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OBJECTIVE: To identify predictive clinico-pathologic factors for concurrent endometrial carcinoma (EC) among patients with endometrial intraepithelial neoplasia (EIN) using machine learning. METHODS: a retrospective analysis of 160 patients with a biopsy proven EIN. We analyzed the performance of multiple machine learning models (n = 48) with different parameters to predict the diagnosis of postoperative EC. The prediction variables included: parity, gestations, sampling method, endometrial thickness, age, body mass index, diabetes, hypertension, serum CA-125, preoperative histology and preoperative hormonal therapy. Python 'sklearn' library was used to train and test the models. The model performance was evaluated by sensitivity, specificity, PPV, NPV and AUC. Five iterations of internal cross-validation were performed, and the mean values were used to compare between the models. RESULTS: Of the 160 women with a preoperative diagnosis of EIN, 37.5% (60) had a post-op diagnosis of EC. In univariable analysis, there were no significant predictors of EIN. For the five best machine learning models, all the models had a high specificity (71%-88%) and a low sensitivity (23%-51%). Logistic regression model had the highest specificity 88%, XG Boost had the highest sensitivity 51%, and the highest positive predictive value 62% and negative predictive value 73%. The highest area under the curve was achieved by the random forest model 0.646. CONCLUSIONS: Even using the most elaborate AI algorithms, it is not possible currently to predict concurrent EC in women with a preoperative diagnosis of EIN. As women with EIN have a high risk of concurrent EC, there may be a value of surgical staging including sentinel lymph node evaluation, to more precisely direct adjuvant treatment in the event EC is identified on final pathology.
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Hiperplasia Endometrial , Neoplasias Endometriales , Embarazo , Humanos , Femenino , Estudios Retrospectivos , Neoplasias Endometriales/patología , Biopsia , Hiperplasia Endometrial/diagnóstico , Hiperplasia Endometrial/patología , Hiperplasia Endometrial/cirugíaRESUMEN
Lynch syndrome is an autosomal dominant disorder that usually results from a pathogenic germline variant in one of four genes (MSH2, MSH6, MLH1, PMS2) involved in DNA mismatch repair. Carriers of such variants are at risk of developing numerous cancers during adulthood. Here we report on a family suspected of having Lynch syndrome due to a history of endometrial adenocarcinoma, ovarian clear cell carcinoma, and adenocarcinoma of the duodenum in whom we identified a germline 29 nucleotide in-frame inversion in exon 3 of MSH2. We further show that this variant is almost completely absent at the protein level, and that the associated cancers have complete loss of MSH2 and MSH6 expression by immunohistochemistry. Functional investigation of this inversion in a laboratory setting revealed a resultant abnormal protein function. Thus, we have identified an unusual, small germline inversion in a mismatch repair gene that does not lead to a premature stop codon yet appears likely to be causal for the observed cancers.
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Adenocarcinoma , Neoplasias Colorrectales Hereditarias sin Poliposis , Humanos , Adulto , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Mutación de Línea Germinal , Adenocarcinoma/genética , Exones , Reparación de la Incompatibilidad de ADN/genética , Homólogo 1 de la Proteína MutL/genética , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/metabolismoRESUMEN
BACKGROUND: Phyllodes tumours of the breast are rare fibroepithelial neoplasms with a propensity for recurrence. While surgical excision remains the standard of care, the optimal margin width is an area of active investigation. Recent studies have questioned the necessity for wide, local excision. METHODS: We conducted a retrospective, cohort study of patients with phyllodes tumours treated at our institution between 2003 and 2021. Demographic, histopathological, and recurrence data were captured; malignant phyllodes were excluded. Cox proportional hazard models were used to identify covariates associated with local recurrence. RESULTS: Of 187 patients with phyllodes tumours, 82.9% (n = 155) were classified as benign while 17.1% (n = 32) were borderline. Initial surgical margins were positive in 26.2% (n = 49), < 2 mm in 50.8% (n = 95), and ≥ 2 mm in 23% (n = 43) patients. Among patients with positive margins, 61.2% (n = 30) underwent margin revision. At a median follow-up of 2.9 years, the recurrence rate was 3.7%. On univariate analysis, only a positive margin at the time of initial surgery and not margin width was significantly associated with a higher rate of disease recurrence (hazard ratio [HR] 9.52, 95% confidence interval [CI] 1.85-49.2), as was a size greater than 4 cm on preoperative imaging (HR 10.78, 95% CI 0.97-120.1). Revision of an initially positive margin was not significantly associated with decreased local recurrence (p = 1). CONCLUSIONS: In this large cohort of benign and borderline phyllodes tumours, positive resection margins and not margin width at the initial surgery were associated with a increased recurrence. Individualization of decisions regarding margin reexcision is important.
