Cell-Free DNA as a Biomarker at Diagnosis and Follow-Up in 256 B and T-Cell Lymphomas.

BACKGROUND: Cell-free DNA (cfDNA) analysis has become a promising tool for the diagnosis, prognosis, and monitoring of lymphoma cases. Until now, research in this area has mainly focused on aggressive lymphomas, with scanty information from other lymphoma subtypes. METHODS: We selected 256 patients diagnosed with lymphomas, including a large variety of B-cell and T-cell non-Hodgkin and Hodgkin lymphomas, and quantified cfDNA from plasma at the time of diagnosis. We further selected 49 large B-cell lymphomas (LBCL) and analyzed cfDNA levels at diagnosis (pre-therapy) and after therapy. In addition, we performed NGS on cfDNA and tissue in this cohort of LBCL. RESULTS: Lymphoma patients showed a statistically significant higher cfDNA concentration than healthy controls (mean 53.0 ng/mL vs. 5.6 ng/mL, p < 0.001). The cfDNA concentration was correlated with lymphoma subtype, lactate dehydrogenase, the International Prognostic Index (IPI) score, Ann Arbor (AA), and B-symptoms. In 49 LBCL cases, the cfDNA concentration decreased after therapy in cases who achieved complete response (CR) and increased in non-responders. The median cfDNA at diagnosis of patients who achieved CR and later relapsed was higher (81.5 ng/mL) compared with levels of those who did not (38.6 ng/mL). A concordance of 84% was observed between NGS results in tumor and cfDNA samples. Higher VAF in cfDNA is correlated with advanced stage and bulky disease. CONCLUSIONS: cfDNA analysis can be easily performed in almost all lymphoma cases. The cfDNA concentration correlated with the characteristics of the aggressiveness of the lymphomas and, in LBCL, with the response achieved after therapy. These results support the utility of cfDNA analysis as a complementary tool in the management of lymphoma patients.

P53 expression correlates with low axillary tumor burden in breast cancer.

BACKGROUND: The p53 mutation in breast cancer confers a worse prognosis and is usually associated with p53 overexpression (p53+) on immunohistochemistry. Previous studies have shown that p53+ tumors could be associated with low axillary tumor burden (ATB). OBJECTIVE: We aimed to evaluate the association between p53+ and ATB in a large series of breast cancers as an aid to personalizing axillary surgical treatment. METHODS: We retrieved 1762 infiltrating breast carcinomas from our database that were treated with upfront surgery in Hospital del Mar from 2004 to 2018. We compared p53+ and p53-negative (p53-) tumors in terms of the percentage of cases with high ATB and overall survival. This comparison was made overall and for each immunophenotype. RESULTS: Overall, 18.7% of breast tumors were p53+. High ATB was less common in p53+ tumors than in p53- tumors in the luminal B-Her2-negative immunophenotype (6.2% versus 16.9%, respectively, P = 0.025), but not in the other immunophenotypes or overall. Overall survival was worse in patients with p53+ breast cancer (P = 0.002). CONCLUSION: p53+ breast cancers were associated with worse overall survival. However, low ATB was more common in these tumors than in p53- tumors in the luminal B-Her2-negative subtype. Information on p53 expression could be of use to predict ATB in some breast cancer tumors.

Characterization and spatial distribution of the immune cell infiltrate in triple-negative breast cancer: a novel classification based on plasma cells and CD8+ T cells.

