Browsing by Author "Castillo, M"

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Apoptosis Pathway–Associated Proteins Are Frequently Expressed in Melanoma: A Study of 32 Cases With Focus on Acral Lentiginous Melanoma
(Lippincott Williams and Wilkins, 2024) Ledesma, DA; Marques-Piubelli, ML; Li-Ning-Tapia, E; Hudgens, C; Gu, J; Lazcano, R; Casavilca-Zambrano, S; Castillo, M; Davies, MA; Hwu, W-J; Aung, PP; Giubellino, A; Curry, JL; Torres-Cabala, C
Acral lentiginous melanoma (ALM) is an aggressive type of cutaneous melanoma (CM) that arises on palms, soles, and nail units. ALM is rare in White population, but it is relatively more frequent in dark-skinned populations. There is an unmet need to develop new personalized and more effective treatments strategies for ALM. Increased expression of antiapoptotic proteins (ie, BCL2, MCL1) has been shown to contribute to tumorigenesis and therapeutic resistance in multiple tumor types and has been observed in a subset of ALM and mucosal melanoma cell lines in vivo and in vitro. However, little is known about their expression and clinical significance in patients with ALM. Thus, we assessed protein expression of BCL2, MCL1, BIM, and BRAF V600E by immunohistochemistry in 32 melanoma samples from White and Hispanic populations, including ALM and non-ALM (NALM). BCL2, MCL1, and BIM were expressed in both ALM and NALM tumors, and no significant differences in expression of any of these proteins were detected between the groups, in our relatively small cohort. There were no significant associations between protein expression and BRAF V600E status, overall survival, or ethnicity. In summary, ALM and NALM demonstrate frequent expressions of apoptosis-related proteins BCL2, MCL1, and BIM. Our findings suggest that patients with melanoma, including ALM, may be potential candidates for apoptosis-directed therapies.
Association between Helicobacter pylori infection, mismatch repair, HER2 and tumor-infiltrating lymphocytes in gastric cancer
(Baishideng Publishing Group Inc, 2024) Castaneda, CA; Castillo, M; Bernabe, LA; Sanchez, J; Fassan, M; Tello, K; Wistuba, II; Passiuri, IC; Ruiz, E; Sanchez, J; Barreda, F; Valdivia, D; Bazan, Y; Abad-Licham, M; Mengoa, C; Fuentes, H; Montenegro, P; Poquioma, E; Alatrista, R; Flores, CJ; Taxa, L
BACKGROUND The influence of Helicobacter-pylori (H. pylori) infection and the characteristics of gastric cancer (GC) on tumor-infiltrating lymphocyte (TIL) levels has not been extensively studied. Analysis of infiltrating-immune-cell subtypes as well as survival is necessary to obtain comprehensive information. AIM To determine the rates of deficient mismatch-repair (dMMR), HER2-status and H. pylori infection and their association with TIL levels in GC. METHODS Samples from 503 resected GC tumors were included and TIL levels were evaluated following the international-TILs-working-group recommendations with assessment of the intratumoral (IT), stromal (ST) and invasive-border (IB) compartments. The density of CD3, CD8 and CD163 immune cells, and dMMR and HER2-status were determined by immunohistochemistry (IHC). H. pylori infection was evaluated by routine histology and quantitative PCR (qPCR) in a subset of samples. RESULTS dMMR was found in 34.4%, HER2+ in 5% and H. pylori-positive in 55.7% of samples. High IT-TIL was associated with grade-3 (P = 0.038), while ST-TIL with grade-1 (P < 0.001), intestinal-histology (P < 0.001) and no-recurrence (P = 0.003). dMMR was associated with high TIL levels in the ST (P = 0.019) and IB (P = 0.01) compartments, and STCD3 (P = 0.049) and ST-CD8 (P = 0.05) densities. HER2-was associated with high IT-CD8 (P = 0.009). H. pylorinegative was associated with high IT-TIL levels (P = 0.009) when assessed by routine-histology, and with high TIL levels in the 3 compartments (P = 0.002-0.047) and CD8 density in the IT and ST compartments (P = 0.001) when assessed by qPCR. A longer overall survival was associated with low IT-CD163 (P = 0.003) and CD8/CD3 (P = 0.001 in IT and P = 0.002 in ST) and high IT-CD3 (P = 0.021), ST-CD3 (P = 0.003) and CD3/CD163 (P = 0.002). CONCLUSION TIL levels were related to dMMR and H. pylori-negativity. Low CD8/CD3 and high CD163/CD3 were associated with lower recurrence and longer survival.