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Neoplasias de la Mama , Tumor Filoide , Humanos , Femenino , Tumor Filoide/cirugía , Tumor Filoide/patología , Estudios Retrospectivos , Estudios de Cohortes , Recurrencia Local de Neoplasia/cirugía , Recurrencia Local de Neoplasia/patología , Canadá/epidemiología , Márgenes de Escisión , Neoplasias de la Mama/cirugíaRESUMEN
OBJECTIVE: To determine the prevalence of underlying high-intermediate (high-IM) and high-risk endometrial cancer (EC) in patients with preoperative diagnosis of Endometrial intraepithelial neoplasia (EIN) and to assess the impact of the information retrieved from the sentinel lymph node (SLN) on adjuvant therapy. METHODS: Retrospective cohort study of women undergoing hysterectomy, optional bilateral salpingo-oophorectomy (BSO) and lymph nodes assessment for EIN between December 2007 and August 2021. RESULTS: One hundred and sixty two (162) eligible patients were included, of whom 101 (62.3%) had a final diagnosis of EIN, while 61 (37.7%) were ultimately diagnosed with carcinoma. Out of 15 patients with high-IM to high-risk disease (9.25% of all EIN), 12 had grade 2-3 EC including 8 with >50% myometrial invasion, 2 with serous subtype, 1 with cervical invasion and 2 with pelvic lymph nodes involvement. Of the 3 patients with grade 1 EC, one patient had disease involving the adnexa and 2 patients had tumor invading >50% of the myometrium and with lymphovascular space invasion (LVSI). Ten patients received vaginal brachytherapy after surgery, 3 patients with extrauterine spread were treated with systemic chemotherapy followed by vaginal brachytherapy and pelvic external-beam radiotherapy and 2 patients with early-stage serous carcinoma received chemotherapy followed by vaginal brachytherapy. CONCLUSIONS: Information from SLN, even when negative, can be helpful in the management of patients with EC after preoperative EIN, as some patients are found to have high-IM to high-risk disease on final pathology. These patients would require either re-staging surgery or adjuvant external beam radiotherapy, both could be avoided by proper staging.
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Carcinoma , Neoplasias Endometriales , Linfadenopatía , Ganglio Linfático Centinela , Humanos , Femenino , Ganglio Linfático Centinela/patología , Escisión del Ganglio Linfático , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/cirugía , Estudios Retrospectivos , Estadificación de Neoplasias , Ganglios Linfáticos/patología , Biopsia del Ganglio Linfático Centinela , Linfadenopatía/patología , Carcinoma/patologíaRESUMEN
The response of triple-negative breast cancer (TNBC) patients to pre-operative (neoadjuvant chemotherapy) is a critical factor of their outcome. To determine the effects of chemotherapy on the tumor genome and to identify mutations associated with chemoresistance and sensitivity, we performed whole exome sequencing on pre/post-chemotherapy tumors and matched lymphocytes from 26 patients. We observed great inter-tumoral heterogeneity with no gene mutated recurrently in more than four tumors besides TP53. Although the degree of response to chemotherapy in residual tumors was associated with more subclonal changes during chemotherapy, there was minimal evolution between pre/post-tumors. Indeed, gene sets enriched for mutations in pre- and post-chemotherapy tumors were very similar and reflected genes involved in the biological process of neurogenesis. Somatically mutated genes present in chemosensitive tumors included COL1A2, PRMD15, APOBEC3B, PALB2 and histone protein encoding genes, while BRCA1, ATR, ARID1A, XRCC3 and genes encoding for tubulin-associated proteins were present in the chemoresistant tumors. We also found that the mutational spectrum of post-chemotherapy tumors was more reflective of matching metastatic tumor biopsies than pre-chemotherapy samples. These findings support a portrait of modest ongoing genomic instability with respect to single-nucleotide variants induced by or selected for by chemotherapy in TNBCs.