Stromal tumor-infiltrating lymphocytes (sTILs) are a robust prognostic and predictive biomarker in triple-negative breast carcinoma. However, the sTIL compartment comprises different cell populations. The aim of the study is to characterize the distribution of T cells (CD3+ and CD8+), B cells, and plasma cells and explore their association with outcome in the surgical specimen of 62 patients. Furthermore, programmed death ligand 1 expression and the presence of tertiary lymphoid structures (TLSs) are explored. Patients with higher sTILs achieve better progression-free survival (PFS) (P = .0013), and tumors have more plasma cells in the infiltrate. Specifically, higher counts of T cells (both CD3+ and CD8+) have better PFS (P = .002 and P = .0086, respectively) as it is observed in tumors with higher infiltration of CD8+ T cells in the tumor core (P = .035). Higher infiltration by B cells and plasma cells shows a positive tendency toward increased PFS (P = .06 and P = .058). Programmed death ligand 1 (SP142) is positive in 56% of tumors. Tumors with at least 1 TLS (42%) show higher CD8+ T cell infiltration in the tumor core and the sTIL value doubles compared to tumors devoid of TLSs [sTIL mean: 36 ± 11% and 18 ± 5% (CI [Confidence Interval]: 95%), respectively]. Our study demonstrates that the characterization of the immune cell infiltration is as relevant as its distribution. Moreover, the importance of considering different immune cell types for classification is emphasized. Therefore, a new classification of triple-negative breast carcinoma immune infiltration with CD8+ T cell and plasma cell densities in the tumor core and infiltrative margin is proposed.

Automated quantification of stromal tumour infiltrating lymphocytes is associated with prognosis in breast cancer.

Stromal tumour infiltrating lymphocytes (sTIL) in haematoxylin and eosin (H&E) stained sections has been linked to better outcomes and better responses to neoadjuvant therapy in triple-negative and HER2-positive breast cancer (TNBC and HER2 +). However, the infiltrate includes different cell populations that have specific roles in the tumour immune microenvironment. Various studies have found high concordance between sTIL visual quantification and computational assessment, but specific data on the individual prognostic impact of plasma cells or lymphocytes within sTIL on patient prognosis is still unknown. In this study, we validated a deep-learning breast cancer sTIL scoring model (smsTIL) based on the segmentation of tumour cells, benign ductal cells, lymphocytes, plasma cells, necrosis, and 'other' cells in whole slide images (WSI). Focusing on HER2 + and TNBC patient samples, we assessed the concordance between sTIL visual scoring and the smsTIL in 130 WSI. Furthermore, we analysed 175 WSI to correlate smsTIL with clinical data and patient outcomes. We found a high correlation between sTIL values scored visually and semi-automatically (R = 0.76; P = 2.2e-16). Patients with higher smsTIL had better overall survival (OS) in TNBC (P = 0.0021). In the TNBC cohort, smsTIL was as an independent prognostic factor for OS. As part of this work, we introduce a new segmentation dataset of H&E-stained WSI.

Round-robin testing for LMO2 and MYC as immunohistochemical markers to screen MYC rearrangements in aggressive large B-cell lymphoma.

Aggressive large B-cell lymphomas (aLBCL) include a heterogeneous group of lymphomas with diverse biological features. One of the approaches to the diagnosis of aLBCL is based on the identification of MYC rearrangements (MYC-R), in addition to BCL2 and BCL6 rearrangements by genetic techniques, mainly fluorescent in situ hybridization (FISH). Because of the low incidence of MYC-R, the identification of useful immunohistochemistry markers to select cases for MYC FISH testing may be useful in daily practice. In a previous work, we identified a strong association between the profile CD10 positive/LMO2 negative expression and the presence of MYC-R in aLBCL and obtained good intralaboratory reproducibility. In this study, we wanted to evaluate external reproducibility. To evaluate whether LMO2 can be a reproducible marker between observers 50 aLBCL cases were circulated among 7 hematopathologists of 5 hospitals. Fleiss' kappa index for LMO2 and MYC were 0.87 and 0.70, respectively, indicating high agreement between observers. In addition, during 2021-2022, the enrolled centers included LMO2 in their diagnostic panels to evaluate prospectively the utility of the marker, and 213 cases were analyzed. Comparing LMO2 with MYC, the group of CD10 positive cases showed higher specificity (86% vs 79%), positive predictive value (66% vs 58%), likelihood positive value (5.47 vs 3.78), and accuracy (83% vs 79%), whereas the negative predictive values remained similar (90% vs 91%). These findings place LMO2 as a useful and reproducible marker to screen MYC-R in aLBCL.

