Impact of hormone receptor status and tumor subtypes of breast cancer in young BRCA carriers.

BACKGROUND: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its prognostic impact on prognosis of young patients harboring a pathogenic variant (PV) in the BRCA1 and/or BRCA2 genes. PATIENTS AND METHODS: This international, multicenter, retrospective cohort study included young patients (aged ≤40 years) diagnosed with invasive breast cancer and harboring germline PVs in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest [disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS)] were first investigated according to hormone receptor expression (positive versus negative), and then according to breast cancer subtype [luminal A-like versus luminal B-like versus triple-negative versus human epidermal growth factor receptor 2 (HER2)-positive breast cancer]. RESULTS: From 78 centers worldwide, 4709 BRCA carriers were included, of whom 2143 (45.5%) had hormone receptor-positive and 2566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% versus 9.6%, P < 0.001), while the rate of second primary breast cancer was lower (9.1% versus 14.7%, P < 0.001) compared to patients with hormone receptor-negative disease. The 8-year DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive versus negative disease changed over time for DFS, BCSS, and OS (P < 0.05 for interaction of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-year DFS: 60.8% in luminal A-like versus 63.5% in triple-negative versus 65.5% in HER2-positive and 69.7% in luminal B-like subtype). CONCLUSIONS: In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.

Uptake of Risk-Reducing Measures, Cascade Testing, and Related Challenges Among Carriers of Breast Cancer-Associated Germline Pathogenic Variants in Mexico.

PURPOSE: Genetic cancer risk assessment (GCRA) provides pathogenic variant (PV) carriers with the invaluable opportunity to undertake timely cancer risk-reducing (RR) measures and initiate cascade testing (CT). This study describes the uptake of these strategies and the related barriers among breast cancer-associated germline PV carriers in Mexico. METHODS: Carriers who were at least 6 months after disclosure of genetic test results at two GCRA referral centers were invited to answer a survey assessing sociodemographic characteristics, awareness of their carrier status and its implications, uptake of RR measures according to international guidelines by PV, CT initiation, and associated challenges. RESULTS: Of the eligible carriers, 246/384 (64%) answered the survey (median age: 44 years). Most were female (88%), married/in domestic partnership (66%), and had personal breast/ovarian cancer history (61%). PVs included BRCA1/2 (75%), CHEK2 (10%), PALB2 (5%), ATM (5%), NF1 (2%), RAD51C (2%), PTEN (1%), and TP53 (1%). Most (87%) participants were aware of their carrier status. When recommended, 37% underwent RR bilateral mastectomy, 48% RR oophorectomy, 70% annual mammogram, and 20% breast magnetic resonance imaging. Challenges hindering the uptake of RR measures included financial limitations (67%), lack of recommendation by their physician (35%), and fear (24%). Nearly all (98%) claimed sharing their results with their relatives. CT was initiated in 63% of families and was associated with carriers being married/in domestic partnership (P = .04) and believing GCRA was useful (P < .001). CONCLUSION: Despite the resource-constrained setting, relevant rates of RR measures and CT were observed. Targeted interventions to reduce out-of-pocket expenses and improve patient-physician communication and patients' understanding on carrier status are warranted to enhance the overall benefit of GCRA and ultimately improve the provision of patient-centered care to both carriers and their at-risk relatives.

Machine Learning Techniques in Predicting BRAF Mutation Status in Cutaneous Melanoma From Clinical and Histopathologic Features.

Melanoma is the cutaneous neoplasm responsible for more patient deaths in all countries. BRAF mutations are the most common driver mutation and with the development of molecular targeted therapy, the precise knowledge of BRAF status has become increasingly important. Evaluation of BRAF mutation status has routinely been performed by polymerase chain reaction, a time consuming and expensive technique. Immunohistochemistry has been suggested as a cheaper alternative, but it has not gained general acceptance. A retrospective observational study in a cohort of 106 patients with invasive melanoma was conducted in order to develop and evaluate a machine learning approach to predict BRAF status using clinical and histologic variables. We compared the performance of different common machine learning algorithms and use SHapley Additive exPlanations (SHAP) to explain individual predictions and extract medical insights to define a heuristic model to estimate BRAF mutation probability. The Extreme Gradient Boosting algorithms obtained the best performance. Interpretability of models shows that the most important variables to estimate BRAF mutation probability are: age, Breslow thickness, and Breslow density. Based in this interpretation and medical knowledge, a simplify heuristic model is proposed to predict BRAF status using only 7 variables and obtain a performance of 0.878 of area under the curve. We propose a heuristic model that could be used by clinicians to obtain a good estimator of BRAF mutation probability.