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Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Terapia Neoadyuvante , Mutación , Histonas , Inestabilidad Genómica , Citidina Desaminasa , Antígenos de Histocompatibilidad MenorRESUMEN
OBJECTIVE: To evaluate if the prognostic value of lymphovascular space invasion (LVSI) is different in endometrial cancer patients with negative lymph nodes following sentinel lymph node (SLN) mapping or lymph node dissection (LND) as staging procedure. MATERIAL AND METHODS: A retrospective study of 510 patients diagnosed with endometrial carcinoma in our institution between 2007 and 2014. We excluded patients that were diagnosed with positive nodes (Stage IIIc). We compared patients' characteristics and survival outcomes as function of their LVSI status (positive LVSI vs negative LVSI subgroups) in each cohort separately. RESULTS: 413 patients met the inclusion criteria, out of whom 239 underwent SLN and 174 patients underwent LND only. In the SLN group, life table analysis showed 5-year OS and PFS of 80% and 72% in patients with LVSI compared to 96%, and 93% without LVSI. Same trend was observed among patients with LND with 5-year OS and PFS of 74% and 64% in patients with LVSI compared to 97%, and 90% without LVSI. On multivariable analysis, adjusted for age, FIGO stage, grade and maximal tumor size, the favorable survival of negative LVSI remained only in the LND cohort (SLN cohort: HR 1.2, CI [0.3-4.0], P = 0.8 and HR 1.7, CI [0.7-4.3], p = 0.2 for OS and PFS, respectively; LND cohort: HR 3.1, CI [1.4-6.5], p < 0.001 and HR 2.5, CI [1.2-4.9], p = 0.01 for OS and PFS, respectively). CONCLUSIONS: The prognostic value of LVSI disappears when patients undergo staging with SLN and are found to have negative nodes in contrast to those who have undergone LND. Future studies should confirm our observation on patients with negative sentinel nodes, and plan on tailoring adjuvant treatment to this specific subgroup.
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Vasos Sanguíneos/patología , Neoplasias Endometriales/mortalidad , Vasos Linfáticos/patología , Adulto , Anciano , Anciano de 80 o más Años , Quimioradioterapia Adyuvante , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/patología , Neoplasias Endometriales/terapia , Femenino , Estudios de Seguimiento , Humanos , Histerectomía , Escisión del Ganglio Linfático , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Pronóstico , Supervivencia sin Progresión , Estudios Retrospectivos , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Salpingooforectomía , Ganglio Linfático Centinela/patología , Ganglio Linfático Centinela/cirugía , Biopsia del Ganglio Linfático Centinela/estadística & datos numéricosRESUMEN
Response to neoadjuvant chemotherapy (NAC) in triple negative breast cancer (TNBC) is highly prognostic and determines whether adjuvant chemotherapy is needed if residual tumor is found at surgery. To evaluate the predictive and prognostic values of circulating tumor DNA (ctDNA) in this setting, we analyzed tumor and serial bloods from 26 TNBC patients collected prior, during, and after NAC. Individual digital droplet PCR assays were developed for 121 variants (average 5/patient) identified from tumor sequencing, enabling ctDNA detection in 96% of patients at baseline. Mutant allele frequency at baseline was associated with clinical characteristics. Levels drastically fell after one cycle of NAC, especially in patients whose tumors would go on to have a pathological complete response (pCR), but then rose significantly before surgery in patients with significant residual tumor at surgery (p = 0.0001). The detection of ctDNA early during treatment and also late at the end of NAC before surgery was strongly predictive of residual tumor at surgery, but its absence was less predictive of pCR, especially when only TP53 variants are considered. ctDNA detection at the end of neoadjuvant chemotherapy indicated significantly worse relapse-free survival (HR = 0.29 (95% CI 0.08-0.98), p = 0.046), and overall survival (HR = 0.27 95% CI 0.075-0.96), p = 0.043). Hence, individualized multi-variant ctDNA testing during and after NAC prior to surgery has prognostic and predictive value in early TNBC patients.