Tratamiento médico del body packer o mulas de drogas

Introducción: Durante el año 2020, más de 284 millones de personas en el mundo se afectaron por el consumo de drogas. Estas se transportan en diferentes formas de embalaje o en el propio cuerpo y son los llamados correos humanos. Las personas que utilizan el interior del cuerpo con esos fines se describen con varios términos, entre ellos body packers o mulas de drogas. Es una práctica peligrosa, con graves consecuencias médico-legales. Se realizó una revisión bibliográfica de documentos indexados en las bases de datos SciELO, PubMed y Google académico. Se incluyeron los artículos a texto completo, en español, portugués e inglés, publicados desde 2018 hasta 2022, relacionados con el tema. Objetivo: Examinar las formas de enfrentar desde el punto de vista médico un problema de salud como el body packer. Desarrollo: En la actividad de body packer participan individuos de ambos sexos, de todos los grupos etarios. Las sustancias trasportadas son: cocaína, heroína, anfetaminas, marihuana, hachís y drogas sintéticas. Se portan entre 50 a 200 cápsulas con 5 a 10 kilogramos de la sustancia total. Para su evaluación son necesarios estudios imagenológicos que varían en sensibilidad y disponibilidad. Más del 80 % de los casos son asintomáticos, resuelven con estricta vigilancia y uso de polietilenglicol para la evacuación intestinal; el resto de los casos, desarrollan el síndrome de body packer, requieren tratamiento quirúrgico y apoyo con tratamiento sintomático y específico. Conclusiones: Para el body packer está prevista la realización de estudios imagenológicos, así como el tratamiento médico o quirúrgico según las formas clínicas que se presenten.

Introduction: During the year 2020, more than 284 million people in the world were affected by the consumption of drugs, which are transported in different forms of packaging or using the body itself, called human couriers; people who use the inside of their body for these purposes are described by various terms, including body packers or drug mules, a dangerous practice, with serious medical-legal consequences. A bibliographic review of documents indexed in the SciELO, PubMed and academic Google databases is carried out. Full text articles, in Spanish, Portuguese and English, published from 2018 to 2022, related to the topic were included. Objective: To examine the ways to deal with a health problem such as body packer from a medical point of view. Development: Individuals of both sexes, of all age groups, participate in the body packer activity. The transported substances are: cocaine, heroin, amphetamines, marijuana, hashish and synthetic drugs. Between 50 and 200 capsules with 5 to 10 kilograms of the total substance are carried. Imaging studies that vary in sensitivity and availability are necessary for its evaluation. More than 80% of cases are asymptomatic, resolve with strict surveillance and use of polyethylene-glycol for bowel evacuation; the rest of the cases develop body packer syndrome and require surgical treatment and support with symptomatic and specific treatment. Conclusions: For the body packer, imaging studies are planned, as well as medical or surgical treatment according to the clinical forms that occur.

Long-Term Risk of Breast Cancer after Diagnosis of Benign Breast Disease by Screening Mammography.

Assessing the long-term risk of breast cancer after diagnosis of benign breast disease by mammography is of utmost importance to design personalised screening strategies. We analysed individual-level data from 778,306 women aged 50-69 years with at least one mammographic screening participation in any of ten breast cancer screening centers in Spain from 1996 to 2015, and followed-up until 2017. We used Poisson regression to compare the rates of incident breast cancer among women with and without benign breast disease. During a median follow-up of 7.6 years, 11,708 (1.5%) women had an incident of breast cancer and 17,827 (2.3%) had a benign breast disease. The risk of breast cancer was 1.77 times higher among women with benign breast disease than among those without (95% CI: 1.61 to 1.95). The relative risk increased to 1.99 among women followed for less than four years, and remained elevated for two decades, with relative risk 1.96 (95% CI: 1.32 to 2.92) for those followed from 12 to 20 years. Benign breast disease is a long-term risk factor for breast cancer. Women with benign breast disease could benefit from closer surveillance and personalized screening strategies.

