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BACKGROUND: The oncologic safety of sentinel lymph node biopsy (SLNB) alone for clinically node-positive (cN1-2) patients who convert to pathologic node-negativity (ypN0) after neoadjuvant chemotherapy (NAC) is not well established. METHODS: This study retrospectively identified 244 consecutive patients with a diagnosis of cT1-3cN0-2 breast cancer who underwent NAC followed by SLNB at the authors' institution between 2013 and 2018. The patients were categorized as clinically node-negative (cN0) or cN1-2 before the onset of NAC, and the Kaplan-Meier method was used to compare locoregional and distant recurrence rates after SLNB alone for ypN0 patients. RESULTS: Among 244 patients who underwent NAC followed by surgery with SLNB for axillary staging, 112 (45.9%) were cN0 at presentation, whereas 132 (54.5%) had biopsy-proven cN1-2 disease and converted to cN0 after treatment. Of the patients presenting with cN0 disease, 102 (91.1%) were ypN0 on SLNB pathology compared with 60 cN1/2 patients (45.5%; p < 0.001). Regional nodal irradiation was administered to 5% of the cN0/ypN0 patients compared with 70.7% of the cN1-2/ypN0 patients (p < 0.001). Overall, 211 patients were treated with SLNB alone and had a median follow-up period of 36 months (interquartile range [IQR], 24-53 months). For 101 cN0/ypN0 patients who underwent SLNB alone, the 5-year local and regional recurrence rates were respectively 5.7% (95% confidence interval [CI], 2.4-13.8) and 1% (95% CI 0.1-7.0). For 58 cN1-2/ypN0 patients who underwent SLNB alone, the 5-year local and regional recurrence rates were respectively 4.1% (95% CI 1.0-15.5) and 0%, with no axillary recurrences noted. CONCLUSION: For ypN0 patients, SLNB alone after NAC is associated with low and acceptable short-term axillary recurrence rates. Additional follow-up data from prospective clinical trials are needed to confirm long-term oncologic safety and define optimal local therapy recommendations.
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Neoplasias da Mama , Linfonodo Sentinela , Axila , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Humanos , Excisão de Linfonodo , Linfonodos/cirurgia , Terapia Neoadjuvante , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Linfonodo Sentinela/cirurgia , Biópsia de Linfonodo SentinelaRESUMO
BACKGROUND: Clinical complete response (cCR) in rectal cancer is being evaluated as a tool to identify patients who would not require surgery in the curative management of rectal cancer. Our study reviews mucosal changes after neoadjuvant therapy for rectal cancer in patients treated at our center. METHODS: Pathology reports were retrieved for patients treated with neoadjuvant chemoradiation therapy (CRT) or high-dose rate brachytherapy (HDRBT). The macroscopic appearance of the specimen was compared with pathologic staging. RESULTS: This study included 282 patients: 88 patients underwent neoadjuvant CRT and 194 patients underwent HDRBT; all patients underwent total mesorectal excision (TME). There were 160 male and 122 female patients with a median age of 65 years (range 29-87). The median time between neoadjuvant therapy and surgery was 50 and 58 days. Sixty patients (21.2%) were staged as ypT0N0, 21.2% had a pathologic complete response (pCR), and only 3.2% had a cCR. Of the 67 patients with initial involvement of the circumferential radial margin (CRM), 44 converted to pathologic CRM-. Two hundred seventy-three patients (96.8%) had mucosal abnormalities. Of the 222 patients with residual tumor, 70 patients had no macroscopic tumor visualized but an ulcer in its place. CONCLUSION: Most patients undergoing neoadjuvant therapy for rectal cancer have residual mucosal abnormalities which preclude to a cCR as per published criteria from Brazil. Further studies are required to optimize clinical evaluation and MRI imaging in selected patients.