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ADN Tumoral Circulante/genética , Neoplasias de la Mama Triple Negativas/genética , Quimioterapia Adyuvante , ADN Tumoral Circulante/sangre , Femenino , Frecuencia de los Genes , Genes p53 , Humanos , Persona de Mediana Edad , Tasa de Mutación , Terapia Neoadyuvante , Pronóstico , Neoplasias de la Mama Triple Negativas/sangre , Neoplasias de la Mama Triple Negativas/diagnóstico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
The aim of this study was to evaluate the impact of discordant endometrial sampling on the prognosis of patients finally diagnosed with uterine papillary serous carcinoma (UPSC) and to analyze UPSC mutational profile. Retrospective cohort study comparing outcomes of patients post-operatively diagnosed with UPSC and preoperatively diagnosed with endometrioid endometrial cancer (EEC) or UPSC. Genes commonly implicated in carcinogenesis were analyzed in a subgroup of 40 patients post-operatively diagnosed with UPSC, using next generation sequencing. 61 patients with UPSC on post-surgical, final pathology were included in the study. Prior to surgery, 15 were diagnosed with EEC (discordant) and 46 were correctly diagnosed with UPSC (concordant). After a median follow-up of 41.6 months [5.4-106.7], a preoperative diagnosis of EEC was associated with better 3-year progression-free survival (100% vs. 60.9%, P = 0.003) and longer disease free interval (63.5 versus 15 months, P = 0.026) compared to patients with an initial diagnosis of UPSC. Patients with a concordant diagnosis of UPSC were 5 times more likely to progress or die compared to those with a discordant EEC diagnosis (P = 0.02, P = 0.03, respectively), and their tumors were associated with higher rates of TP53 (88.9% vs. 61.5%, P = 0.04), and a lower rate of PTEN (14.8% vs. 38.5%, P = 0.09) and ARID1A (3.7% vs. 23.1%, P = 0.05) mutations. A pre-surgical diagnosis of EEC is associated with improved prognosis in patients with UPSC. Some histologically defined UPSC tumors contain endometrioid-like molecular characteristics that may confer a survival advantage, suggesting a possible need for molecular approaches to better stratify patients into risk groups.
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OBJECTIVE: Evaluation of the impact of lower uterine segment involvement (LUSI) in type II endometrial cancer, and mutational profile of uterine papillary serous carcinomas (UPSC). METHODS: Retrospective cohort study comparing patients with type II endometrial cancer with LUSI to patients without LUSI. Genes commonly implicated in carcinogenesis were analyzed in a subgroup of 42 patients with UPSC using next generation sequencing. RESULTS: 83 patients with type II endometrial cancer were included in the study, of these, LUSI was diagnosed in 31.3%. During a median follow-up of 45.5â¯months, patients with LUSI developed more local and distant recurrences (local: 19.2% vs. 3.5%, Pâ¯=â¯.03; distant: 50% vs. 17.5%, Pâ¯=â¯.004) and progression events (73.1% vs. 26.3%, Pâ¯<â¯.001), with shorter mean progression-free survival (16â¯months compared to 26.5â¯months, Pâ¯<â¯.01). In a multivariate analysis, LUSI was the only significant pathological factor, associated with a 2.9-fold increase in the risk of progression (Pâ¯=â¯.007), and a 2.6-fold increase in the risk of death (Pâ¯=â¯.02). In the subgroup of patients with UPSC, mutations were identified in 54 genes, including TP53 (80%), PPP2R1A (40%), and PTEN (22.5%). Frequent mutations in the PTEN-PI3K-AKT signaling pathway were found in patients with tumor in the upper uterine segment only (Pâ¯=â¯.04), with PTEN being mutated in 29% of the samples (Pâ¯=â¯.07). CONCLUSION: Type II endometrial cancers presenting in the LUS have a significantly worse prognosis and this might be associated with a unique mutational profile.