Cutaneous Involvement of Angioimmunoblastic T-Cell Lymphoma Masquerading as B-Cell Reactive Lymphoid Hyperplasia.

ABSTRACT: A 59-year-old woman presented with a persistent eruption manifested as multiple agminated miliary facial papules. Histopathological examination showed prominent nodular dermal lymphoid infiltrates with hyperplastic follicles that were initially interpreted as B-cell reactive lymphoid hyperplasia. Several years later, an additional biopsy showed a dense perifollicular infiltrate with reactive primary and secondary follicles. Accompanying T cells corresponded to CD3/CD4/PD1/CXCL13-positive cells and scattered Epstein-Barr virus-positive B cells were identified by in situ hybridization. A monoclonal T-cell population was demonstrated by TCRγ and TCRß Polymerase Chain Reaction amplification, as well as a minor abnormal circulating T-cell population by flow cytometry (0.62% of the white blood cells, CD4+CD3s-CD7-). A biopsy specimen from an enlarged right supraclavicular lymph node disclosed nodal involvement by angioimmunoblastic T-cell lymphoma. The observation of B-cell dermal nodular infiltrates with well-demarcated lymphoid aggregates forming primary lymphoid follicles may lead to overlook the T-cell component in some cases of angioimmunoblastic T-cell lymphoma. In such cases, a careful assessment of the apparently minor T-cell component is important to establish a correct diagnosis.

Mammographic features of benign breast lesions and risk of subsequent breast cancer in women attending breast cancer screening.

OBJECTIVES: To evaluate the mammographic features in women with benign breast disease (BBD) and the risk of subsequent breast cancer according to their mammographic findings. METHODS: We analyzed data from a Spanish cohort of women screened from 1995 to 2015 and followed up until December 2017 (median follow-up, 5.9 years). We included 10,650 women who had both histologically confirmed BBD and mammographic findings. We evaluated proliferative and nonproliferative BBD subtypes, and their mammographic features: architectural distortion, asymmetries, calcifications, masses, and multiple findings. The adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for breast cancer were estimated using a Cox proportional hazards model. We plotted the adjusted cumulative incidence curves. RESULTS: Calcifications were more frequent in proliferative disease with atypia (43.9%) than without atypia (36.8%) or nonproliferative disease (22.2%; p value < 0.05). Masses were more frequent in nonproliferative lesions (59.1%) than in proliferative lesions without atypia (35.1%) or with atypia (30.0%; p value < 0.05). Multiple findings and architectural distortion were more likely in proliferative disease (16.1% and 4.7%) than in nonproliferative disease (12.8% and 1.9%). Subsequent breast cancer occurred in 268 (2.5%) women. Compared with women who had masses, the highest risk of subsequent breast cancer was found in those with architectural distortions (aHR, 2.21; 95% CI, 1.16-4.22), followed by those with multiple findings (aHR, 1.89; 95% CI, 1.34-2.66), asymmetries (aHR, 1.66; 95% CI, 0.84-3.28), and calcifications (aHR, 1.60; 95% CI, 1.21-2.12). CONCLUSION: BBD subtypes showed distinct mammographic findings. The risk of subsequent breast cancer was high in those who have shown architectural distortion, multiple findings, asymmetries, and calcifications than in women with masses. KEY POINTS: • The presence of mammographic findings in women attending breast cancer screening helps clinicians to assess women with benign breast disease (BBD). • Calcifications were frequent in BBDs with atypia, which are the ones with a high breast cancer risk, while masses were common in low-risk BBDs. • The excess risk of subsequent breast cancer in women with BBD was higher in those who showed architectural distortion compared to those with masses.

