Clinicopathological features associated with CD44 and CD63 expression in breast cancer.

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.

Complicated Appendicitis Associated With Appendiceal Mucinous Neoplasm Within Amyand's Hernia in a Patient With Previous Hernia Repair: A Case Report and Literature Review.

Amyand's hernia is defined as the presence of the appendix within an inguinal hernia sac, which is often associated with appendicitis. The association of an Amyand's hernia with an appendicular tumor has been reported in very few cases. This case report presents a 67-year-old female patient who came to the emergency department with symptoms indicative of a complicated inguinal hernia. Following surgical treatment, the diagnosis of Amyand's hernia with cecal perforation associated with an appendicular tumor was established in the context of a previous laparoscopic femoral hernia repair. The combination of these conditions has not been previously reported. The presentation of this case provides data on the clinical presentation, diagnosis, and treatment of this rare pathology that requires a high clinical suspicion to achieve a preoperative diagnosis.

Subcutaneous Trastuzumab: An Observational Study of Safety and Tolerability in Patients With Early HER2-Positive Breast Cancer.

Purpose: In Peru, breast cancer (BC) stands as the most predominant malignancy neoplasm among women. Trastuzumab has marked a significant milestone in the management of this disease. It has been shown to improve prognosis in human epidermal growth factor receptor 2 (HER2)-expressing female patients, but its repercussions and efficacy are yet to be analyzed in a context with limited resources. Methods: The study population is made of woman patients aged 18 years and older diagnosed with HER2-positive BC at Instituto Nacional de Enfermedades Neoplásicas (INEN, Lima, Peru) during 2019-2021 and treated with at least one dose of subcutaneous trastuzumab. We reviewed medical records to register treatment characteristics, adverse events (AEs), disease progression, and survival status. We considered a median follow-up time of 36 and 45 months for progression and survival status. Results: The majority of patients were over 50 years old (54.29%). Tumor size averaged 19.7 ± 16.1 mm. Lymph nodes were present in 44.78% of patients. Most patients received adjuvant chemotherapy (63.8%) as first-line treatment. Descriptive analyses of treatment outcomes revealed a 30% toxicity rate, primarily attributed to arthralgia (47.62%), followed by diarrhea, fatigue, and injection site reactions, with relatively lower discontinuation rates compared to larger scale studies. Differences in demographic, clinical, and treatment characteristics were not statistically significant concerning the emergence of AEs (p > 0.05). Progression appeared in nine patients, and the overall survival (OS) rate stood at 98.6% and 92.8%, respectively, during a median follow-up of 36 and 45 months. Conclusion: The research suggests that subcutaneous trastuzumab is comparable in effectiveness and safety to the intravenous administration. Regional-specific studies may provide valuable insights into demographic factors influencing treatment outcomes in Peru or other countries. Furthermore, it could represent a more accessible alternative, potentially enhancing patient adherence and optimizing healthcare resource logistics.

Association between Helicobacter pylori infection, mismatch repair, HER2 and tumor-infiltrating lymphocytes in gastric cancer.

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 ST-CD3 (P = 0.049) and ST-CD8 (P = 0.05) densities. HER2- was associated with high IT-CD8 (P = 0.009). H. pylori-negative 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.

Subpopulation treatment effect pattern plot analysis: a prognostic model for distant recurrence-free survival to estimate delayed adjuvant chemotherapy initiation effect in triple-negative breast cancer.