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OBJECTIVE: The expression of homologous recombination (HR) genes in high grade ovarian cancer (HGOC) samples from debulking surgeries were correlated to outcomes in patients selected for chemotherapy treatment regimens. STUDY DESIGN: RNA was extracted from 96 fresh frozen tumor samples from debulking surgeries from chemotherapy naïve patients with HGOC (primary derived surgeries (PDS), nâ¯=â¯55) or following neoadjuvant chemotherapy treatment (NACT), nâ¯=â¯41). The samples were selected for high tumor content by a gynecological pathologist, and cancer cell content was further confirmed using a percent tumor content covariate, and mutation score covariate analysis. Gene expression analysis was performed using a tailored NanoString-based Pancancer Pathway Panel. Cox proportional hazard regression models were used to assess the associations between the expression of 19 HR genes and survival. RESULTS: In the PDS group, over-expression of six HR genes (C11orf30, NBN, FANCF, FANCC, FANCB, RAD50) was associated with improved outcome, in contrast to the NACT group where four HR genes (BRCA2, TP53, FANCB, RAD51) were associated with worse outcome. With the adding extent of debulking as a covariate, three HR genes (NBN, FANCF, RAD50), and only one HR gene (RAD51) remained significantly associated with survival in PDS and NACT groups, respectively. CONCLUSION: Distinct HR expression profiles define subgroups associated with overall outcome in patients that are exposed to neoadjuvant chemotherapy and not only chemotherapy-naïve patients.
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Antineoplásicos/uso terapéutico , Carcinoma Endometrioide/genética , Procedimientos Quirúrgicos de Citorreducción , Terapia Neoadyuvante , Neoplasias Quísticas, Mucinosas y Serosas/genética , Neoplasias Ováricas/genética , Reparación del ADN por Recombinación/genética , Ácido Anhídrido Hidrolasas , Anciano , Proteína BRCA1/genética , Proteína BRCA2/genética , Antígeno Ca-125/sangre , Carcinoma Endometrioide/sangre , Carcinoma Endometrioide/tratamiento farmacológico , Carcinoma Endometrioide/patología , Proteínas de Ciclo Celular/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Proteína del Grupo de Complementación C de la Anemia de Fanconi/genética , Proteína del Grupo de Complementación F de la Anemia de Fanconi/genética , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Proteínas de la Membrana/sangre , Persona de Mediana Edad , Clasificación del Tumor , Proteínas de Neoplasias/genética , Neoplasias Quísticas, Mucinosas y Serosas/sangre , Neoplasias Quísticas, Mucinosas y Serosas/tratamiento farmacológico , Neoplasias Quísticas, Mucinosas y Serosas/patología , Proteínas Nucleares/genética , Neoplasias Ováricas/sangre , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Ovariectomía , Fosfohidrolasa PTEN/genética , Pronóstico , Modelos de Riesgos Proporcionales , Recombinasa Rad51/genética , Proteínas Represoras/genética , Tasa de Supervivencia , Transcriptoma , Proteína p53 Supresora de Tumor/genéticaRESUMEN
One of the major challenges in biomarker development is the collection of tumor tissue of adequate quality for analysis. A prospective clinical trial was initiated to collect tissues from triple negative breast cancers prior to and after neoadjuvant chemotherapy in order to study the mechanisms of chemoresistance. Sixty patients had pre-chemotherapy biopsies performed by either a surgeon or a radiologist, while those with residual tumor after chemotherapy had research-only biopsies and/or surgical samples collected in liquid nitrogen, RNA-later and formalin. We examined each core for tumor cellularity, stromal content, and necrosis after which, RNA and DNA extraction was performed. We found that biopsies collected with ultrasound guidance were more likely to contain tumor than those collected by the surgeon. Patient reluctance to undergo research-only biopsies after chemotherapy was not a problem. Pre-chemotherapy tumor biopsies frequently did not contain any tumor cells (15%) or did not have ≥50% tumor content (63%). Indeed, 50% of patients had at least 2 pre-chemotherapy core biopsies with <50% tumor content. After chemotherapy, 30% of biopsy or surgical samples in patients with incomplete response did not contain any tumor. Finally, RNA-later not only made histopathological assessment of tumor content difficult, but yielded less DNA than fresh snap frozen samples. We recommend that high-quality tissue procurement can be best accomplished if at least three image-guided core biopsies be obtained per sample, each of these cores be examined for tumor cellularity and that at least some of them be freshly snap frozen in liquid nitrogen.