Development, Characterization, Optimization, and In Vivo Evaluation of Methacrylic Acid-Ethyl Acrylate Copolymer Nanoparticles Loaded with Glibenclamide in Diabetic Rats for Oral Administration.

The methacrylic acid-ethyl acrylate copolymer nanoparticles were prepared using the solvent displacement method. The independent variables were the drug/polymer ratio, surfactant concentration, Polioxyl 40 hydrogenated castor oil, the added water volume, time, and stirring speed, while size, PDI, zeta potential, and encapsulation efficiency were the response variables analyzed. A design of screening experiments was carried out to subsequently perform the optimization of the nanoparticle preparation process. The optimal formulation was characterized through the dependent variables size, PDI, zeta potential, encapsulation efficiency and drug release profiles. In vivo tests were performed in Wistar rats previously induced with diabetes by administration of streptozotocin. Once hyperglycemia was determined in rats, a suspension of nanoparticles loaded with glibenclamide was administered to them while the other group was administered with tablets of glibenclamide. The optimal nanoparticle formulation obtained a size of 18.98 +/- 9.14 nm with a PDI of 0.37085 +/- 0.014 and a zeta potential of -13.7125 +/- 1.82 mV; the encapsulation efficiency was of 44.5%. The in vivo model demonstrated a significant effect (p < 0.05) between the group administered with nanoparticles loaded with glibenclamide and the group administered with tablets compared to the group of untreated individuals.

Evaluation of routine CT scans in the follow-up of diffuse large B-cell lymphomas.

OBJECTIVE: Our aim was to retrospectively assess the role of routine CT scans within the first year of follow-up with a limited surveillance policy prior to Lugano recommendations in diffuse large B-cell lymphomas (DLBCL) achieving complete metabolic remission (CMR). We also evaluated the type of relapse detection and exposure to CT scans within the first five years. METHODS: Patients diagnosed with DLBCL who achieved CMR after first-line immunochemotherapy were included. Imaging studies and medical records were thoroughly reviewed. RESULTS: Among 101 DLBCL patients in the first CMR, a total of 19 relapses were identified in the study period (18.8% of DLBCL patients included). Nine patients relapsed within the first year (47.4% of all relapses) but only 3 of them were detected by the 202 surveillance CT scans performed during this first year of follow-up. CONCLUSIONS: Our real-world data provide clinically applicable results which are in agreement with the Lugano recommendations based on trial data, highlighting the lack of utility of routine CTs in DLBCL patients achieving CMR.

Lack of expression of LMO2 clone SP51 identifies MYC rearrangements in aggressive large B-cell lymphomas.

MYC rearrangements (MYC-R) confer unfavorable prognosis to large B-cell lymphomas (LBCL). Because of the low incidence of such genetic alteration, surrogates to screen MYC-R may be useful in daily practice. Previous studies suggested that clone 1A9-1 of LMO2 loss may be a good predictor for the presence of MYC-R in LBCL. The present study examines the utility of LMO2 clone SP51. For this purpose, we have analyzed 20 Burkitt lymphomas and 325 LBCL. Among them, 245 cases were studied prospectively using whole tissue sections, and 100 retrospectively by tissue microarrays. The cohort of CD10-positive prospective cases achieved the best results. Lack of LMO2 SP51 expression predicted the presence of MYC-R with high specificity, accuracy, positive and negative predictive value (PPV/NPV), and positive and negative likelihood ratios (PLR/NLR). Compared with MYC protein expression, LMO2 SP51 obtained significantly higher specificity, accuracy, PPV, and PLR (94%, 91%, 85%, and 14.33 vs 73%, 77%, 56%, and 3.26, respectively), and similar NPV and NLR (92% and 0.22 vs 95% and 0.12). Compared with LMO2 clone 1A9-1, the sensitivity of LMO2 SP51 was lower (79% vs 89%). We conclude that LMO2 SP51 may be a useful marker to screen MYC-R in CD10-positive LBCL.