Introduction: Triple-negative breast cancer (TNBC) is a heterogeneous disease associated with a poor prognosis. Delaying in time to start adjuvant chemotherapy (TTC) has been related to an increased risk of distant recurrence-free survival (DRFS). We aimed to develop a prognostic model to estimate the effects of delayed TTC among TNBC risk subgroups. Materials and methods: We analyzed 687 TNBC patients who received adjuvant chemotherapy at the Instituto Nacional de Enfermedades Neoplasicas (Lima, Peru). Database was randomly divided to create a discovery set (n=344) and a validation set (n=343). Univariate and multivariate Cox regression models were performed to identify prognostic factors for DRFS. Risk stratification was implemented through two models developed based on proportional hazard ratios from significant clinicopathological characteristics. Subpopulation treatment effect pattern plot (STEPP) analysis was performed to determine the best prognostic cut-off points for stratifying TNBC subgroups according to risk scores and estimate Kaplan-Meier differences in 10-year DRFS comparing TTC (≤30 vs.>30 days). Results: In univariate analysis, patients aged ≥70 years (HR=4.65; 95% CI: 2.32-9.34; p=<0.001), those at stages pT3-T4 (HR=3.28; 95% CI: 1.57-6.83; p=0.002), and pN2-N3 (HR=3.00; 95% CI: 1.90-4.76; p=<0.001) were notably associated with higher risk. STEPP analysis defined three risk subgroups for each model. Model N°01 categorized patients into low (score: 0-31), intermediate (score:32-64), and high-risk (score: 65-100) cohorts; meanwhile, Model N°02: low (score: 0-26), intermediate (score: 27-55), and high (score: 56-100). Kaplan-Meier plots showed that in the discovery set, patients with TTC>30 days experienced a 17.5% decrease in 10-year DRFS rate (95%CI=6.7-28.3), and the impact was more remarkable in patients who belong to the high-risk subgroup (53.3% decrease in 10 years-DRFS rate). Similar results were found in the validation set. Conclusions: We developed two prognostic models based on age, pT, and pN to select the best one to classify TNBC. For Model N°02, delayed adjuvant chemotherapy conferred a higher risk of relapse in patients ≥70 years and who were characterized by pT3/T4 and pN2/N3. Thus, more efforts should be considered to avoid delayed TTC in TNBC patients, especially those in high-risk subgroups.

Polyubiquitin ligand-induced phase transitions are optimized by spacing between ubiquitin units.

Biomolecular condensates form via multivalent interactions among key macromolecules and are regulated through ligand binding and/or posttranslational modifications. One such modification is ubiquitination, the covalent addition of ubiquitin (Ub) or polyubiquitin chains to target macromolecules. Specific interactions between polyubiquitin chains and partner proteins, including hHR23B, NEMO, and UBQLN2, regulate condensate assembly or disassembly. Here, we used a library of designed polyubiquitin hubs and UBQLN2 as model systems for determining the driving forces of ligand-mediated phase transitions. Perturbations to either the UBQLN2-binding surface of Ub or the spacing between Ub units reduce the ability of hubs to modulate UBQLN2 phase behavior. By developing an analytical model based on polyphasic linkage principles that accurately described the effects of different hubs on UBQLN2 phase separation, we determined that introduction of Ub to UBQLN2 condensates incurs a significant inclusion energetic penalty. This penalty antagonizes the ability of polyUb hubs to scaffold multiple UBQLN2 molecules and cooperatively amplify phase separation. The extent to which polyubiquitin hubs promote UBQLN2 phase separation is encoded in the spacings between Ub units. This spacing is modulated by chains of different linkages and designed chains of different architectures, thus illustrating how the ubiquitin code regulates functionality via the emergent properties of the condensate. The spacing in naturally occurring linear polyubiquitin chains is already optimized to promote phase separation with UBQLN2. We expect our findings to extend to other condensates, emphasizing the importance of ligand properties, including concentration, valency, affinity, and spacing between binding sites in studies and designs of condensates.

The STOP Program: a Hybrid Smoking Prevention and Cessation Training for Cancer Care Providers in Colombia and Peru.