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Biomarcadores de Tumor/análisis , Biopsia Guiada por Imagen/métodos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Ultrasonografía Intervencional/métodos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia/métodos , Quimioterapia Adyuvante , Femenino , Humanos , Persona de Mediana Edad , Terapia NeoadyuvanteRESUMEN
OBJECTIVES: Breast tumor resembling tall cell variant of papillary thyroid carcinoma (BTRPTC) is a rare breast lesion that is unrelated to thyroid carcinoma. Morphologically, it shows a solid papillary lesion with bland cytology, eosinophilic/amphophilic secretions, nuclear grooves, reversal of nuclear polarity (recently described), and nuclear inclusions. Clinical course is often uneventful with few exceptions reported in the literature. Herein, we report three additional cases. METHODS: Immunohistochemical staining and next-generation sequencing was performed on all three cases. RESULTS: The lesional cells on all cases were positive for cytokeratin 5 and S100, with weak expression/lack of estrogen receptor. No staining was observed for myoepithelial markers (p63 and myosin heavy chain) around the lesion. IDH2 mutations were identified in two cases at nucleotide 172 (cases 1 and 3). ATM gene mutation was identified in cases 2 and 3 and PIK3CA mutation in case 3. All patients are currently without disease. CONCLUSIONS: BTRPTC is a slow-growing neoplastic lesion that needs to be distinguished from other papillary lesions for optimizing therapy.
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Neoplasias de la Mama/patología , Carcinoma/patología , Mutación , Neoplasias de la Tiroides/patología , Anciano , Neoplasias de la Mama/química , Neoplasias de la Mama/genética , Carcinoma Papilar , Femenino , Humanos , Inmunohistoquímica , Queratina-5/análisis , Proteínas de la Membrana/análisis , Persona de Mediana Edad , Cadenas Pesadas de Miosina/análisis , Receptores de Estrógenos/análisis , Cáncer Papilar TiroideoRESUMEN
BACKGROUND: Sentinel lymph node (SLN) mapping has emerged as a promising solution to the ongoing debate regarding lymphadenectomy in the initial surgical management of endometrial cancer. Currently, little is known about its possible impact on location of disease recurrence compared to systematic lymphadenectomy. METHODS: In this retrospective study, 472 consecutive patients with endometrial cancer who underwent either SLN mapping (SLN cohort, n=275) or systematic lymphadenectomy (LND cohort, n=197) from sequential, non-overlapping historical time points were compared. Clinical characteristics were extracted from a prospectively gathered electronic database. Both overall and pelvic sidewall recurrence free survival (RFS) were evaluated at 48-month post-operative follow-up. RESULTS: No significant difference in overall RFS could be identified between the cohorts at 48months (HR 0.74, 95% CI 0.43-1.28, p=0.29). However, the SLN cohort had improved pelvic sidewall RFS compared to the LND cohort (HR 0.32, 95% CI 0.14-0.74, p=0.007). The pelvic sidewall recurrences accounted for 30% of recurrences in the SLN cohort (8 out of 26 recurrences) compared to 71.4% in the LND cohort (20 out of 28 recurrences). CONCLUSIONS: SLN mapping may enable more efficient detection of the LNs at greatest risk of metastasis and help to guide adjuvant therapy, which in turn seems to decrease the risk of pelvic sidewall recurrences.