Biological characteristics of a sub-population of cancer stem cells from two triple-negative breast tumour cell lines
(Heliyon, 2021) Enciso-Benavides, J; Alfaro, L; Castañeda-Altamirano, C; Rojas, N; Gonzalez-Cabeza, J; Enciso, N; Riesco, F; Castillo, M; Enciso, J
Triple-negative breast tumours (TNBTs) make up 15-20% of all breast tumours. There is no treatment for them, and the role that cancer stem cells (CSCs) have in carcinogenesis is still unclear, so finding markers and therapeutic targets in CSC exosomes requires these cells to exist as a homogeneous cell population. The objective of this work was to determine differences in ultrastructural morphology, proliferative capacity, and mouse-xenotransplantation characteristics of the MDA-MB-231 and MDA-MB-436 TNBT cell lines with the CD44 high /CD24 low phenotype in order to study their exosomes. The results show that the CD44 high /CD24 low MBA-MB-231 cells had a population doubling time of 41.56 h, compared to 44.79 h in the MDA-MB-436 cell line. After magnetic immunoseparation, 18.75% and 14.56% of the stem cell population of the MDA-MB-231 and MDA-MB-436 cell lines, respectively, were of the CD44 high /CD24 low phenotype, which were expanded to reach purities of 80.4% and 87.6%. The same expanded lineage in both cell lines was shown to possess the pluripotency markers Nanog and Oct4. Under a scanning electron microscope, the CD44 high /CD24 low lineage of the MBA-MD-231 cell line formed groups of more interconnected cells than this lineage of the MBA-MD-436 line. A total of 16% of the mice inoculated with the CD44 high /CD24 low lineage of either cell line presented tumours of the breast, lung, and submandibular ganglia, in whose tissues variable numbers of inoculated cells were found 30 days post-inoculation. By magnetic immunoselection, it was possible to isolate in similar quantities and characterize, expand, and xenotransplant the CD44 high /CD24 low lineage of the MDA-MB-231 and MDA-MB-436 cell lines. The former cell line has greater proliferative capacity, the two lines differ under scanning electron microscopy in how they intercommunicate, and both cell lines induce new tumours in mice and persist at least 30 days post-inoculation in the transplanted animal so their exosomes would also be different.
Clinicopathological features associated with CD44 and CD63 expression in breast cancer
(ecancer Global Foundation, 2024) Castaneda, CA; Castillo, M; Sanchez, J; Bernabe, L; Tello, K; Suarez, N; Alatrista, R; Quiroz-Gil, X; Granda-Oblitas, A; Enciso, J; Enciso, N; Gomez, HL
Background: CD44 is a cell-surface transmembrane glycoprotein that participates in the regulation of many cellular processes, including cell division, adhesion, migration and stem-like characteristics. CD63 is involved in the exocytosis process. Objective: To evaluate the relationship between CD44 and CD63 expression and clinicopathological features, including tumor-infiltrating lymphocytes (TILs), phosphoinositide 3-kinase (PIK3CA) mutation and survival. Methodology: CD44 and CD63 were stained in samples from 101 breast cancer cases from Peruvian women. Results: Median age was 52 years, most were most were grade-3 (68%), estrogen receptor (ER)+ (64%) and stage II-III (92%). Median ki67 was 30%, median stromal TIL was 30% and PIK3CA mutation was found in 49%. Longer survival was associated with earlier stages (p = 0.016), lower ki67 (p = 0.023), ER+ (p = 0.034), luminal phenotype (p = 0.029) and recurrence (p < 0.001). CD44 was classified as high cell density staining in 57% and high intensity in 55%. High CD44 density was associated with younger age (p = 0.043), triple-negative phenotype (p = 0.035) and shorter survival (p = 0.005). High CD44 expression was associated with short survival (p = 0.005). High CD63 cell density was found in 56% of cases and was associated with ER-positive (p = 0.045), low TIL levels (p = 0.007), Luminal-A (p = 0.015) and low CD44 intensity (p = 0.032). Conclusion: CD44 expression was associated with aggressive features and low CD63 density staining.
