In silico transcriptomic mapping of integrins and immune activation in Basal-like and HER2+ breast cancer.

PURPOSE: Integrins, transmembrane receptors that mediate cell-extracellular matrix and cell-cell interactions, have been linked to several cancer-associated features. A less explored function of integrins in cancer is their role in leukocyte homing and activation. Understanding their relationship with immune cell infiltrates and immune checkpoints is an area of interest in cancer research. METHODS: The expression of 33 different integrins was evaluated in relation with breast cancer patient outcome using transcriptomic data (Affymetrix dataset, exploratory cohort) and the METABRIC study (validation cohort). The TIMER online tool was used to assess the association of the identified integrin genes with immune cell infiltration, and the TCGA and METABRIC studies to assess correlations between integrin gene expression and genomic signatures of immune activation. RESULTS: We identified 7 genes coding for integrin α and ß subunits, i.e., ITGA4, ITGB2, ITGAX, ITGB7, ITGAM, ITGAL and ITGA8, which predict a favorable prognosis in Basal-like and HER2+ breast cancers. Their expression positively correlated with the presence of immune cell infiltrates within the tumor (dendritic cells, CD4+ T-cells, neutrophils, CD8+ T-cells and B-cells), with markers of T-cell activation and antigen presentation, and with gene signatures of immune surveillance (cytotoxic T lymphocyte activation and IFN gamma signature). By contrast, we found that genes coding for integrins that predicted a detrimental outcome (IBSP, ITGB3BP, ITGB6, ITGB1 and ITGAV) were not associated with any of these parameters. CONCLUSIONS: We identified an integrin signature composed of 7 genes with potential to recognize immune infiltrated and activated Basal-like and HER2+ breast cancers with a favorable prognosis.

ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity.

Pancreatic cancer stem cells (PaCSCs) drive pancreatic cancer tumorigenesis, chemoresistance and metastasis. While eliminating this subpopulation of cells would theoretically result in tumor eradication, PaCSCs are extremely plastic and can successfully adapt to targeted therapies. In this study, we demonstrate that PaCSCs increase expression of interferon-stimulated gene 15 (ISG15) and protein ISGylation, which are essential for maintaining their metabolic plasticity. CRISPR-mediated ISG15 genomic editing reduces overall ISGylation, impairing PaCSCs self-renewal and their in vivo tumorigenic capacity. At the molecular level, ISG15 loss results in decreased mitochondrial ISGylation concomitant with increased accumulation of dysfunctional mitochondria, reduced oxidative phosphorylation (OXPHOS) and impaired mitophagy. Importantly, disruption in mitochondrial metabolism affects PaCSC metabolic plasticity, making them susceptible to prolonged inhibition with metformin in vivo. Thus, ISGylation is critical for optimal and efficient OXPHOS by ensuring the recycling of dysfunctional mitochondria, and when absent, a dysregulation in mitophagy occurs that negatively impacts PaCSC stemness.

Genomic Signatures of Immune Activation Predict Outcome in Advanced Stages of Ovarian Cancer and Basal-Like Breast Tumors.

There is an unmet need for new therapies in metastatic ovarian cancer and basal-like breast cancer since no curative therapies are currently available. Immunotherapy has shown to be active in several solid tumors, but particularly more in those where a pre-activated immune state does exist. In this work, we aim to identify biomarkers that could distinguish immune-activated tumors and predict response to therapies in ovarian and basal-like breast cancer, as well as their association with the level of tumor immune infiltration. We found that the combined expression of IFNG, CD30, CXCL13, and PRF1 correlated with better overall survival (OS) in advanced stage ovarian cancer. This was confirmed using an independent dataset from TCGA. Interestingly, we observed that this gene combination also predicted for better prognosis in ovarian tumors with low mutational load, which typically respond less to immunotherapy. Expression of IFNG, CD30, CXCL13, and PRF1 was associated with increased level of immune infiltrates (CD8+ T cells, dendritic cells, and neutrophils) within the tumor. Moreover, we found that these gene signature also correlated with an increased OS and with a higher level of tumor immune infiltrates (B cells, CD8+ T cells, CD4+ T cells, neutrophils, and dendritic cells) in basal-like breast cancer. In conclusion, our analysis identifies genes signatures with potential to recognize immune activated ovarian and basal-like breast cancers with favorable prognosis and with a remarkable predictive capacity in tumors with low mutational burden. The presented results led to a hypothesis being formulated, but prospective clinical studies are needed to support a potential clinical application.