We designed and tested the feasibility of the Smoking Cessation Training Program for Oncology Practice (STOP), a hybrid (face-to-face plus web-based) educational intervention to enhance Spanish-speaking cancer care professionals' (CCPs') ability to provide brief smoking prevention and cessation counseling to cancer patients and survivors. Changes in the CCPs' competencies (knowledge, attitude, self-efficacy, and practices toward smoking and smoking cessation services) were assessed post-training. Sixty CCPs from one major cancer center in Colombia (n = 30) and Peru (n = 30) were invited to participate in a 4-module hybrid training program on smoking prevention and cessation. Demographic and pre- and post-test evaluation data were collected. The training's acceptability was measured after each module. Bivariate analysis was conducted using Wilcoxon signed-rank test to compare the CCPs' competencies before and after the delivery of the STOP Program. Effect sizes were computed over time to assess the sustainability of the acquired competencies. Twenty-nine CCPs in Colombia and 24 CCPs in Peru completed the STOP Program (96.6% and 80.0% retention rates, respectively). In both countries, 98.2% of the CCPs reported that the overall structure and organization of the program provided an excellent learning experience. The pre-post-test evaluations indicated that the CCPs significantly improved their knowledge, attitude, self-efficacy, and practices toward smoking, smoking prevention, and cessation services. We found that the CCPs' self-efficacy and practices increased over time (1-, 3-, and 6-month assessments after completing the 4 educational modules). The STOP Program was effective and well-received, demonstrating remarkable changes in CCPs' competencies in providing smoking prevention and cessation services to cancer patients.

Breast cancer subtype and clinical characteristics in women from Peru.

Introduction: Breast cancer is a heterogeneous disease, and the distribution of the different subtypes varies by race/ethnic category in the United States and by country. Established breast cancer-associated factors impact subtype-specific risk; however, these included limited or no representation of Latin American diversity. To address this gap in knowledge, we report a description of demographic, reproductive, and lifestyle breast cancer-associated factors by age at diagnosis and disease subtype for The Peruvian Genetics and Genomics of Breast Cancer (PEGEN-BC) study. Methods: The PEGEN-BC study is a hospital-based breast cancer cohort that includes 1943 patients diagnosed at the Instituto Nacional de Enfermedades Neoplásicas in Lima, Peru. Demographic and reproductive information, as well as lifestyle exposures, were collected with a questionnaire. Clinical data, including tumor Hormone Receptor (HR) status and Human Epidermal Growth Factor Receptor 2 (HER2) status, were abstracted from electronic medical records. Differences in proportions and mean values were tested using Chi-squared and one-way ANOVA tests, respectively. Multinomial logistic regression models were used for multivariate association analyses. Results: The distribution of subtypes was 52% HR+HER2-, 19% HR+HER2+, 16% HR-HER2-, and 13% HR-HER2+. Indigenous American (IA) genetic ancestry was higher, and height was lower among individuals with the HR-HER2+ subtype (80% IA vs. 76% overall, p=0.007; 152 cm vs. 153 cm overall, p=0.032, respectively). In multivariate models, IA ancestry was associated with HR-HER2+ subtype (OR=1.38,95%CI=1.06-1.79, p=0.017) and parous women showed increased risk for HR-HER2+ (OR=2.7,95%CI=1.5-4.8, p<0.001) and HR-HER2- tumors (OR=2.4,95%CI=1.5-4.0, p<0.001) compared to nulliparous women. Multiple patient and tumor characteristics differed by age at diagnosis (<50 vs. >=50), including ancestry, region of residence, family history, height, BMI, breastfeeding, parity, and stage at diagnosis (p<0.02 for all variables). Discussion: The characteristics of the PEGEN-BC study participants do not suggest heterogeneity by tumor subtype except for IA genetic ancestry proportion, which has been previously reported. Differences by age at diagnosis were apparent and concordant with what is known about pre- and post-menopausal-specific disease risk factors. Additional studies in Peru should be developed to further understand the main contributors to the specific age of onset and molecular disease subtypes in this population and develop population-appropriate predictive models for prevention.

A Spectrophotometric Turbidity Assay to Study Liquid-Liquid Phase Separation of UBQLN2 In Vitro.