Clinicopathological predictors of long-term benefit in breast cancer treated with neoadjuvant chemotherapy
(Baishideng Publishing Group, 2018) Galvez, M; Castaneda, CA; Sanchez, J; Castillo, M; Rebaza, LP; Calderon, G; Cruz, M; Cotrina, JM; Abugattas, J; Dunstan, J; Guerra, H; Mejia, O; Gomez, HL
Aim: To investigate the survival impact of clinicopathological factors, including pathological complete response (pCR) and tumor-infiltrating lymphocytes (sTIL) levels according to subtypes, in breast cancer (BC) patients who received neo-adjuvant chemotherapy (NAC). Methods: We evaluated 435 BC patients who presented and received NAC at the Instituto Nacional de Enfermedades Neoplasicas from 2003 to 2014. sTIL was analyzed as the proportion of tumor stroma occupied by lymphocytes, and was prospectively evaluated on hematoxylin and eosin-stained sections of the preNAC core biopsy. pCR was considered in the absence of infiltrating cancer cells in primary tumor and axillary lymph nodes. Analysis of statistical association between clinical pathological features, sTIL, pCR and survival were carried out using SPSSvs19. Results: Median age was 49 years (range 24-84 years) and the most frequent clinical stage was IIIB (58.3%). Luminal A, Luminal B, HER2-enriched and (triple-negative) TN phenotype was found in 24.6%, 37.9%, 17.7% and 19.8%, respectively. pCR was observed in 11% and median percentage of sTIL was 40% (2%-95%) in the whole population. pCR was associated to Ct1-2 (P = 0.045) and to high sTIL (P = 0.029) in the whole population. There was a slight trend towards significance for sTIL (P = 0.054) in Luminal A. sTIL was associated with grade III (P < 0.001), no-Luminal A subtype (P < 0.001), RE-negative (P < 0.001), PgR-negative (P < 0.001), HER2-positive (P = 0.002) and pCR (P = 0.029) in the whole population. Longer disease-free survival was associated with grade I-II (P = 0.006), cN0 (P < 0.001), clinical stage II (P = 0.004), ER-positive (P < 0.001), PgR-positive (P < 0.001), luminal A (P < 0.001) and pCR (P = 0.002). Longer disease-free survival was associated with grade I-II in Luminal A (P < 0.001), N0-1 in Luminal A (P = 0.045) and TNBC (P = 0.01), clinical stage II in Luminal A (P = 0.003) and TNBC (P = 0.038), and pCR in TNBC (P < 0.001). Longer overall survival was associated with grade I-II (P < 0.001), ER-positive (P < 0.001), PgR-positive (P < 0.001), Luminal A (P < 0.001), cN0 (P = 0.002) and pCR (P = 0.002) in the whole population. Overall survival was associated with clinical stage II (P = 0.017) in Luminal A, older age (P = 0.042) in Luminal B, and pCR in TNBC (P = 0.005). Conclusion: Predictive and prognostic values of clinicopathological features, like pCR and sTIL, differ depending on the evaluated molecular subtype.
Gene content, phage cycle regulation model and prophage inactivation disclosed by prophage genomics in the Helicobacter pylori Genome Project
(Taylor and Francis Ltd., 2024) Vale, FF; Roberts, RJ; Kobayashi, I; Camargo, MC; Rabkin, CS; Wang, D; Hicks, B; Zhu, B; Yeager, M; Hutchinson, A; Teshome, K; Jones, K; Luo, W; Goldstein, AM; Hu, N; Taylor, PR; Song, M; Gutiérrez-Escobar, AJ; Yu, K; Abnet, CC; Chanock, SJ; Romero-Gallo, J; Krishna, U; Peek, RM; Piazuelo, MB; Wilson, KT; Loh, JT; Cover, TL; Raaf, N; Aftab, H; Akada, J; Matsumoto, T; Yamaoka, Y; Haesebrouck, F; Bartelli, TF; Nunes, DN; Pelosof, A; Sztokfisz, CZ; Dias-Neto, E; Assumpção, PP; Tishkov, I; Goodman, KJ; Geary, J; Cromarty, TJ; Price, NL; Quilty, D; Corvalan, AH; Serrano, CA; Gonzalez, R; Riquelme, A; García-Cancino, A; Parra-Sepúlveda, C; Castillo, F; Bravo, MM; Pazos, A; Bravo, LE; Fox, JG; Ramírez-Mayorga, V; Molina-Castro, S; Durán-Bermúdez, S; Campos-Núñez, C; Chaves-Cervantes, M; Tshibangu-Kabamba, E; Tumba, GD; Tshimpi-Wola, A; de Jesus