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Terapia Neoadjuvante , Neoplasias Retais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Braquiterapia , Relação Dose-Resposta à Radiação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pelve/diagnóstico por imagem , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
BACKGROUND AND AIM: Insulin-like growth factor-1 (IGF-1) bioactivity has been shown to be attenuated by insulin-like growth factor binding protein-3 (IGFBP-3), one of six IGF-binding proteins. While prior work revealed no major phenotype associated with IGFBP-3 knockout mice, we explored the possibility that a phenotype could be revealed under specific conditions of gastrointestinal stress. METHODS: The dextran sodium sulfate (DSS) murine model of ulcerative colitis was used for this study. RESULTS: Insulin-like growth factor binding protein-3 knockout mice had significantly reduced colitis on exposure to DSS as measured by lower levels of pro-inflammatory cytokines IL-6 (P < 0.0001), TNF-α (P = 0.0035), and IL-1ß (P = 0.0112), reduced weight loss (P < 0.0001), reduced myeloperoxidase activity (P = 0.0025), and maintenance of colorectal length (P < 0.05), all relative to wild-type mice exposed to DSS. IGFBP-3 knockout mice also exhibited increased colon epithelial cell proliferation (P < 0.0001) following DSS exposure. Semi-quantitative immunohistochemistry showed greater IGF-1 receptor activation in colon epithelial cells of IGFBP-3 knockout mice compared with control mice following DSS exposure. CONCLUSION: Our data demonstrate that IGFBP-3 influences severity of DSS-induced colitis. The observations suggest that in the absence of IGFBP-3, enhanced IGF bioactivity leads to increased epithelial proliferation and mucosal barrier repair, thereby lessening inflammation.
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Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/genética , Sulfato de Dextrana/efeitos adversos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Fenótipo , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Índice de Gravidade de DoençaRESUMO
Insulin-like growth factor binding protein-3 (IGFBP-3) is an important carrier protein for insulin-like growth factors (IGFs) in the circulation. IGFBP-3 antagonizes the growth-promoting and anti-apoptotic activities of IGFs in experimental systems, but in certain contexts can increase IGF bioactivity, probably by increasing its half-life. The goal of this study was to investigate the role of IGFBP-3 in breast carcinogenesis and breast cancer metastasis. In the first part of the study, we exposed IGFBP-3 knockout and wild-type female mice to dimethylbenz[a]anthracene (DMBA) and followed them for appearance of primary tumors for up to 13 months. In the second part, mice of each genotype received an IV injection of 4T1 mammary carcinoma cells and then lung nodules were counted. Our results show that IGFBP-3 knockout mice developed breast tumors significantly earlier than the wild-type (13.9 ± 1.1 versus 22.5 ± 3.3 weeks, respectively, P = 0.0144), suggesting tumor suppression activity of IGFBP-3. In tumors of IGFBP-3 knockout mice, levels of phospho-AKT(Ser473) were increased compared to wild-type mice. The lung metastasis assay showed significantly more and larger lung nodules in IGFBP-3 knockout mice than in wild-type mice. While we observed increased levels of IGFBP-5 protein in the IGFBP-3 knockout mice, our findings suggest that this was not sufficient to completely compensate for the absence of IGFBP-3. Even though knockout of IGFBP-3 is associated with only a subtle phenotype under control conditions, our results reveal that loss of this gene has measurable effects on breast carcinogenesis and breast cancer metastasis.
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Neoplasias da Mama/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Neoplasias Pulmonares/genética , Neoplasias/genética , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Apoptose/genética , Neoplasias da Mama/patologia , Carcinogênese , Feminino , Células Germinativas , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Glândulas Mamárias Animais/patologia , Camundongos , Camundongos Knockout , Neoplasias/induzido quimicamente , Neoplasias/patologiaRESUMO
BACKGROUND: RNA-binding motif protein 3 (RBM3), involved in cell survival, has paradoxically been linked to both oncogenesis as well as an increased survival in several cancers, including urothelial carcinoma (UCA). METHODS: The putative prognostic role of RBM3 was studied using cystectomy specimens with 152 invasive UCA with 35 matched metastases, 65 carcinomas in situ (CIS), 22 high-grade papillary UCAs (PAP), and 112 benign urothelium cases. RESULTS: The H-score (HS, staining intensity × % of positive cells) was used for RBM3 immunoexpression. CIS showed the highest HS (mean = 140) followed by benign urothelium (mean = 97). Metastases showed higher HS than primary invasive UCA (P ≤ 0.0001), and high HS was associated with a lower pT stage (P ≤ 0.0001) and a trend toward the absence of lymphovascular invasion (LVI, P = 0.09), but not pN stage (P = 0.35) and surgical margin status (P = 0.81). Univariate analysis (UVA) of disease recurrence only showed an association between pN stage and LVI (P = 0.005 and 0.03, respectively). On UVA of mortality, pT stage was strongly associated with death (P = 0.01) while pN stage, LVI, surgical margin status, and HS were not. Multivariate analysis confirmed the lack of HS association with recurrence (P = 0.08) and death (P = 0.32). CONCLUSIONS: Stronger RBM3 immunoexpression correlated with lower stage tumors and a diminished risk for LVI. However, RBM3 does not seem to carry a prognostic significance for clinical outcome (recurrence and mortality). The exact prognostic role of RBM3 in UCA is yet to be determined.