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Neoplasias Endometriales/patología , Recurrencia Local de Neoplasia/patología , Ganglio Linfático Centinela/patología , Anciano , Estudios de Cohortes , Neoplasias Endometriales/diagnóstico , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Biopsia del Ganglio Linfático CentinelaRESUMEN
Leptomeningeal carcinomatosis carries a poor prognosis in breast cancer. Treatment modalities are geared towards tumour molecular characteristics, as well as symptoms and patient performance status. It has previously been postulated that endocrine treatments used for the treatment of metastatic breast cancer do cross the blood-brain barrier and can achieve antineoplastic effects in the central nervous system. We report a case of metastatic breast cancer in a 65-year-old woman who developed leptomeningeal carcinomatosis. She was initially treated with intrathecal methotrexate, which was stopped due to toxicity, followed by maintenance endocrine therapy. She achieved a sustained complete radiological and cerebrospinal fluid cytological response for over 9â years. She eventually passed away of ischaemic bowel unrelated to her cancer.
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Androstadienos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Carcinomatosis Meníngea/tratamiento farmacológico , Nitrilos/administración & dosificación , Neoplasias de la Columna Vertebral/tratamiento farmacológico , Triazoles/administración & dosificación , Anciano , Femenino , Humanos , Letrozol , Carcinomatosis Meníngea/líquido cefalorraquídeo , Carcinomatosis Meníngea/secundario , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Neoplasias de la Columna Vertebral/líquido cefalorraquídeo , Neoplasias de la Columna Vertebral/secundarioRESUMEN
BACKGROUND: PARP inhibitors have shown promising clinical results in cancer patients carrying BRCA1/2 mutations. Their clinical efficacy could logically be influenced by PARP1 protein levels in patient tumors. METHODS: We screened three cohorts of patients with ovarian cancer, totaling 313 samples, and evaluated PARP1 protein expression by immunohistochemistry with further validation by western blotting. RESULTS: We observed that up to 60 % of tumors showed little PARP1 protein expression. In serous ovarian tumors, comparing intratumoral PARP1 expression between chemo-naïve and post-chemotherapy patients revealed a decrease in intratumoral PARP1 following chemotherapy in all three cohorts (immunohistochemistry: p < 0.001, n = 239; western blot: p = 0.012, n = 74). The findings were further confirmed in a selection of matched samples from the same patients before and after chemotherapy. CONCLUSION: Our data suggest that patients should be screened for PARP1 expression prior to therapy with PARP inhibitors. Further, the observed reduction of intratumoral PARP1 post-chemotherapy suggests that treating chemo-naïve patients with PARP inhibitors prior to the administration of chemotherapy, or concurrently, might increase the responsiveness to PARP1 inhibition. Thus, a change in the timing of PARP inhibitor administration may be warranted for future clinical trials.
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Antineoplásicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/enzimología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/biosíntesis , Anciano , Estudios de Cohortes , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/análisisRESUMEN
The formation of iliopsoas bursal cystic lesions after total hip arthroplasty is an infrequently reported condition. This article describes an unusual complication of a current-generation metal-on-metal total hip arthroplasty.A woman presented with unilateral spontaneous lower-limb swelling that developed 5 years postoperatively. It occurred secondary to venous obstruction by a metallosis-induced iliopsoas bursal cyst associated with markedly elevated intralesional cobalt and chromium levels. Metal artifact reduction sequence magnetic resonance imaging showed that the bursal cyst was communicating with the hip joint and that it severely compressed the common femoral vein. Based on the findings of high local tissue metal ions and vertical cup positioning causing edge loading, the authors proposed an inflammatory reaction to metal debris that tracked into the iliopsoas bursa and formed a cyst. The patient underwent revision of the excessively vertical acetabular component and conversion to a ceramic-on-ceramic bearing interface, drainage of the bursal cyst, and synovectomy. No signs existed of local recurrence at 1-year follow-up.To the authors' knowledge, the occurrence of metallosis-induced iliopsoas bursitis with secondary pressure effects after contemporary metal-on-metal total hip arthroplasty has not been reported. When treating hip dysplasia, one must avoid maximizing cup-host bone contact at the risk of oververticalization. Iliopsoas bursal cystic lesions can lead to severe vascular compressive symptoms with no ominous radiographic findings. Physicians and orthopedic surgeons should be aware of the possibility of this complication in patients with unexplained unilateral lower-limb swelling.
