Contribution of tumour and immune cells to PD-L1 expression as a predictive biomarker in metastatic triple-negative breast cancer: exploratory analysis from KEYNOTE-119.

The efficacy of pembrolizumab monotherapy versus chemotherapy increased with increasing programmed death ligand 1 (PD-L1) expression, as quantified by combined positive score (CPS; PD-L1 expression on both tumour cells and immune cells) in patients with previously treated metastatic triple-negative breast cancer (mTNBC) in the phase 3 KEYNOTE-119 study. This exploratory analysis was conducted to determine whether the expression of PD-L1 on tumour cells contributes to the predictive value of PD-L1 CPS in mTNBC. PD-L1 expression in tumour samples was assessed using PD-L1 IHC 22C3 pharmDx and quantified using both CPS and tumour proportion score (TPS; PD-L1 expression on tumour cells alone). Calculated immune cell density (CID) was defined as CPS minus TPS. The ability of each scoring method (CPS, TPS, and CID) to predict clinical outcomes with pembrolizumab was evaluated. With pembrolizumab, the area under the receiver operating characteristic curve was 0.69 (95% CI = 0.58-0.80) for CPS, 0.55 (95% CI = 0.46-0.64) for TPS, and 0.67 (95% CI = 0.56-0.77) for CID. After correction for cutoff prevalence, CPS performed as well as, if not better than, CID with respect to predicting objective response rate, progression-free survival, and overall survival. Data from this exploratory analysis suggest that, although PD-L1 expression on immune cells alone is predictive of response to programmed death 1 blockade in mTNBC, adding tumour PD-L1 expression assessment (i.e. CPS, which combines immune cell and tumour cell PD-L1 expression) may improve prediction. PD-L1 CPS thus remains an effective and broadly applicable uniform scoring system for enriching response to programmed death 1 blockade with pembrolizumab in mTNBC as well as other tumour types.

Caracterización histológica del melanoma cutáneo en reportes de patología en la ciudad de Cali, 2016-2021 / Histological characterization of cutaneous melanoma in pathology reports in the city of Cali, 2016-2021

Introducción. El melanoma es la proliferación maligna de melanocitos asociado a un comportamiento agresivo. El objetivo de este estudio fue determinar las variables histológicas del melanoma cutáneo. Métodos. Estudio observacional retrospectivo, transversal descriptivo, realizado con reportes de patologías de pacientes con diagnóstico de melanoma cutáneo en un laboratorio de patología en Cali, Colombia, entre 2016-2021. Se incluyeron las variables edad, sexo, localización, subtipo, espesor de Breslow, ulceración, márgenes, mitosis, invasión linfovascular, neurotrofismo, regresión tumoral, nivel de Clark e infiltración tumoral por linfocitos. Resultados. Se obtuvieron 106 reportes y fueron excluidos 54 por duplicación. Se incluyeron 52 registros, la media de edad fue de 61 años, con una mayor frecuencia de mujeres (55,8 %). De los 33 casos donde se especificó el subtipo histológico, el más frecuente fue el de extensión superficial (66,6 %), seguido del acral lentiginoso (18,1 %) y nodular con (15,2 %). La localización más frecuente fue en extremidades (61,5 %). El espesor de Breslow más común fue IV (34,6 %) y el nivel de Clark más frecuente fue IV (34,6 %). La ulceración estuvo en el 40,4 %. El subtipo nodular fue el de presentación más agresiva, donde el 100 % presentaron espesor de Breslow IV. Conclusiones. El subtipo de melanoma más común en nuestra población fue el de extensión superficial; el segundo en frecuencia fue el subtipo acral lentiginoso, que se localizó siempre en extremidades. Más del 50 % de los melanomas tenían espesor de Breslow mayor o igual a III, lo que impacta en el pronóstico.

Background. Melanoma is the malignant proliferation of melanocytes associated with aggressive behavior. The objective of this study was to determine the histological variables of cutaneous melanoma. Methods. Observational, cross-sectional, descriptive, retrospective study carried out with reports of pathologies with a diagnosis of cutaneous melanoma in a pathology laboratory in Cali between 2016-2021. The variables were age, sex, location, subtype, Breslow thickness, ulceration, margins, mitosis, lymphovascular invasion, neurotropism, tumoral regression, Clark level and tumor infiltration by lymphocytes. Results. One hundred and six reports were obtained and 54 were excluded due to duplication. A descriptive analysis was made on the 52 records that were included, the mean age was 61 years, with a higher frequency in women with 55.8%. Of the 33 cases where the histological subtype was specified, the most frequent was superficial extension with 66.6%, followed by acral lentiginous with 18.1% and nodular with 15.2%. The most frequent location was in the extremities (61.5%); the most common Breslow was IV (34.6%), and the most frequent Clark was IV (34.6%). Ulceration was in 40.4%. The nodular subtype was the most aggressive presentation where 100% presented Breslow IV. Conclusions. The most common subtype of melanoma was that of superficial extension. In our population, the second most frequent was the acral lentiginous subtype, which was always located on the extremities. More than 50% of the melanomas had Breslow greater than or equal to III, which affects the prognosis.