[Clinical features and toxicity of tuberculosis treatment in patients with cancer]. / Características clínicas y toxicidad del tratamiento de tuberculosis en pacientes con cáncer.

OBJECTIVES: To assess the clinical and epidemiological characteristics of active tuberculosis in patients with malignancy and to assess the influence of TB treatment on cancer management at the National Institute of Neoplastic Diseases from 2008 to 2013. MATERIALS AND METHODS: Observational study of TB cases diagnosed by positive sputum microscopy in patients with cancer. Clinical information, evolution, and pathologic information of neoplasia was reviewed. RESULTS: 76 cases of active tuberculosis after being diagnosed with cancer were found. The median age was 51.3 years. Median follow-up was 2.1 years. The most common cancers were acute lymphocytic leukemia (14.5%), for the hematologic cancers; and cancer of the cervix (14.5%), breast (10.5%), and gastric (7.9%) for non-hematological cancers. 27.6% of patients had recurrence of the tumor; TB diagnosis confounded the initial staging by 6.9% and was initially stated as cancer recurrence in 11.1% (breast and colon cancers). The diagnosis of tuberculosis delayed or influenced the dose reduction of the antineoplastic treatment in 11.1% of the cases (acute lymphocytic leukemia and non-Hodgkin lymphoma). 8.3% of patients had toxicity to the TB treatment. CONCLUSIONS: Cancer patients may have active tuberculosis infection. The interference effect of diagnosis and treatment of tuberculosis on the assessment of cancer and cancer treatment in our series is minimal.

Características cl¡nicas y toxicidad del tratamiento de tuberculosis en pacientes con cáncer / Clinical features and toxicity of tuberculosis treatment in patients with cancer

Objetivos. Evaluar las características clínico-epidemiológicas de la tuberculosis activa en pacientes portadores de neoplasia maligna y evaluar la influencia del tratamiento antituberculoso sobre el manejo de cáncer en el Instituto Nacional de Enfermedades Neoplásicas entre el 2008 y 2013. Materiales y métodos. Estudio observacional de casos de tuberculosis diagnosticados mediante baciloscopía positiva en pacientes con cáncer. Se revisó la información clínica, evolución, e información patológica de la neoplasia. Resultados. Se encontraron 76 casos de tuberculosis activa luego del diagnóstico de cáncer. La mediana de edad fue 51,3 años. La mediana de seguimiento fue 2,1 años. Las neoplasias más frecuentes fueron leucemia linfática aguda (14,5%) para las hematológicas y cáncer de cérvix (14,5%), mama (10,5%) y gástrico (7,9%) para las no hematológicas. El 27,6% de los pacientes presentó recurrencia de la neoplasia; el diagnóstico de tuberculosis confundió el estadiaje inicial en 6,9% y se planteó inicialmente como recurrencia del cáncer en 11,1% (neoplasias de mama y colon). El diagnóstico de tuberculosis retrasó o influyó en la reducción de dosis del tratamiento antineoplásico en 11,1% de los casos (leucemia linfática aguda y linfoma no Hodgkin). El 8,3% de los pacientes presentó toxicidad al tratamiento antituberculoso. Conclusiones. Los pacientes con cáncer pueden presentar infección activa por tuberculosis. El efecto de interferencia del diagnóstico y tratamiento de tuberculosis sobre la evaluación del cáncer y el tratamiento antineoplásico en nuestra serie es mínimo.

Objectives. To assess the clinical and epidemiological characteristics of active tuberculosis in patients with malignancy and to assess the influence of TB treatment on cancer management at the National Institute of Neoplastic Diseases from 2008 to 2013. Materials and methods. Observational study of TB cases diagnosed by positive sputum microscopy in patients with cancer. Clinical information, evolution, and pathologic information of neoplasia was reviewed. Results.76 cases of active tuberculosis after being diagnosed with cancer were found. The median age was 51.3 years. Median follow-up was 2.1 years. The most common cancers were acute lymphocytic leukemia (14.5%), for the hematologic cancers; and cancer of the cervix (14.5%), breast (10.5%), and gastric (7.9%) for non-hematological cancers. 27.6% of patients had recurrence of the tumor; TB diagnosis confounded the initial staging by 6.9% and was initially stated as cancer recurrence in 11.1% (breast and colon cancers). The diagnosis of tuberculosis delayed or influenced the dose reduction of the antineoplastic treatment in 11.1% of the cases (acute lymphocytic leukemia and non-Hodgkin lymphoma). 8.3% of patients had toxicity to the TB treatment. Conclusions. Cancer patients may have active tuberculosis infection. The interference effect of diagnosis and treatment of tuberculosis on the assessment of cancer and cancer treatment in our series is minimal.