Liquid-liquid phase separation (LLPS) is hypothesized to be the underlying mechanism for how membraneless organelles or biomolecular condensates form inside both prokaryotic and eukaryotic cells. Protein LLPS is a biophysical process during which proteins demix from homogeneous solution to form protein-dense droplets with liquid-like properties. Disruptions to LLPS, such as changes to material properties of condensates or physicochemical parameters for LLPS onset, are implicated in neurodegenerative diseases and cancer. Therefore, it is essential to determine the physicochemical parameters that promote protein LLPS. Here, we present our UV-Vis spectrophotometric turbidity assay to characterize the temperature and concentration dependence of LLPS for UBQLN2, a protein that undergoes LLPS via homotypic interactions in vitro and forms stress-induced condensates in cells. Mutations in UBQLN2 cause amyotrophic lateral sclerosis (ALS) and disrupt UBQLN2 LLPS. We present a detailed expression and purification protocol for a C-terminal construct of UBQLN2 and how we use microscopy to image UBQLN2 LLPS. We use our UV-Vis assay to construct temperature-concentration phase diagrams for wild-type and mutant UBQLN2 constructs to determine the effects of domain deletions and/or mutations on UBQLN2 phase separation.

The Surgical Safety Checklist from the resident's perspective. Observational study / La lista de cirugía segura desde la perspectiva del residente. Estudio observacional

Abstract Introduction The Surgical Safety Checklist implemented by the World Health Organization has proven to decrease perioperative morbidity and mortality; however, the barriers and limitations to its implementation are consistently reported in the literature. Objective To establish the level of appropriation of the surgical safety checklist in the training of human resources in anesthesiology, in addition to identifying the perception and the level of implementation of such checklist at the national scale. Methods Descriptive cross-sectional study conducted through a survey administered to the residents of anesthesiology in Colombia. Likert-type questions were included, distributed into three domains: appropriation, perception and implementation. Results 215 answers corresponding to 54.5 % of the population were analyzed, comprising participants from all of the anesthesiology programs in the country. 20% of the residents have never been subject to formal academic reviews about checklists, and this trend did not change throughout the residency; 97.2 % considers that the implementation of the lists improves the safety of surgical procedures and 40 % have seen rejection or indifference by surgeons. 80.5 % of the residents have seen the frequent use of the checklist, while only 13.5% have seen the use of the checklist during the three surgical moments - before the induction of anesthesia, before the surgical incision, and before the patient leaves the operating room 88 % have observed that the form is completed without actually doing the verification. Conclusions There is limited exposure to education about the surgical safety checklist in anesthesiology postgraduate programs in the country. The residents have a favorable perception about the value of the list, however, there are some shortcomings in its administration.

Resumen Introducción: La lista de verificación de cirugía segura implementada por la Organización Mundial de la Salud ha demostrado disminuir la morbimortalidad perioperatoria; no obstante, en la literatura se reportan de manera sistemática las barreras y limitaciones en su aplicación. Objetivo: Establecer el grado de apropiación de la lista de verificación de cirugía segura en la formación del talento humano en anestesiología en entrenamiento, así como determinar la percepción y el nivel de implementación de dicha lista a escala nacional. Métodos: Estudio descriptivo de corte transversal realizado mediante una encuesta a los residentes de anestesiología en Colombia. Se incluyeron preguntas tipo Likert distribuidas en 3 dominios: apropiación, percepción e implementación. Resultados: Se analizaron 215 respuestas correspondiente a un 54,5 % de la población y se contó con la participación de todos los programas de anestesiología del país. El 20 % de los residentes nunca ha tenido revisiones académicas formales sobre listas de verificación y esta tendencia no se modificó a lo largo de la residencia, el 97,2 % considera que la implementación de las listas incrementa la seguridad de los procedimientos quirúrgicos y el 40 % ha observado rechazo o indiferencia por parte de los cirujanos. El 80,5 % de los residentes ha observado su aplicación frecuente, solo el 13,5 % ha observado aplicar la lista en los tres momentos (antes de la inducción anestésica, antes de la incisión quirúrgica, antes de la salida del paciente del quirófano) y el 88 % ha observado diligenciar el formato sin realizar la verificación. Conclusiones: Existe poca exposición a la enseñanza de la lista de verificación de cirugía segura en los posgrados de anestesiología del país. Los residentes tienen una percepción favorable sobre la utilidad de la lista; sin embargo, su implementación tiene falencias en cuanto a la forma de aplicación.