A Phase 2 Study of In Situ Oncolytic Virus Therapy and Stereotactic Body Radiation Therapy Followed by Pembrolizumab in Metastatic Non-Small Cell Lung Cancer.

PURPOSE: A phase 2 study of stereotactic body radiation therapy (SBRT) and in situ oncolytic virus therapy in metastatic non-small cell lung cancer (mNSCLC) followed by pembrolizumab (STOMP) was designed to explore the dual approach in enhancing single pembrolizumab with ADV/HSV-tk plus valacyclovir gene therapy and SBRT in mNSCLC. METHODS AND MATERIALS: STOMP is a single-arm, open-label phase 2 study. Patients with mNSCLC received intratumoral injections of ADV/HSV-tk (5 × 1011 vp) and SBRT (30 Gy in 5 fractions) followed by pembrolizumab 200 mg IV every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was overall response rate (ORR) (complete response [CR] and partial response [PR]). Secondary endpoints included clinical benefit rate (CBR) (CR, PR and stable disease [SD]), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: 28 patients were enrolled, of whom 27 were evaluated for response. The ORR was 33.3%, including 2 CR (7.4%) and 7 PR (25.9%). CBR was 70.4%. Six of eight (75.0%) patients who were immune checkpoint inhibitor (ICI) refractory derived clinical benefits. Responders had durable responses with median PFS, and OS not reached. The entire cohort had a median PFS of 7.4 months (95% CI, 5.1-9.6 months), and median OS of 18.1 months (95% CI, 15.4-20.9 months). The combination was well tolerated, with grade 3 or higher toxicity in 6 (21.4%) patients. CONCLUSIONS: The dual approach of in situ ADV/HSV-tk plus valacyclovir gene therapy and SBRT as a chemotherapy-sparing strategy to enhance the antitumor effect of pembrolizumab is a well-tolerated encouraging treatment in patients with mNSCLC.

Impact of pembrolizumab versus chemotherapy on health-related quality of life in patients with metastatic triple-negative breast cancer: results from the phase 3 randomised KEYNOTE-119 study.

BACKGROUND: In KEYNOTE-119 (ClinicalTrials.gov, NCT02555657), overall survival (primary end-point) was similar between pembrolizumab and chemotherapy in patients with previously treated metastatic triple-negative breast cancer (TNBC), although the pembrolizumab treatment effect increased with tumour PD-L1 expression. We report results of prespecified health-related quality of life (HRQoL) analyses from KEYNOTE-119. METHODS: Eligible patients were randomised 1:1 to pembrolizumab 200 mg Q3W intravenously for up to 35 cycles or treatment of physician's choice per local/country guidelines. Prespecified exploratory end-points were the change from baseline in HRQoL (EORTC QLQ-C30, QLQ-BR23) and to characterise utilities (EQ-5D-3L). Time to deterioration (TTD) was the time from start of treatment to first onset of a ≥10-point worsening from baseline. RESULTS: HRQoL analyses included 187 patients with tumour PD-L1 combined positive score (CPS) ≥10. Changes from baseline at 6 weeks (primary analysis time point) were directionally better with pembrolizumab versus chemotherapy for QLQ-C30 GHS/QoL (between-group difference in least-squares mean scores of 4.21 [95% CI, -1.38 to 9.80]), QLQ-C30 functional scales (physical, role, cognitive, social), QLQ-C30 symptom scales/items (fatigue, nausea/vomiting, dyspnoea, appetite loss), and QLQ-BR23 symptom scales/items (systemic therapy side-effects, upset by hair loss). Median TTD was directionally longer for pembrolizumab versus chemotherapy for QLQ-C30 QHS/QoL (4.3 versus 1.7 months), QLQ-C30 nausea/vomiting (7.7 versus 4.8 months), and QLQ-BR23 systemic therapy side-effects (6.1 versus 3.4 months). Minimal treatment differences were observed for other HRQoL end-points. CONCLUSIONS: HRQoL results were consistent with clinical outcomes and appeared to be driven by results for patients with tumour PD-L1 CPS ≥10.