Novel RB1 germline mutation in a healthy man.

BACKGROUND: Retinoblastoma (Rb) most frequently presents as a unilateral sporadic disease up to 40% of cases, however, arise from a monoallelic germline pathogenic variant. Only 10% of the germline mutations are inherited, and high penetrance is seen in up to 90% of these cases. As an effort to optimize counseling and screening, mutations are classified according to inheritance patterns. However, RB1 spectrum is highly heterogeneous, and information for unaffected carriers remains scarce. MATERIALS AND METHODS: The Mexican family of a 5-month-old patient diagnosed with Rb was studied. The family consisted of five individuals (father, mother, and three siblings). Genetic testing using a next-generation sequencing assay targeting RB1 with oligonucleotide baits designed to capture its exons and 20 bases flanking intronic sequences was performed in every family member. Clinical history and a complete ophthalmological examination (best-corrected visual acuity, slit-lamp biomicroscopy, macular optical coherence tomography, fundus autofluorescence, optical coherence tomography angiography, and electrophysiological studies) were performed in members testing positive to RB1 mutation. RESULTS: The father and her five-month-old daughter tested positive for a non-synonymous RB1 mutation c.459del (p.Lys154Serfs*21). The girl presented with bilateral retinoblastoma, successfully treated with cryotherapy and intravenous chemotherapy. The father had no relevant findings on imaging studies or ophthalmologic evaluation. CONCLUSIONS: This report describes a rare case of a novel low-penetrance RB1 germline mutation. Long-term follow-up of the father will include periodic evaluation of the eyes and orbits, and surveillance for systemic sarcoma and secondary malignancies. Implications for unaffected individuals need to be further studied.

New insights on the removal of diclofenac and ibuprofen by CWPO using a magnetite-based catalyst in an up-flow fixed-bed reactor.

This research has been focused on the removal of two anti-inflammatory drugs, diclofenac (DCF) and ibuprofen (IBU), by a continuous catalytic wet peroxide oxidation (CWPO) process using a lab-synthesized nanomagnetic catalyst (Fe3O4/MWCNTs). The central composite rotatable design (CCRD) method was used to study the effect of DCF and IBU concentration (expressed as theoretical oxygen demand (ThOD) between 0 and 52.5 mg L-1) and of the feed stream pH (from 3 to 7) on the removal of total organic carbon (TOC) and the concentration of aromatic compounds (Arm) and total phenolic compounds (TP) by CWPO. It could be observed that DCF was preferably removed from the DCF-IBU aqueous mixture at pH values ranging from 3 to 5. In addition, feed stream pH had a significant effect on the pollutants removal, as well as on TOC, TP and aromatic compounds removal, observing an increasing in the pollutants degradation when feed stream pH decreased from 7 to 3. Quadratic models predicted for response variable, such as TOC, TP and aromatic compounds removal, and their maximum model-predicted removal values were of 90.0, 80.2 and 90.0%, respectively. Finally, as a proof of concept, three environmentally-relevant aqueous matrices, spiked with DCF-IBU mixture, were treated. In this case, relatively high TOC degradation values were found after 20 h reaction time (ca. 57.7, 73.9 and 54.5% in surface water, WWTP effluent and hospital wastewater, respectively). This work deals the first study about DCF-IBU removal in aqueous solution by CWPO, as well as a continuous study using real wastewater that allow to extend the experimental results to a real scenario.

Orbital histiocytosis with systemic involvement: A case with complex affiliations.

A 70-year-old male presented with orbital masses affecting the muscular cone. His past medical history was notable for diabetes mellitus, ischemic cardiopathy, sleep-apnea syndrome, and multiple serous effusions. The first biopsy specimen of affected orbital tissue revealed fibrohistiocytic infiltration resembling xanthogranuloma or Erdheim-Chester disease (ECD). An ulterior biopsy of affected orbital tissue showed lymphocyte emperipolesis with immunopositivity for CD68 and S100 but negative staining for CD1a marker, strongly suggesting Rosai-Dorfman disease (RDD). Afterward, pericardium and peritoneal effusions resulted in constrictive pericarditis and retroperitoneal fibrosis, respectively. The absence of distinctive clinical features made the diagnosis especially challenging. Attempts to control the disease using corticosteroids, radiation, orbital surgery, and interferon were unsuccessful. Aggressive treatments such as chemotherapy were not considered appropriate due to the general deterioration of our patient. Although the possibility of two concurrent diseases (e.g., systemic ECD and orbital RDD) cannot be discarded, we interpreted the orbital findings as likely due to RDD, and the entire condition of our patient as an extranodal RDD with atypical clinicopathological findings and outcome.