Association between PIK3CA Mutations in Blood and Tumor-Infiltrating Lymphocytes in Peruvian Breast Cancer Patients.

OBJECTIVE: To evaluate the relationship between circulating tumor DNA (ctDNA) presence and tumor features including tumor-infiltrating lymphocyte (TIL) levels in Peruvian breast cancer patients. MATERIALS AND METHODS: This was a prospective study conducted at the Instituto Nacional de Enfemedades Neoplasicas, Peru. We evaluated level of TIL and PIK3CA mutations in ctDNA. Clinical characteristics, including outcome data, were collected from the patient file. Survival was calculated from the date of blood sample drawn to the event time. Data collected were analyzed using SPSS software version 25. RESULTS: We analyzed plasma samples from 183 breast cancer patients. most cases were of Luminal-B (44.8%) phenotype and stage II (41.5%), and median stromal TIL was 30%. PIK3CA mutation in ctDNA was detected in 35% cases (most with E545K) and was associated with lower TIL level (p=0.04). PIK3CA in ctDNA tended to be associated with advanced stages (p=0.09) in the whole series and with higher recurrence rates (p=0.053) in the non-metastatic setting. Patients with presence of PIK3CA in ctDNA tended to have shorter survival (p=0.083). CONCLUSION: Presence of PIK3CA mutation in ctDNA was frequently found in our Peruvian breast cancer series, was associated with lower TIL levels and tended to predict poor outcomes.

Mechanistic insights into enhancement or inhibition of phase separation by different polyubiquitin chains.

Ubiquitin-binding shuttle UBQLN2 mediates crosstalk between proteasomal degradation and autophagy, likely via interactions with K48- and K63-linked polyubiquitin chains, respectively. UBQLN2 comprises self-associating regions that drive its homotypic liquid-liquid phase separation (LLPS). Specific interactions between one of these regions and ubiquitin inhibit UBQLN2 LLPS. Here, we show that, unlike ubiquitin, the effects of multivalent polyubiquitin chains on UBQLN2 LLPS are highly dependent on chain types. Specifically, K11-Ub4 and K48-Ub4 chains generally inhibit UBQLN2 LLPS, whereas K63-Ub4, M1-Ub4 chains, and a designed tetrameric ubiquitin construct significantly enhance LLPS. We demonstrate that these opposing effects stem from differences in chain conformations but not in affinities between chains and UBQLN2. Chains with extended conformations and increased accessibility to the ubiquitin-binding surface promote UBQLN2 LLPS by enabling a switch between homotypic to partially heterotypic LLPS that is driven by both UBQLN2 self-interactions and interactions between multiple UBQLN2 units with each polyubiquitin chain. Our study provides mechanistic insights into how the structural and conformational properties of polyubiquitin chains contribute to heterotypic LLPS with ubiquitin-binding shuttles and adaptors.

Association between Ancestry-Specific 6q25 Variants and Breast Cancer Subtypes in Peruvian Women.

BACKGROUND: Breast cancer incidence in the United States is lower in Hispanic/Latina (H/L) compared with African American/Black or Non-Hispanic White women. An Indigenous American breast cancer-protective germline variant (rs140068132) has been reported near the estrogen receptor 1 gene. This study tests the association of rs140068132 and other polymorphisms in the 6q25 region with subtype-specific breast cancer risk in H/Ls of high Indigenous American ancestry. METHODS: Genotypes were obtained for 5,094 Peruvian women with (1,755) and without (3,337) breast cancer. Associations between genotype and overall and subtype-specific risk for the protective variant were tested using logistic regression models and conditional analyses, including other risk-associated polymorphisms in the region. RESULTS: We replicated the reported association between rs140068132 and breast cancer risk overall [odds ratio (OR), 0.53; 95% confidence interval (CI), 0.47-0.59], as well as the lower odds of developing hormone receptor negative (HR-) versus HR+ disease (OR, 0.77; 95% CI, 0.61-0.97). Models, including HER2, showed further heterogeneity with reduced odds for HR+HER2+ (OR, 0.68; 95% CI, 0.51-0.92), HR-HER2+ (OR, 0.63; 95% CI, 0.44-0.90) and HR-HER2- (OR, 0.77; 95% CI, 0.56-1.05) compared with HR+HER2-. Inclusion of other risk-associated variants did not change these observations. CONCLUSIONS: The rs140068132 polymorphism is associated with decreased risk of breast cancer in Peruvians and is more protective against HR- and HER2+ diseases independently of other breast cancer-associated variants in the 6q25 region. IMPACT: These results could inform functional analyses to understand the mechanism by which rs140068132-G reduces risk of breast cancer development in a subtype-specific manner. They also illustrate the importance of including diverse individuals in genetic studies.