Prognostic factors for patients with newly diagnosed brain metastasis from breast cancer.

AIM: This retrospective study determined features associated with brain metastasis (BM) in women with breast cancer. PATIENTS & METHODS: A total of 215 initially early breast cancer cases were included. We reviewed files and CT scan images of BM. RESULTS: Median age was 47 years and most of our cases were stage III (58.6%), grade III (62.8%), ER negative (62.3%) and nonluminal (59.1%). Median survival after BM was 4 months. Nonluminal, extracranial disease, time to CNS shorter than 15 months, >three brain lesions and poor breast-graded prognostic assessment and recursive partitioning analysis scores were associated with shorter survival. Adding extracranial disease to breast-graded prognostic assessment score also predicted survival after BM. Radiation response was assessed in 57 patients and response tended to be associated with nonluminal phenotype but not with survival. CONCLUSION: Factors associated with both initial tumor and clinical features at BM time are associated with shorter survival in our Latinas population.

PIK3CA mutations in Peruvian patients with HER2-amplified and triple negative non-metastatic breast cancers.

PURPOSE: To determine the frequency of PIK3CA mutations in a Peruvian cohort with HER2-amplified and triple negative breast cancers (TNBC). METHODS: We analyzed two cohorts of 134 primary non-metastatic breast cancer patients from Peru. Cohorts consisted of 51 hormone receptors (+)/HER2-amplified breast tumor patients surgically resected as first treatment included in the ALTTO trial (ALTTO cohort) and 81 TNBC patients with residual disease after neoadjuvant treatment (neoadjuvant cohort). Genomic DNA was extracted from paraffin-embedded tumor samples. Samples from the ALTTO and neoadjuvant cohorts were taken at biopsies and from residual tumors, respectively. PIK3CA mutations were detected by sequencing DNA fragments obtained by PCR amplification of exons and their flanking introns. All of the detected PIK3CA mutations were confirmed in a second independent run of sample testing. RESULTS: PIK3CA mutations were present in 21/134 cases (15.7%). Mutations in exon 9 and 20 were present in 10/134 (7.5%) and 11/134 (8.2%), respectively. No cases had mutations in both exons. Mutations in exon 9 consisted of E545A (seven cases), E545K (two cases) and E545Q (one case); while in exon 20, mutations consisted of H1047R (10 cases) and H1047L (one case). Compared to TNBC patients, HER2-amplified patients were more likely to have PIK3CA mutated (23% vs 9.6%; P=0.034). There were no associations between mutational status of PIK3CA with estrogen receptor status (P=0.731), progesterone receptor status (P=0.921), age (P=0.646), nodal status (P=0.240) or histological grade (P=1.00). No significant associations were found between PIK3CA mutational status and clinicopathological features. CONCLUSIONS: We found a similar frequency of PIK3CA mutations to that reported in other series. Although we did not include HR+/HER2 patients, those with HER2-amplified tumors were more likely to present PIK3CA mutations compared to patients with triple negative tumors.

Association between mammographic features and response to neoadjuvant chemotherapy in locally advanced breast carcinoma.

PURPOSE: Mammography is the cornerstone of breast cancer (BC) evaluation. This report investigates whether breast density (BD) and mammographic features of the tumor can provide information on both BC susceptibility to chemotherapy and other clinicopathologic features of locally advanced BC (LA BC). MATERIALS AND METHODS: We evaluated mammography films and clinicopathological information of patients with LA BC who received neoadjuvant chemotherapy (NAC) followed by tumor resection at the Instituto Nacional de Enfermedades Neoplásicas (INEN) from 2000 to 2011. RESULTS: We selected 494 LA BC cases. Most cases were at clinical tumor stage 4 (48.5%), node stage 1 (58.8%) and had high histologic grade (53.3%). BI-RADS 1, 2, 3, and 4 BD were found in 16.9%, 22%, 35.7% and 25.1% of patients, respectively. High BD has been associated with younger age (p<0.001), obesity (p=0.017) and no skin infiltration (T3 vs T4) (p=0.018). An association between dusty microcalcifications and HER2 group, as well as between casting microcalcifications and TN BC group (p=0.05) was found. NAC included anthracyclines and taxanes in 422 (85.5%) cases. Miller-Payne pathologic responses 4 and 5 (pCR) in the primary lesion and absence of axillary lymph nodes involvement were found in 15.3% of cases and were associated with younger age (p<0.001) and HG-3 lesions (p<0.001), but not with mammographic images. CONCLUSION: Mammographic features are associated with specific clinicopathological features of pre-NAC BC lesions but do not predict pCR. The implications and biological reasons for these findings require further study.

