thyroid nodules. Using TSH levels as an adjunctive diagnostic test for stratifying the risk of malignancy associated with a thyroid nodule may help on defining the best therapeutic approaches.