The relationship between tumour infiltrating lymphocytes, Epstein-Barr virus and Helicobacter pylori infection in gastric cancer.

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.

Human Papillomavirus, Cytomegalovirus Infection and P16 Staining in Breast Tumors from Peruvian Women.

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.

Immunotherapy in triple-negative breast cancer: A literature review and new advances.

Triple-negative breast cancer (TNBC) is a highly complex, heterogeneous disease and historically has limited treatment options. It has a high probability of disease recurrence and rapid disease progression despite adequate systemic treatment. Immunotherapy has emerged as an important alternative in the management of this malignancy, showing an impact on progression-free survival and overall survival in selected populations. In this review we focused on immunotherapy and its current relevance in the management of TNBC, including various scenarios (metastatic and early -neoadjuvant, adjuvant-), new advances in this subtype and the research of potential predictive biomarkers of response to treatment.

Biomarkers of human papillomavirus (HPV)-driven head and neck cancer in Latin America and Europe study: Study design and HPV DNA/p16INK4a status.

BACKGROUND: Human papillomavirus (HPV)-driven head/neck squamous cell carcinomas (HNSCC) prevalence varies globally. We evaluated HPV DNA and p16INK4a in formalin fixed paraffin embedded (FFPE) HNSCC from Argentina, Brazil, Colombia, and Peru. METHODS: HPV was genotyped by PCR-hybridization. All HPV DNA positive and some HPV DNA negative cases underwent p16INK4a immunohistochemistry. RESULTS: HPV DNA was detected in 32.8%, 11.1%, and 17.8% of oropharyngeal (OPC), oral cavity (OCC) and laryngeal (LC) cancers, respectively. OPC HPV prevalence was higher in Colombia (94.7%), and Argentina (42.6%) compared to Brazil (10.6%) and Peru (0.0%). HPV-16 was the most detected. Other HPVs were found in LC. Higher rates of p16INK4a positivity were observed among HPV positive OPC/OCC cases compared to LC cases. CONCLUSIONS: Our results support a role for HPV-16 in a subset of HNSCC, corroborate the heterogeneity observed in samples from different countries, and contribute additional etiological and biomarkers information in tumors of significant impact worldwide.

The tale of TILs in breast cancer: A report from The 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.

A biomarker study in Peruvian males with breast cancer.