Heterogeneidad intratumoral en cáncer de mama: reporte de dos casos y revisión de la literatura / Intratumoral heterogeneity in breast cancer: case report and literature review

El cáncer de mama (CM) es una enfermedad de gran complejidad. Presenta una gran variabilidad molecular, lo cual se puede observar cuando se comparan los tumores de distintos pacientes, dos regiones del mismo tumor, los ganglios regionales comprometidos versus el tumor primario y la metástasis a distancia versus la lesión primaria. Reportamos el caso de dos pacientes con CM con heterogeneidad en el fenotipo tumoral del tumor primario; el primer caso presentó dos tumores simultáneos de diferentes características dentro de la misma mama y el segundo caso mostró variación en el fenotipo del tumor luego del tratamiento neoadyuvante (TN). Así mismo, realizamos un análisis de la información publicada recientemente.

Breast Cancer (BC) is a complex disease. It shows notable molecular differences when we compare tumors from different patients, two intra-tumor distant regions, metastasis in regional lymph node versus primary lesion, and distant metastasis versus primary lesion. We report two cases of BC with tumor phenotype heterogeneity of the primary tumor. The first case developed two different simultaneous lesions inside the same breast and the second one developed a change in tumor phenotype after neoadjuvant treatment. Furthermore, we performed an evaluation of recently published information.

Gliosarcoma con diferenciación epitelial. Reporte de un caso y revisión de la literatura / gliosarcoma with epithelial differentiation. Case report and literature review

El gliosarcoma es una neoplasia del sistema nervioso central de la cual se desconocen la mayoría de sus aspectos debido a su rara presentación. Presentamos el caso de un paciente de 19 años con diagnóstico de meduloblastoma que fue referido al INEN para recibir tratamiento de quimioterapia recurrente con radioterapia. La resonancia magnética realizada en dicha institución mostró una lesión sólida multilobulada heterogénea ubicada a nivel del cuarto ventrículo, con un di metro longitudinal de 4x 4,5 x 5cm, de aspecto maligno, neoformativo y con dos formaciones quísticas menores de 2 cm. A la espectroscopia por resonancia magnética (ERM), la relación de NAA/CR, fue 1,04. La revisión de l minas y análisis inmunohistoquímico dio como resultado GFAP (+), CD99 (+/-), S100 (+/-), CD56 (+/-), sinaptofisina(-), Bcl2 (-), NF(-), EMA(-), CD34(-), SMA(-), desmina(-) y Ki67: 20%. Además, se encontraron depósitos intercelulares de reticulina lo cual indicó la presencia de GSM. Recibió tratamiento con radioterapia seguido de temozolamida por 7 cursos, alcanzando una reducción del tratamiento tumoral en un 20%. A la fecha del reporte, se encuentra con enfermedad estable, en observación. AU)

The GSM is a malignancy of the CNS, most of its rare presentation. We present the case of a 19 year old women who had undergone cranial trepanation diagnosed as medulloblastoma. The patient was referred to INEN for receiving treatment with no results. The magnetic resonance images showed a solid heterogeneous multilobulated lesion localized in the 4th ventricle, multilobulated lesion localized in the 4th ventricle, with a longitudinal diameter of 4,5 x 4 x 5cm, with a malignant aspect, neoformative and with two cysts under 2 cm. To the spectroscopy (ERM), the relation NAA/CR was 1,04 revision of biopsy slides the inmunohistochemisty results were GFAP (+) , CD99 (+/-) , S100 (+ /-) , CD56 (+/-), sinaptopfisin (-), bcl2 (-), NF (-), EMA(-), CD34(-), EMA(-), CD34 (-), SMA(-), desmin(-) and Ki67: 20%. Besides, there were fou d intracellular reticulin deposits, this demonstrated the presence of GSM. The patient received treatment with radiotherapy followed by 7 courses of temozolomide, reaching a tumor size reduction of 20%. To the report’s date the patient has a stable disease condition continues with observation.