Ngoma-Kisoko, P; Ngoyi, DM; Cruz, M; Hosking, C; Abreu, JJ; Varon, C; Benejat, L; Jehanne, Q; Lehours, P; Megraud, F; Secka, O; Link, A; Malfertheiner, P; Adinortey, MB; Bockarie, AS; Adinortey, CA; Ofori, EG; Sgouras, DN; Martinez-Gonzalez, B; Michopoulos, S; Georgopoulos, S; Hernandez, E; Dominguez, RL; Morgan, DR; Harðardóttir, H; Gunnarsdóttir, AI; Guðjónsson, H; Jónasson, JG; Björnsson, ES; Ballal, M; Shetty, V; Miftahussurur, M; Sugihartono, T; Alfaray, RI; Waskito, LA; Fauzia, KA; Syam, AF; Maulahela, H; Malekzadeh, R; Sotoudeh, M; Peretz, A; Azrad, M; On, A; De, Re, V; Zanussi, S; Cannizzaro, R; Canzonieri, V; Shimura, T; Tokunaga, K; Osaki, T; Kamiya, S; Jadallah, K; Matalka, I; Sagynbekuly, IN; Moldobaeva, MS; Rakhat, A; Choi, IJ; Kim, JG; Kim, N; Leja, M; Vangravs, R; Šķenders, Ģ; Rūdule, A; Kikuste, I; Vanags, A; Rudzīte, D; Kupcinskas, J; Skieceviciene, J; Jonaitis, L; Kiudelis, G; Jonaitis, P; Kiudelis, V; Varkalaite, G; Vadivelu, J; Loke, MF; Vellasamy, KM; Herrera-Goepfert, R; Alonso-Larraga, JO; Yee, TT; Htet, K; Matsuhisa, T; Shrestha, PK; Ansari, S; Abiodun, O; Jemilohun, C; Akande, KO; Olu-Abiodun, O; Magaji, FA; Omotoso, A; Okonkwo, U; Osuagwu, CC; Owoseni, OO; Castaneda, C; Castillo, M; Velapatino, B; Gilman, RH; Krzyżek, P; Gościniak, G; Pawełka, D; Korona-Glowniak, I; Cichoz-Lach, H; Oleastro, M; Figueiredo, C; Machado, JC; Ferreira, RM; Bordin, DS; Livzan, MA; Tsukanov, VV; Tan, P; Yeoh, KG; Zhu, F; Ally, R; Haas, R; Fischer, W; Montes, M; Fernández-Reyes, M; Tamayo, E; Lizasoain, J; Bujanda, L; Lario, S; Ramírez-Lázaro, MJ; Calvet, X; Brunet-Mas, E; Domper-Arnal, MJ; García-Mateo, S; Abad-Baroja, D; Delgado-Guillena, P; Moreira, L; Botargues, J; Pérez-Martínez, I; Barreiro-Alonso, E; Flores, V; Gisbert, JP; Muro, EA; Linares, P; Alcoba, L; Martin, V; Fleitas-Kanonnikoff, T; Altayeb, HN; Engstrand, L; Enroth, H; Keller, PM; Wagner, K; Pohl, D; Lee, Y-C; Liou, J-M; Wu, M-S; Kocazeybek, B; Sarıbas, S; Tasçı, İ; Demiryas, S; Kepil, N; Quiel, L; Villagra, M; Norton, M; Johnson, D; Huang, RJ; Hwang, JH; Szymczak, W; Rajagopalan, S; Asare, E; Jacobs, WR; In, H; Bollag, R; Lopez, A; Kruse, EJ; White, J; Graham, DY; Lane, C; Gao, Y; Gold, BD; Cruz-Correa, M; González-Pons, M; Rodriguez, LM; Tuan, VP; Dung, HDQ; Binh, TT; Trang, TTH; Van, Khien, V; Chen, X; Zhao, Y; Raley, C; Kessing, B; Tran, B; Katsura, Y; Gonzalez-Hormazabal, P; Didelot, X; Sheppard, S; Tarazona-Santos, E; Zamudio, R; Mariño-Ramírez, L; Backert, S; Naumann, M; Smet, A; Berg, DE; Chiner-Oms, Á; Comas, I; Martínez-Martínez, FJ; Yahara, K; Blaser, MJ; Vincze, T; Morgan, RD; Dekker, JP; Torres, J; Noureen, M; Cherry, JL; Osada, N; Fukuyo, M; Arita, M; Sandoval-Motta, S; Agostini, RB; Ghirotto, S; Muñoz-Ramírez, ZY; Torres, RC; Falush, D; Thorell, K; Uchiyama, I
Prophages can have major clinical implications through their ability to change pathogenic bacterial traits. There is limited understanding of the prophage role in ecological, evolutionary, adaptive processes and pathogenicity of Helicobacter pylori, a widespread bacterium causally associated with gastric cancer. Inferring the exact prophage genomic location and completeness requires complete genomes. The international Helicobacter pylori Genome Project (HpGP) dataset comprises 1011 H. pylori complete clinical genomes enriched with epigenetic data. We thoroughly evaluated the H. pylori prophage genomic content in the HpGP dataset. We investigated population evolutionary dynamics through phylogenetic and pangenome analyses. Additionally, we identified genome rearrangements and assessed the impact of prophage presence on bacterial gene disruption and methylome. We found that 29.5% (298) of the HpGP genomes contain prophages, of which only 32.2% (96) were complete, minimizing the burden of prophage carriage. The prevalence of H. pylori