Developing and validating an individualized breast cancer risk prediction model for women attending breast cancer screening.

BACKGROUND: Several studies have proposed personalized strategies based on women's individual breast cancer risk to improve the effectiveness of breast cancer screening. We designed and internally validated an individualized risk prediction model for women eligible for mammography screening. METHODS: Retrospective cohort study of 121,969 women aged 50 to 69 years, screened at the long-standing population-based screening program in Spain between 1995 and 2015 and followed up until 2017. We used partly conditional Cox proportional hazards regression to estimate the adjusted hazard ratios (aHR) and individual risks for age, family history of breast cancer, previous benign breast disease, and previous mammographic features. We internally validated our model with the expected-to-observed ratio and the area under the receiver operating characteristic curve. RESULTS: During a mean follow-up of 7.5 years, 2,058 women were diagnosed with breast cancer. All three risk factors were strongly associated with breast cancer risk, with the highest risk being found among women with family history of breast cancer (aHR: 1.67), a proliferative benign breast disease (aHR: 3.02) and previous calcifications (aHR: 2.52). The model was well calibrated overall (expected-to-observed ratio ranging from 0.99 at 2 years to 1.02 at 20 years) but slightly overestimated the risk in women with proliferative benign breast disease. The area under the receiver operating characteristic curve ranged from 58.7% to 64.7%, depending of the time horizon selected. CONCLUSIONS: We developed a risk prediction model to estimate the short- and long-term risk of breast cancer in women eligible for mammography screening using information routinely reported at screening participation. The model could help to guiding individualized screening strategies aimed at improving the risk-benefit balance of mammography screening programs.

Risk of breast cancer two years after a benign biopsy depends on the mammographic feature prompting recall.

OBJECTIVE: We aimed to explore whether the type of mammographic feature prompting a false-positive recall (FPR) during mammography screening influences the risk and timing of breast cancer diagnosis, particularly if assessed with invasive procedures. STUDY DESIGN: We included information on women screened and recalled for further assessment in Spain between 1994 and 2015, with follow-up until 2017, categorizing FPRs by the assessment (noninvasive or invasive) and mammographic feature prompting the recall. MAIN OUTCOME MEASURES: Breast cancer rates in the first two years after FPR (first period) and after two years (second period). RESULTS: The study included 99,825 women with FPRs. In both periods, the breast cancer rate was higher in the invasive assessment group than in the noninvasive group (first period 12 ‰ vs 1.9 ‰, p < 0.001; second period 4.4‰ vs 3.1‰, p < 0.001). During the first period, the invasive assessment group showed diverse breast cancer rates for each type of mammographic feature, with a higher rate for asymmetric density (31.9‰). When the second period was compared with the first, the breast cancer rate decreased in the invasive assessment group (from 12‰ to 4.4‰, p < 0.001) and increased in the noninvasive assessment group (from 1.9‰ to 3.1‰, p < 0.001). CONCLUSION: In the context of mammography screening, the risk of breast cancer diagnosis during the first two years after FPR was particularly high for women undergoing invasive assessment; importantly, the risk was modified by type of mammographic feature prompting the recall. This information could help to individualize follow-up after exclusion of malignancy.

Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma With Secondary Cutaneous Involvement: A Diagnostic Challenge.