A novel method to detect the Mexican founder mutation BRCA1 ex9­12del associated with breast and ovarian cancer using quantitative polymerase chain reaction and TaqMan® probes.

In 2015, according to the National Institute of Statistics and Geography (INEGI), malignant breast tumors were the first cause of cancer fatality in women (6,273 fatalities) in Mexico, whereas 2,793 fatalities in women were due to ovarian cancer. A total of 5­10% of breast cancer and 10­15% of ovarian cancer cases are caused by a hereditary breast­ovarian cancer syndrome, with mutations predominantly identified in the BRCA1 and BRCA2 genes. Recently, the Mexican founder mutation BRCA1 ex9­12del was identified (deletion of exons 9­12 with recombination between introns 8­12). This is the most frequently reported mutation in hereditary breast/ovarian cancer in Mexico. Current detection methods include end­point polymerase chain reaction (PCR) and Multiplex Ligation­dependent Probe Amplification (MLPA). In the present study a cheap, sensitive and fast detection method was developed based on quantitative PCR and two TaqMan® probes, one to detect the deletion (recombination region between introns 8 and 12), and the other one a region from exon 11. With this assay, 90 samples were able to be analyzed in 2 h using 2.5 ng of DNA/reaction at a cost of ~2­3 USD. This method is capable of detecting positive samples for DNA deletion and excluding negative ones. Therefore, the method proposed may be a useful high­throughput diagnostic option that could be useful in future association or prevalence studies that use large populations.

Acute kidney injury secondary to diarrhea caused by "sprue-like" enteropathy associated with olmesartan / Daño renal agudo secundario a diarrea debido a enteropatía "sprue-like" asociada al olmesartan

No disponible

Cancer vaccine characterization: from bench to clinic.

BACKGROUND: The development of safe, effective, and affordable vaccines has become a global effort due to its vast impact on overall world health conditions. A brief overview of vaccine characterization techniques, especially in the area of high-resolution mass spectrometry, is presented. It is highly conceivable that the proper use of advanced technologies such as high-resolution mass spectrometry, along with the appropriate chemical and physical property evaluations, will yield tremendous in-depth scientific understanding for the characterization of vaccines in various stages of vaccine development. This work presents the physicochemical and biological characterization of cancer vaccine Racotumomab/alumina, a murine anti-idiotypic antibody that mimics N-glycolyl-GM3 gangliosides. This antibody has been tested as an anti-idiotypic cancer vaccine, adjuvated in Al(OH)3, in several clinical trials for melanoma, breast, and lung cancer. METHODS: Racotumomab was obtained from ascites fluid, transferred to fermentation in stirred tank at 10 L and followed to a scale up to 41 L. The mass spectrometry was used for the determination of intact molecule, light and heavy chains masses; amino acids sequence analysis, N- and C-terminal, glycosylation and posttranslational modifications. Also we used the DLS for the size distribution and zeta potential analysis. The biological analyses were performed in mice and chickens. RESULTS: We observed differences in glycosylation pattern, charge heterogeneity and structural stability between in vivo-produced and bioreactor-obtained Racotumomab products. Interestingly, these modifications had no significant impact on the immune responses elicited in two different animal models. CONCLUSIONS: We are demonstrated that this approach could potentially be more efficient and effective for supporting vaccine research and development.

Neurogenic bladder treatment by doubling the recommended antimuscarinic dosage.

INTRODUCTION AND OBJECTIVES: The dosage of the antimuscarinic drugs: Tolterodine ER or Trospium was increased to a higher-than-recommended dosage in patients where the manufacturer's recommended dosage had failed. All patients were suffering from neurogenic detrusor overactivity incontinence. Tolerability and success were evaluated in the present study. MATERIALS AND METHODS: Twenty-one patients with neurogenic detrusor overactivity were evaluated: 17 with spinal cord injury, 3 with multiple sclerosis, and 1 with a meningomyelocele. All patients catheterized themselves or were catheterized. If neurogenic detrusor overactivity continued and the medication was well tolerated, the dosage was doubled to either 8 mg of Tolterodine ER [2 x 4 mg (n = 11)] or 90 mg of Trospium [3 x 30 mg (n = 10)]. The follow-up was monitored by a bladder diary and urodynamic evaluation. RESULTS: Sixteen patients significantly decreased their incontinence episodes from 8-12 episodes before to 0-2 episodes during the doubled treatment. The reflex volume increased from 202 +/- 68 to 332 +/- 50 ml (P < 0.001). Cystometric capacity enlarged from 290 +/- 56 to 453 +/- 63 ml (P < 0.001). One patient had to stop the medication because of intolerable side effects and five patients did not experience satisfactory benefit. CONCLUSION: The increased dosage of Tolterodine or Trospium is an effective treatment in patients with neurogenic bladder.