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Biomarcadores Tumorais/metabolismo , Carcinoma in Situ/metabolismo , Carcinoma Papilar/metabolismo , Recidiva Local de Neoplasia/metabolismo , Proteínas de Ligação a RNA/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Carcinoma in Situ/mortalidade , Carcinoma in Situ/patologia , Carcinoma Papilar/mortalidade , Carcinoma Papilar/patologia , Estudos de Casos e Controles , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática , Invasividade Neoplásica , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Análise Serial de Tecidos , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , UrotélioRESUMO
BACKGROUND: Ki-67 immunostaining is commonly used in neuroendocrine tumors to estimate the proliferative index and for grading. This study investigates its association with the invasiveness of follicular-derived thyroid carcinomas (TCs). METHODS: A retrospective analysis of patients with TC at three McGill University teaching hospitals between January 2018 and November 2023 was conducted. The inclusion criteria included patients with malignant thyroid tumors and accessible Ki-67 LI data from final pathology specimens. The data collected included patient demographics, Ki-67 LI values, and different invasiveness attributes, such as molecular mutations, the histological subtype, lymphovascular invasion (LVI), extrathyroidal extension (ETE), and positive lymph nodes (LNs). RESULTS: In total, 212 patients met the inclusion criteria, of which 80.7% were females and 19.3% were males. The Ki-67 LI ranged from 1% to 30%, with the majority of the cases within the range of 1-15%. A significant association was observed between higher Ki-67 LI and high-risk histological subtypes of thyroid carcinoma (p < 0.001). Similarly, Ki-67 LI was significantly associated with LVI and positive LN metastasis (p < 0.001 and p = 0.036, respectively). However, no significant association was found between the Ki-67 LI and gene mutations or ETE (p = 0.133 and p = 0.190, respectively). Using percentiles to establish a cutoff, patients with a Ki-67 LI higher than 6.7 showed a higher likelihood of being associated with invasive features. CONCLUSION: Elevated Ki-67 LI can serve as an indicator of aggressiveness in follicular-derived TC, especially when associated with distinct histological subtypes, LVI and positive LNs.
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Antígeno Ki-67 , Invasividade Neoplásica , Neoplasias da Glândula Tireoide , Humanos , Feminino , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Masculino , Estudos Retrospectivos , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Adulto , Idoso , Metástase Linfática , Adulto JovemRESUMO
Mammary-type myofibroblastoma (MTMF) is an unusual and rare benign tumor that typically presents in older men or post-menopausal females. A 53-year-old female presented with a 6-month history of an asymptomatic pink/white submucosal nodule involving the left lateral tongue. Clinical examination showed a 5 mm × 5 mm × 5 mm firm submucosal nodule with intact overlying mucosa. Differential diagnoses focused on benign nodular connective tissue tumors. An excisional biopsy was performed and submitted for histopathological examination. The patient underwent conservative local excision. Histopathology and immunocytochemistry revealed a lipomatous variant of MTMF. Hematoxylin and eosin sections revealed an unencapsulated soft tissue lesion with a lobular growth pattern. The neoplasm was biphasic, comprising adipose tissue and cellular fibrous components. By immunohistochemistry, tumor cells were positive for desmin, estrogen receptor, and CD34. In summary, we presented an unusual case of a lipomatous variant of myofibroblastoma on the tongue. MTMF rarely occurs in the head and neck and its accurate diagnosis necessitates awareness of its histomorphological spectrum and application of appropriate immunohistochemical stains.
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Spindle cell proliferations originating in follicular derived thyroid neoplasms are rare and known to cause diagnostic conundrums. We describe a unique case of a spindle cell variant of follicular thyroid carcinoma (FTC) in a 48-year-old female without relevant past medical history, who was being followed for a 1.4 cm left thyroid nodule for the past 15 months. A fine needle aspiration (FNA) of the nodule was interpreted as benign (Bethesda II). On follow-up ultrasound the nodule demonstrated a slight increase in size (to 1.5 cm) and the appearance of coarse calcifications A repeat FNA was performed 12 months later and interpreted as malignant neoplasm (Bethesda VI), containing a population of spindle and epithelioid cells that could not be further classified. A left subtotal thyroidectomy showed an encapsulated tumor mainly composed of fibroblast-like spindle cells, extensive foci of calcifications and focal ossification, with minimal tumor capsule invasion without vascular invasion. Tumor cells expressed vimentin, ERG and SMA (focal), while being negative for pancytokeratin, thyroglobulin, TTF-1, Pax-8, calcitonin, CEA and other lineage-specific mesenchymal, neuroendocrine and melanocytic markers. Importantly, a few residual thyroid follicles were identified within the nodule, and a diagnosis of minimally invasive FTC with extensive spindle cell changes, calcification and osseous metaplasia was rendered. This is only the second cytologic report of a pure spindle cell FTC. The rarity of this neoplasm and its potential broad differential diagnosis create diagnostic difficulties both on cytology and histology.