ABSTRACT: A 45-year-old woman presented with a solitary breast nodule that histologically corresponded to a dense dermal/subcutaneous infiltration of atypical cytotoxic T-lymphocytes (CD3+, CD8+, CD56+, TIA-1+, CD5-, CD4-, CD30-, EBV-), resembling subcutaneous panniculitic T-cell lymphoma. The presence of TCRδ gene rearrangement and the absence of ßF1 expression let to suspect the diagnosis of primary cutaneous γδT-cell lymphoma. As a consequence of jejunum perforation following chemotherapy treatment, a mucosal atypical lymphoid infiltration with marked epitheliotropism was observed in the resected intestinal sample, and the diagnosis of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) was finally established. Disease progression appeared with multiple erythematous plaques showing a dense lichenoid atypical cytotoxic T-cell infiltrate with intense epidermotropism, mimicking primary cutaneous epidermotropic aggressive CD8+ T-cell lymphoma. MEITL is an uncommon and aggressive peripheral T-cell lymphoma that often presents in adults with gastrointestinal symptoms. Secondary cutaneous involvement is a rare phenomenon that may show clinicopathologic and immunohistochemical features that overlap with different subtypes of primary cutaneous cytotoxic T-cell lymphomas. In the absence of gastrointestinal symptoms, the diagnosis may be challenging, and only the evidence of underlying MEITL may allow to establish the definite diagnosis.

Clinical Interest of LMO2 Testing for the Diagnosis of Aggressive Large B-Cell Lymphomas.

MYC rearrangements usually confer aggressive biological behavior to large B-cell lymphomas. In this study, we aimed to evaluate the relevance of LMO2 detection to the clinical approach to these tumors. First, the ability of LMO2 loss of expression to recognize the presence of MYC rearrangements was evaluated. A series of 365 samples obtained from 351 patients, including 28 Burkitt lymphoma, 230 diffuse large B-cell lymphoma, 30 high-grade B-cell lymphoma with MYC and BCL2/BCL6 rearrangements, eight high-grade B-cell lymphoma-NOS, 43 transformed diffuse large B-cell lymphoma, and 26 high-grade follicular lymphomas was analyzed. Among the CD10-positive tumors prospectively analyzed in whole tissue sections, LMO2 negative expression obtained values of 88% sensitivity, 94% specificity, and 93% accuracy, proving the utility of LMO2 to screen MYC rearrangements. In addition, survival analyses were performed in a series of 155 patients. As per univariate analyses, the prognosis relevance of LMO2 was as useful as that of the diagnostic categories, MYC rearrangements, and MYC immunohistochemistry. Multivariate models revealed that both LMO2 (hazard ratio 0.51 p = 0.02) and IPI (hazard ratio 1.67 p < 0.005) were independent variables predicting overall survival. Finally, MYC and LMO2 mRNA expression were analyzed in a small group of cases. Taken together, these findings show the interest of LMO2 testing in large B-cell lymphomas.

Coordinated signals from PARP-1 and PARP-2 are required to establish a proper T cell immune response to breast tumors in mice.

Poly(ADP-ribose)-polymerase (PARP)-1 and PARP-2 play an essential role in the DNA damage response. Based on this effect of PARP in the tumor cell itself, PARP inhibitors have emerged as new therapeutic tools both approved and in clinical trials. However, the interactome of multiple other cell types, particularly T cells, within the tumor microenvironment are known to either favor or limit tumorigenesis. Here, we bypassed the embryonic lethality of dually PARP-1/PARP-2-deficient mice by using a PARP-1-deficient mouse with a Cd4-promoter-driven deletion of PARP-2 in T cells to investigate the understudied role of these PARPs in the modulation of T cell responses against AT-3-induced breast tumors. We found that dual PARP-1/PARP-2-deficiency in T cells promotes tumor growth while single deficiency of each protein limited tumor progression. Analysis of tumor-infiltrating cells in dual PARP-1/PARP-2-deficiency host-mice revealed a global change in immunological profile and impaired recruitment and activation of T cells. Conversely, single PARP-1 and PARP-2-deficiency tends to produce an environment with an active and partially upregulated immune response. Our findings pinpoint opposite effects of single and dual PARP-1 and PARP-2-deficiency in modulating the antitumor response with an impact on tumor progression, and will have implications for the development of more selective PARP-centered therapies.

Complementary value of electron microscopy and immunohistochemistry in the diagnosis of non-small cell lung cancer: A potential role for electron microscopy in the era of targeted therapy.