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Artroplastia de Reemplazo de Cadera , Quistes/complicaciones , Artropatías/complicaciones , Enfermedades Vasculares/etiología , Quistes/etiología , Femenino , Humanos , Artropatías/etiología , Pierna , Imagen por Resonancia Magnética , Persona de Mediana Edad , Músculos PsoasRESUMEN
OBJECTIVE: The objective of this study is to evaluate the detection rate and diagnostic accuracy of sentinel lymph node (SLN) mapping using intra-operative cervical injection of filtered 99mTc-sulfur colloid (99mTc-SC) and patent blue in patients with endometrial cancer. METHODS: Prospective evaluation of the first 100 endometrial cancer patients undergoing SLN mapping using cervical injection of patent blue combined with filtered 99mTc-SC in the operating room was done. Patients underwent robotic-assisted lymphatic mapping with frozen section, hysterectomy, BSO, and completion bilateral lymphadenectomy (including para-aortic nodes in grade 2 and 3 tumors). RESULTS: At least one SLN was detected in 92% of patients; in 66 of these (72%) bilateral SLN were detected, and in 15 cases the SLN was in the para-aortic area. Eleven percent of all patients had lymph node metastases, and 4 of which had pre-operative grade 1 tumor. The SLN was the only positive node in 44% of the cases with positive nodes. Sensitivity was 89% with 1 false negative result, yielding a negative predictive value of 99% (95% CI 93-100). Specificity was 100% (95% CI 94-100), and positive predictive value was 100% (95% CI 60-100). No complications or anaphylactic reactions were noted. CONCLUSIONS: Intra-operative SLN biopsy, using cervical injection of patent blue and filtered 99mTc-SC in endometrial cancer patients is feasible and yields adequate detection rates.
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Colorantes , Neoplasias Endometriales/patología , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/patología , Radiofármacos , Colorantes de Rosanilina , Azufre Coloidal Tecnecio Tc 99m , Adulto , Anciano , Anciano de 80 o más Años , Colorantes/administración & dosificación , Neoplasias Endometriales/cirugía , Reacciones Falso Negativas , Femenino , Humanos , Histerectomía , Inyecciones , Ganglios Linfáticos/diagnóstico por imagen , Metástasis Linfática , Persona de Mediana Edad , Estadificación de Neoplasias , Pelvis , Valor Predictivo de las Pruebas , Estudios Prospectivos , Cintigrafía , Radiofármacos/administración & dosificación , Robótica , Colorantes de Rosanilina/administración & dosificación , Sensibilidad y Especificidad , Azufre Coloidal Tecnecio Tc 99m/administración & dosificaciónRESUMEN
OBJECTIVE: Invasive synovial fibroblasts are suggested to be the major effectors of cartilage and bone destruction, and this aggressive phenotype can lead to irreversible damage. In cancer cells, invasion across tissue boundaries and metastasis have recently been shown to depend on the capacity of the cells to breach the basement membrane, a process that was linked to the formation of the actin-rich cell protrusions called invadopodia. This study was undertaken to investigate whether arthritic synovial cells use invadopodia to invade and degrade cartilage components. METHODS: Fibroblast-like synoviocytes (FLS) from control rats or rats with collagen-induced arthritis (CIA) were cultured on fluorescent matrix in the presence of Src inhibitors or were transfected with wild-type or variants of Src kinases. The in vivo effect of Src inhibition on cartilage degradation and invasion was studied in a rat model of CIA. RESULTS: FLS from rats with CIA produced more invadopodia-like structures than did FLS from control rats, leading to increased extracellular matrix degradation. Furthermore, c-Src activation was increased in synovial cells from rats with CIA, and Src activity was found to mediate the formation of invadopodia. Pharmacologic blockade of Src activity by PP2 or intraarticular expression of a c-Src-specific short hairpin RNA in the CIA model reduced synovial membrane hyperplasia and cartilage degradation, an event linked to decreased invadopodia formation by synovial fibroblasts. CONCLUSION: This study demonstrates that inhibition of invadopodia formation in arthritic synovial cells leads to a direct effect on extracellular matrix degradation in vitro and in vivo, making invadopodia a relevant therapeutic target for interfering with this process.