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Adenocarcinoma Folicular , Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Adenocarcinoma Folicular/patologia , Calcitonina , Antígeno Carcinoembrionário , Feminino , Humanos , Pessoa de Meia-Idade , Tireoglobulina , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/patologia , VimentinaRESUMO
The Milan system for reporting salivary gland cytopathology (MSRSGC) is a novel standardized classification tool for salivary gland cytology specimens based on the use of direct smears. Formalin-fixed paraffin-embedded (FFPE) cell blocks facilitate the use of ancillary studies, leading to improved diagnostic accuracy. However, the application of the MSRSGC with only cell blocks has not been well established. Consecutive cohort of all parotid gland cytology specimens between 01/01/2018 and 30/06/2021 was performed. All cytology specimens were processed into cell blocks only. Cytologic diagnoses were classified prospectively according to the MSRSGC categories. The risk of malignancy (ROM) for each diagnostic category and the diagnostic performance were calculated. A total of 230 FNA samples from 221 patients were identified, including 47% and 78.4% with surgical or clinical follow-up, respectively. The ROMs based on surgical follow-up for the non-diagnostic, non-neoplastic, AUS, neoplasm: benign, SUMP, SFM and malignant categories were 21.4%,0%,50%,0%,30%,100% and 100%, respectively. The ROMs based on the clinical follow-up for these categories were 7.3%,0%,37.3%,0%,27.3%,100% and 100%, respectively. Following surgical excision, all Milan IVa category samples were confirmed as benign, and all Milan V and VI category samples were confirmed as malignant. This study validates the application of the MSRSGC with the sole use of FFPE cell blocks. The diagnostic accuracy of MSRSGC is high and compares favorably to other institutions using traditional cytology assessment methods. Furthermore, FNA results using this technique enabled to provide optimal patient management based on the ROM of the different Milan system categories.
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Neoplasias das Glândulas Salivares , Biópsia por Agulha Fina , Citodiagnóstico/métodos , Formaldeído , Humanos , Estudos Retrospectivos , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/patologia , Glândulas Salivares/patologiaRESUMO
The role of estrogen replacement therapy in postmenopausal women remains controversial. The authors hypothesized that contradictory results with estrogen therapy may be explained by estrogen's potent proangiogenic property, which could be protective in women without atherosclerotic disease but in the presence of chronic inflammation, could lead to destabilization of atherosclerotic plaques. The authors thus examined the interaction between 17beta-estradiol (E2) and the inflammatory cytokine tumor necrosis factor alpha (TNFalpha) in an early stage of angiogenesis. Human umbilical endothelial cells were grown to confluence. Migration was assessed with a wound assay and proliferation was assessed with 5-bromo-2'-deoxyuridine (BrDU). Cells were treated with medium alone, TNFalpha at 0.3, 1, or 20 ng/ml, E2 at 20 nM, or the combination of E2 and TNFalpha. The authors used real-time polymerase chain reaction (PCR) to measure changes in expression of the angiogenesis genes angiopoeitin-2 (Ang-2), vacular endothelial growth factor (VEGF)-A and -C, and interleukin (IL)-8. A large dose of TNFalpha (20 ng/ml) inhibited healing at 24 to 48 h and the addition of E2 preserved some healing. E2 by itself doubled migration, with only a minimal effect on proliferation. A low dose of TNFalpha (0.3 ng/ml) had no effect on migration, 1.0 ng/ml moderately increased it, but the addition of E2 to both doses of TNFalpha increased migration. There was no change in migration when cells were pretreated with E2 and given TNFalpha after wounding, whereas pretreatment with TNFalpha followed by E2 significantly increased wound healing. The nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine-methyl ester (l-NAME) completely blocked the E2 effect on migration. TNFalpha (0.3 and 1.0 ng/ml) increased expression of VEGF-C (2.8 +/- 0.1- and 2.5 +/- 0.2-fold, respectively) and IL-8 (32.8 +/- 1.2- and 42.7 +/- 3.6-fold, respectively) mRNA, but E2 had no significant effect on these molecules. E2 increases the angiogenic activity of TNFalpha. This could potentially worsen the stability of complex atherosclerotic plaques and increase cardiovascular events.