BACKGROUND: Breast cancer (BC) frequency in males is extremely low and tumor features vary from its female counterpart. Breast cancer clinical and pathological features differ by race in women. Tumor infiltrating lymphocyte (TIL) levels, mismatch repair (MMR) protein loss, androgen receptor (AR) expression, and PIK3CA gene mutations are predictive biomarkers of response to biological therapy in female BC. There is limited information about clinical and pathological features as well as predictive biomarkers in males of non-Caucasian races with BC. AIM: To investigate clinicopathological features and biomarkers of BC tumors in males and their prognostic value in Peruvian population. METHODS: This study looked at a single-institution series of 54 Peruvian males with invasive BC who were diagnosed from Jan 2004 to June 2018. Standard pathological features, TIL levels, MMR proteins, AR immunohistochemistry staining, and PIK3CA gene mutations were prospectively evaluated in cases with available paraffin material. Percentage of AR and estrogen receptor (ER) positive cells was additionally calculated by software after slide scanning. Statistical analyses included association tests, intraclass correlation test and Kaplan Meier overall survival curves. RESULTS: The median age was 63 years and most cases were ER-positive (85.7%), HER2 negative (87.2%), Luminal-A phenotype (60%) and clinical stage II (41.5%) among our male breast tumors. Median TIL was 10% and higher levels tended to be associated with Luminal-B phenotype and higher grade. AR-positive was found in 85.3% and was correlated with ER (intraclass index of 0.835, P < 0.001). Loss of MMR proteins was found in 15.4% and PIK3CA mutation (H1047R) in 14.3% (belonged to the Luminal-A phenotype). Loss of MMR proteins was associated with AR-negative (P = 0.018) but not with ER (P = 0.43) or TIL (P = 0.84). Early stages (P < 0.001) and lower grade (P = 0.006) were associated with longer overall survival. ER status, phenotype, AR status, TIL level, MMR protein loss nor PIK3CA mutation was not associated with survival (P > 0.05). CONCLUSION: Male BC is usually ER and AR positive, and Luminal-A. MMR loss and PIK3CA mutations are infrequent. Stage and grade predicted overall survival in our South American country population.

COVID-19 en pacientes con cáncer: revisión sistemática / COVID-19 in cancer patients: a systematic review

RESUMEN Objetivo: El desarrollo de cuadros severos y la muerte por COVID-19 son más frecuentes en poblaciones con comorbilidades. Algunos estudios describen mayor frecuencia de cuadros severos en pacientes con cáncer. Esta revisión sistemática tiene por objetivo describir el riesgo de infección y de presentar un cuadro severo por COVID-19 en pacientes oncológicos. Materiales y métodos: Se realizó una revisión sistemática mediante una búsqueda de la literatura en PubMed y Scopus hasta mayo de 2020. Se amplió la inclusión de estudios con una búsqueda secundaria. Resultados: La búsqueda inicial identificó 2192 registros, de los que se incluyeron 17 publicaciones con al menos 10 pacientes oncológicos infectados. Además, se incluyeron cinco artículos de la búsqueda adicional de las referencias citadas en los 17 artículos. Diez publicaciones provenían de autores chinos. El análisis de la información indicó que la infección es más frecuente en pacientes con cáncer, y las frecuentes visitas terapéuticas al establecimiento de salud serían las causantes. La COVID-19 severa es más frecuente en pacientes con cáncer, y factores como la edad avanzada, comorbilidades asociadas, estadio avanzado y marcadores séricos de inflamación incrementan la severidad del cuadro. Estudios iniciales realizados en China encuentran que el uso de tratamiento antineoplásico sistémico podría también ser un factor predisponente. Conclusiones: El riesgo de infección y de desarrollar cuadro severo por COVID-19 es mayor en la población oncológica.

ABSTRACT Objective: Development of severe disease and death from COVID-19 is more frequent in patients with comorbidities. Some studies report an increased frequency of severe COVID-19 in cancer patients. This review aims to describe the risk of infection and developing severe COVID-19 in cancer patients. Materials and methods: A systematic review was carried out through an exhaustive search of literature in PubMed and Scopus until May 2020. A secondary search was performed to include more studies. Results: The initial search identified 2,192 records, which included 17 publications with at least 10 infected cancer patients. Also, 5 articles were added from the additional search of the references cited by those 17 publications. Ten publications were from Chinese authors. Data analysis showed that COVID-19 infection is more frequent in cancer patients, and frequent therapeutic visits to the healthcare facility may be the cause. The presence of neoplasia predisposed patients to develop severe disease. Advanced age, associated comorbidities, advanced malignancy, and the presence of serum inflammatory markers increased the risk of developing severe disease. Initial studies indicate that the use of systemic treatment may also be a predisposing factor. Conclusions: The risk of becoming infected by COVID-19 and developing severe disease is higher in the oncological population.