Interim results of a randomized trial of mitomycin C as an adjunct to radical radiotherapy in the treatment of locally advanced squamous-cell carcinoma of the cervix.

The purpose of this study was to determine the efficacy of mitomycin C as an adjunct to radiotherapy for the treatment of locally advanced cervix cancer. Patients with squamous-cell carcinoma of the cervix, stages IB2-IVA, were randomized to receive radiotherapy alone or radiotherapy with concomitant mitomycin C. An initial cohort of 160 patients, having a mean follow-up of 46 months, is analyzed. Intravenous mitomycin C, 15 mg/M(2), was given on the first and sixth week of radiotherapy. The 78 patients in the radiotherapy with mitomycin C group and 82 patients in the radiotherapy alone group have a comparable distribution by age and stage (mean age 47 years; stage IB 3%, IIA 11%, IIB 48%, IIIA 1%, IIIB 36%, IVA 3%). The four-year actuarial survival rates for radiotherapy with mitomycin C and radiotherapy alone were 72% and 56%, respectively (P = 0.13). The four-year actuarial disease-free survival rates for radiotherapy with mitomycin C and radiotherapy alone were 71% and 44%, respectively, a statistically significant difference (P = 0.01). The four-year actuarial local recurrence-free survival rates for patients receiving radiotherapy with mitomycin C and radiotherapy alone were 78% and 63%, respectively (P = 0.11). Differences in four-year distant recurrence-free survival between radiotherapy plus mitomycin C and radiotherapy alone were significantly different at 85% vs. 61% (P = 0.01); this analysis is not adjusted for local failure. On subgroup analysis, stage III-IVA patients had a four-year actuarial disease-free survival of 75% for radiotherapy plus mitomycin C compared with 35% for radiotherapy alone (P = 0.03). There were no treatment- related deaths. Mild hematologic toxicity was seen only in the group treated with mitomycin C. No excess in non-hematologic toxicity has been observed thus far with combined mitomycin C and radiotherapy. In this open phase III trial of mitomycin C as an adjunct to radical radiotherapy for squamous-cell carcinoma of the cervix, there were minimal hematologic effects and no increase in acute radiation reactions. A statistically significant difference in favor of patients receiving mitomycin C is shown for disease-free survival. Thus far, there are trends in favor of those patients receiving mitomycin C for survival and local control. Patients with more advanced stage disease, predominantly stage IIIB, appear to have the most benefit. These preliminary results support the hypothesis that targeting hypoxic cells may lead to a therapeutic enhancement in the radiotherapy of cervix cancer. This trial continues to accrue patients and follow-up data. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 206-223 (2000).

[Brainstem auditory evoked potentials in low and high risk newborns]. / Potenciales provocados auditivos del tallo cerebral en recién nacidos de bajo y alto riesgo.

Brainstem auditory evoked potentials (BAEP) were performed in a population of preterm infants of 32-34, 35-37 and 38-41 weeks of gestational age (GE) high risk newborns, and in 38-41 weeks GE low risk newborns. Statistical differences were found between both 38-41 weeks GE groups. High risk newborns showed longer latencies of waves III and V (P < 0.001), and I-III and I-V interwave intervals (P < 0.01). Our data show that auditory brainstem system suffer in high risk newborns. Results is discussed in relationship with other brainstem auditory evoked potentials studies in high risk newborns due it's clinical implications of present data.

[Earthquakes in Mexico in 1985. Their psychological repercussions and intervention by psychoanalysts]. / Les tremblements de terre au Mexique en 1985. Leurs répercussions psychologiques et l'intervention des psychanalystes.

Starting with a real event, the Mexican earthquake of 1985, this article describes a certain number of practices of Mexican psychoanalysts and their theoretical reflections which grew out of the experience of helping a disaster-struck population during a crisis period. The result of this intervention was that it enhanced the elaboration of the emotional and traumatic conflict created by this kind of natural phenomenon. This work, a; though not constituting a generalized practice within psychoanalysis, corroborates certain processes in Freud's second theory of drives.