With the identification of therapeutic targets for lung adenocarcinoma, it has become mandatory to distinguish it from other entities. Some cases remain classified as non-small cell lung carcinoma, not otherwise specified (NSCLC-NOS) with immunohistochemistry. Electron microscopy (EM) can be useful, allowing the identification of glandular differentiation. The aim of this study was to determine the complementary value of immunohistochemistry and EM.Forty-eight NSCLC-NOS cases were selected (PSMAR-Biobank, Barcelona, Spain). Immunohistochemistry (TTF-1, p40) was performed. Tissue was retrieved from paraffin blocks. Results were compared to the final diagnosis, derived from combination of light microscopy, immunohistochemistry, EM, molecular studies and resection specimen.Immunohistochemistry concurred with final diagnosis in 36 cases (75%, Kappa = 0.517). EM agreed with final diagnosis in 35 (72.9%, Kappa = 0.471). Immunohistochemistry had a sensitivity = 73%, specificity = 100%, positive predictive value (PPV) = 100% and negative predictive value (NPV) = 52.4% for adenocarcinoma. All adenocarcinoma cases not solved by immunohistochemistry (n = 10) were classified by EM, and vice versa. Data from EM were identical to those of immunohistochemistry: sensitivity = 73%, specificity = 100%, PPV = 100% and NPV = 52.4%. Combining both techniques, 47 cases were coincident with final diagnosis (97.9%, Kappa = 0.943).EM can provide valuable information in subtyping NSCLC-NOS, being particularly useful when immunohistochemistry is inconclusive. EM could be considered as a complementary tool for decision-making in NSCLC-NOS.

NK Cell Infiltrates and HLA Class I Expression in Primary HER2+ Breast Cancer Predict and Uncouple Pathological Response and Disease-free Survival.

PURPOSE: We investigated the value of tumor-infiltrating NK (TI-NK) cells and HLA class I tumor expression as biomarkers of response to neoadjuvant anti-HER2 antibody-based treatment in breast cancer. EXPERIMENTAL DESIGN: TI-NK cells and HLA-I were determined by IHC in pretreatment tumor biopsies from two cohorts of patients with HER2-positive breast cancer [discovery cohort (n = 42) and validation cohort (n = 71)]. Tumor-infiltrating lymphocytes (TIL) were scored according to international guidelines. Biomarker association with pathologic complete response (pCR) and disease-free survival (DFS) was adjusted for prognostic factors. Gene set variation analysis was used for determining immune cell populations concomitant to NK-cell enrichment in HER2-positive tumors from the Cancer Genome Atlas (n = 190). RESULTS: TI-NK cells were significantly associated with pCR in the discovery cohort as well as in the validation cohort (P < 0.0001), independently of clinicopathologic factors. A ≥3 TI-NK cells/50x high-power field (HPF) cutoff predicted pCR in the discovery and validation cohort [OR, 188 (11-3154); OR, 19.5 (5.3-71.8)]. Presence of TI-NK cells associated with prolonged DFS in both patient cohorts [HR, 0.07 (0.01-0.6); P = 0.01; HR, 0.3 (0.08-1.3); P = 0.1]. NK-, activated dendritic- and CD8 T-cell gene expression signatures positively correlated in HER2-positive tumors, supporting the value of NK cells as surrogates of effective antitumor immunity. Stratification of patients by tumor HLA-I expression identified patients with low and high relapse risk independently of pCR. CONCLUSIONS: This study identifies baseline TI-NK cells as an independent biomarker with great predictive value for pCR to anti-HER2 antibody-based treatment and points to the complementary value of tumor HLA-I status for defining patient prognosis independently of pCR.

Inflammatory Myofibroblastic Tumor Diagnosed by Transbronchial Needle Aspiration / Tumor inflamatorio miofibroblástico diagnosticado por punción aspirativa transbronquial

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