prophage sequences was variable by geography and ancestry, but not by disease status of the human host. Prophage insertion occasionally results in gene disruption that can change the global bacterial epigenome. Gene function prediction allowed the development of the first model for lysogenic-lytic cycle regulation in H. pylori. We have disclosed new prophage inactivation mechanisms that appear to occur by genome rearrangement, merger with other mobile elements, and pseudogene accumulation. Our analysis provides a comprehensive framework for H. pylori prophage biological and genomics, offering insights into lysogeny regulation and bacterial adaptation to prophages. © 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.
Human Papillomavirus, Cytomegalovirus Infection and P16 Staining in Breast Tumors from Peruvian Women
(Asian Pacific Organization for Cancer Prevention, 2022) Calderon-Valencia, G; Castaneda-Altamirano, C; Castillo, M; Sanchez, J; Bernabe, L; Suarez, N; Tello, K; Torres, E; Cotrina-Concha, JM; Dunstan Yataco, J; De-La-Cruz-Sacasqui, M; Abugattas Saba, J; Guerra Miler, H; Manrique Hinojosa, E; Aguayo, F; Gomez Moreno, HL
Objective: To evaluate the frequency distribution of viral infections in Peruvian Breast Cancer (BC) lesions and its association with clinicopathological features. Additionally, a prospective evaluation of p16 and Tumor-infiltrating lymphocytes (TIL) levels were performed for developing a comprehensive analysis. Methods: Detection of high risk- human papillomavirus (HR- HPV) through qPCR was performed in 447 BC and 79 non-cancer frozen samples. Paired paraffin samples from 238 BC were stained with Human cytomegalovirus (HCMV) and p16 immunohistochemistry. TIL was calculated in 397 BC cases. Results: HCMV was positive in 72.5%. HR- HPV was detected in 2.9% of BC and 1.3% of non-malignant samples. P16+ was found in 28.15% and median TIL percentage was 30. HR- HPV infection was associated with non-ductal histology (p=0.003) and p16+ (p=0.017). Positive P16+ was associated with higher T stage (p=0.022), grade (p=0.009), TIL level (p=0.002), and triple-negative phenotype (p=0.021). Conclusion: HCMV is frequent, but HR- HPV infection is unusual in Peruvian BC. P16+ is associated with HR- PVH infection, high TIL and aggressive features. © 2022. All Rights Reserved.
MGMT promoter methylation in Peruvian patients with glioblastoma
(Cancer Intellilgence, 2018) Belmar-Lopez, C; Castaneda, CA; Castillo, M; García-Corrochano, P; Orrego, E; Meléndez, B; Casavilca, S; Flores, C; Orrego, E
Purpose: O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation predicts the outcome and response to alkylating chemotherapy in glioblastoma. The aim of this study is to evaluate the prevalence of MGMT methylation in Peruvian glioblastoma cases. Patients and methods: We evaluated retrospectively 50 cases of resected glioblastoma during the period 2008-2013 at Instituto Nacional de Enfermedades Neoplasicas in Peru. Samples consisted of paraffin embedded and frozen tumour tissue. MGMT-promoter methylation status and the expression level of MGMT gene were evaluated by methylation-specific PCR and real-time PCR, respectively. Results: Unmethylated, methylated and partially methylated statuses were found in 54%, 20% and 26% of paraffin-embedded samples, respectively. Methylation status was confirmed in the Virgen de la Salud Hospital and frozen samples. There was an association between the status of MGMT-promoter methylation and the level of gene expression (p = 0.001). Methylation was associated with increased progression-free survival (p = 0.002) and overall survival (OS) (p < 0.001). Conclusion: MGMT-promoter methylation frequency in Peruvian glioblastoma is similar to that reported in other populations and the detection test has been standardised.
Prognostic factors for patients with newly diagnosed brain metastasis from breast cancer
(Future Medicine Ltd., 2015) Castaneda, Carlos; Flores, R; Castillo, Miluska; Rojas, KY; Castillo, M; Dolores-Cerna, K; Flores, C; Belmar-Lopez, C; Milla, E; Gomez, HL
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.
Prognostic implications of residual disease tumor-infiltrating lymphocytes and residual cancer burden in triple-negative breast cancer patients after neoadjuvant chemotherapy
(Elsevier Ltd., 2019) Luen, SJ; Salgado, R; Dieci, MV; Vingiani, A; Curigliano, G; Gould, RE; Castaneda, C; D'Alfonso, T; Sanchez, J; Cheng, E; Andreopoulou, E; Castillo, M; Adams, S; Demaria, S; Symmans, WF; Michiels, S; Lo,i S
Background: For primary triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC), higher pretreatment tumor-infiltrating lymphocytes (TILs) correlates with increased pathologic complete response (pCR) rates, and improved survival. We evaluated the added prognostic value of residual disease (RD) TILs to residual cancer burden (RCB) in predicting survival post-NAC. Patients and methods: We combined four TNBC NAC patient cohorts who did not achieve pCR. RD TILs were investigated for associations with recurrence-free survival (RFS), and overall survival (OS) using Cox models with stromal TILs as a continuous variable (per 10% increment). The likelihood ratio test was used to evaluate added prognostic value of RD TILs. Results: A total of 375 RD TNBC samples were evaluable for TILs and RCB. The median age was 50 years, with 62% receiving anthracycline/taxane chemotherapy. The RCB class after NAC was 11%, 50%, and 39% for I, II, and III, respectively. The median RD TIL level was 20% (IQR 10-40). There was a positive correlation between RD TIL levels and CD8+ T-cell density (ρ = 0.41). TIL levels were significantly lower with increasing post-NAC tumor (P = 0.005), nodal stage (P = 0.032), but did not differ by RCB class (P = 0.84). Higher RD TILs were significantly associated with improved RFS (HR: 0.86; 95% CI 0.79-0.92; P < 0.001), and improved OS (HR: 0.87; 95% CI 0.80-0.94; P < 0.001), and remained significant predictors in multivariate analysis (RFS P = 0.032; OS P = 0.038 for OS). RD TILs added significant prognostic value to multivariate models including RCB class (P < 0.001 for RFS; P = 0.021 for OS). The positive prognostic effect of RD TILs significantly differed by RCB class for RFS (PInt=0.003) and OS (PInt=0.008) with a greater magnitude of positive effect observed for RCB class II than class III. Conclusions: TIL levels in TNBC RD are significantly associated with improved RFS and OS and add further prognostic information to RCB class, particularly in RCB class II.
The Helicobacter pylori Genome Project: insights into H. pylori population structure from analysis of a worldwide collection of complete genomes
(Nature Research, 2023) Thorell, K; Muñoz-Ramírez, ZY; Wang, D; Sandoval-Motta, S; Boscolo-Agostini, R; Ghirotto, S; Torres, RC; Romero-Gallo, J; Krishna, U; Peek, RM; Piazuelo, MB; Raaf, N; Bentolila, F; Aftab, H; Akada, J; Matsumoto, T; Haesebrouck, F; Colanzi, RP; Bartelli, TF; Castaneda, C; Castillo, M; Velapatino, B; Gilman, RH; Krzyżek, P; Gościniak, G; Pawełka, D; Korona-Glowniak, I; Cichoz-Lach, H; Oleastro, M; Figueiredo, C; Machado, JC; Ferreira, RM; Bordin, DS; Camargo, MC; Rabkin, CS
Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We found evidence of substantial contribution of population hpNorthAsia and subpopulation hspUral in Northern European H. pylori. The genomes of H. pylori isolated from northern and southern Indigenous Americans differed in that bacteria isolated in northern Indigenous communities were more similar to North Asian H. pylori while the southern had higher relatedness to hpEastAsia. Notably, we also found a highly clonal yet geographically dispersed North American subpopulation, which is negative for the cag pathogenicity island, and present in 7% of sequenced US genomes. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics.
The relationship between tumour infiltrating lymphocytes, Epstein–Barr virus and Helicobacter pylori infection in gastric cancer
(ecancer Global Foundation, 2022) Castañeda, C; Castillo, M; Bernabe, L; Suarez, N; Fassan, M; Sanchez, J; Tello, K; Alatrista, R; Chavez-Pasiuri, I; Ruiz-figueroa, E; Bazan, Y; Barreda, F; Valdivia, D; Meng, W; Chakravarti, A; Sanchez, J; Taxa Rojas, L; Montenegro, P
Objective: Epstein–Barr virus (EBV) and Helicobacter pylori (HP) infections have been extensively recognised as gastric cancer (GC) triggers, and recent publications suggest they could behave as predictive markers for immune-modulating therapies. Tumour-infiltrating lymphocytes (TILs) have also been identified as a predictive biomarker for immunotherapy in different malignancies. This study aimed to investigate the association between EBV and HP infection with TIL levels in GC. Methods: TIL evaluation in haematoxylin-eosin was performed by a pathologist and density of CD3, CD8 and CD163 positive (immunohistochemistry staining) immune cells was calculated with the use of digital pathology software. EBV infection was detected by in situ hybridisation (ISH) and by quantitative polymerase chain reaction (qPCR). Methylation status of EBV-related genes was detected by PCR and a methylome analysis was performed by the Illumina Infinium MethylationEPIC BeadChip. HP status was detected by qPCR. Results: We included 98 resected GC Peruvian cases in our evaluation. Median TIL percentage was 30. The proportion of EBV+ detected by ISH was 24.1%, of EBV+ detected by qPCR was 41.8%, while 70% showed methylation of EBV-related genes, and 58.21% of cases were HP+. Younger age (p = 0.024), early stages (p = 0.001), HP+ (p = 0.036) and low CD8 density (p = 0.046) were associated with longer overall survival (OS). High TIL level was associated with intestinal subtype (p < 0.001), with grade 2 (p < 0.001), with EBV qPCR+ (p = 0.001), and with methylation of EBV-related genes (p = 0.007). Cases with high TIL level and cases that are EBV positive share eight genes with similarly methylated status in the metabolomic analysis. High CD8 density was associated with EBV PCR+ (p = 0.012) and HP− (0.005). Conclusion: Lower CD8 density and HP+ predict longer OS. High TIL level is associated with EBV+ and methylation of EBV-related genes, while lower CD8 density is associated with HP+ GC. Copyright: © the authors
The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group
(Nature Publishing Group, 2021) El Bairi, K; Haynes, HR; Blackley, E; Fineberg, S; Shear, J; Turner, S; de Freitas, JR; Sur, D; Amendola, LC; Gharib, M; Kallala, A; Arun, I; Azmoudeh-Ardalan F; Fujimoto, L; Sua, LF; Liu, SW; Lien, HC; Kirtani, P; Balancin, M; El Attar, H; Guleria, P; Yang WShash, E; Chen, IC; Bautista, V; Do Prado Moura, JF; Rapoport, BL; Castaneda, C; Spengler, E; Acosta-Haab, G; Frahm, I; Sanchez, J; Castillo, M; Bouchmaa, N; Md Zin, RR; Shui, R; Onyuma, T; Yang, W; Husain, Z; Willard-Gallo, K; Coosemans, A; Perez, EA; Provenzano, E; Ericsson, PG; Richardet, E; Mehrotra, R; Sarancone, S; Ehinger, A; Rimm, DL; Bartlett, JMS; Viale, G; Denkert, C; Hida, AI; Sotiriou, C; Loibl, S; Hewitt, SM; Badve, S; Symmans, WF; Kim, RS; Pruneri, G; Goel, S; Francis, PA; Inurrigarro, G; Yamaguchi, R; Garcia-Rivello, H; Horlings, H; Afqir, S; Salgado, R; Adams, S; Kok, M; Dieci, MV; Michiels, S; Demaria S; Loi, S; International Immuno-Oncology Biomarker Working Group
The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.