Caracterización de consorcios microbianos lixiviantes de sulfuro de cobre aislados de drenajes ácidos de minas altoandinas

La biolixiviación, usando consorcios microbianos, es considera una alternativa ecoeficiente y de bajo costo para la recuperación de metales a partir de minerales de baja ley. En este estudio, se realizó la caracterización fisiológica y molecular de consorcios microbianos psicrotolerantes lixiviantes (CMPL), aislados de drenajes ácidos de minas de cuatro localidades mineras de las provincias de Pasco y Huarochirí, Perú, ubicados sobre los 4200 m de altitud. Se aislaron seis consorcios adaptados a medio 9K con ion ferroso y medio basal 9K con CuS al 0.5% p/v a 15 °C. Se evidenció la liberación de cobre en todos los consorcios. El CMPL con mejor crecimiento, presentó una recuperación de cobre de 12.47% en 30 días de evaluación. Los análisis de la secuenciación del gen ARNr 16S de la comunidad bacteriana, mostraron que los CMPL están dominados por el género Acidithiobacillus, seguido de Acidiphilium. En conclusión, se obtuvieron consorcios que pueden ser aplicados en biolixiviación de cobre en la minería altoandina.

Bioleaching, using microbial consortia, is regarded as an eco-efficient and cost-effective alternative for the recovery of metals from low-grade ores. In this study, we conducted physiological and molecular characterization of psychrotolerant leaching microbial consortia (PLMC) isolated from acid mine drainage in four mining sites within the Pasco and Huarochirí provinces of Peru, situated at altitudes above 4200 meters. Six consortia adapted to a medium containing ferrous ions (9K medium) and a basal medium with 0.5% w/v CuS at 15°C were isolated. All consortia exhibited copper release. The PLMC with the most robust growth achieved a copper recovery of 12.47% within 30 days of evaluation. 16S rRNA gene sequencing analysis of the bacterial community revealed that the PLMCs were predominantly dominated by the genus Acidithiobacillus, followed by Acidiphilium. In conclusion, consortia suitable for copper biolixiviation in high-altitude mining contexts were successfully obtained.

Response to Neoadjuvant Therapy and Long-Term Survival in Patients With Triple-Negative Breast Cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC. PATIENTS AND METHODS: Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC. RESULTS: Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates (P < .0001) and 3-year overall survival (OS) rates (P < .0001). TNBC was associated with increased risk for visceral metastases (P = .0005), lower risk for bone recurrence (P = .027), and shorter postrecurrence survival (P < .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival (P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC (P < .0001). CONCLUSION: Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.

A Phase 2 Trial of Enhancing Immune Checkpoint Blockade by Stereotactic Radiation and In Situ Virus Gene Therapy in Metastatic Triple-Negative Breast Cancer.

PURPOSE: A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC. PATIENTS AND METHODS: In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. RESULTS: Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2 CR (7.1%), 1 PR (3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imaging mass cytometry (IMC) revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders. CONCLUSIONS: The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.

Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial.

BACKGROUND: Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer. METHODS: KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS <1]) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657. FINDINGS: From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31·4 months (IQR 27·8-34·4) for the pembrolizumab group and 31·5 months (27·8-34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9-16·3) for the pembrolizumab group and 11·6 months (8·3-13·7) for the chemotherapy group (hazard ratio [HR] 0·78 [95% CI 0·57-1·06]; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3-12·5) for the pembrolizumab group and 10·2 months (7·9-12·6) for the chemotherapy group (HR 0·86 [95% CI 0·69-1·06]; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3-11·4) for the pembrolizumab group and 10·8 months (9·1-12·6) for the chemotherapy group (HR 0·97 [95% CI 0·82-1·15]). The most common grade 3-4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [<1%] vs 14 [5%]), decreased neutrophil count (one [<1%] vs 29 [10%]), and neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (<1%) of 601 participants had treatment-related adverse events that led to death (one [<1%] in the pembrolizumab group due to circulatory collapse; two [1%] in the chemotherapy group, one [<1%] due to pancytopenia and sepsis and one [<1%] haemothorax). INTERPRETATION: Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer. FUNDING: Merck Sharp & Dohme.

Personalizing Gastric Cancer Screening With Predictive Modeling of Disease Progression Biomarkers.

Gastric cancer (GC) remains the third most common cause of cancer-related death worldwide. Infection with Helicobacter pylori is responsible for over 70% of GC incidence; colonization induces chronic inflammation, which can facilitate progression to intestinal metaplasia, dysplasia, and GC (Correa pathway). Although H. pylori eradication is a necessary first step in GC prevention, some patients continue to progress to advanced stage disease if substantial tissue damage has occurred or inflammation persists. This progression is often asymptomatic until cancer reaches stage IV, yet efficient, cost-effective screening protocols for patients who present with early stages of the Correa pathway do not exist. Given the high interpatient heterogeneity in progression time through this pathway, such screening protocols must necessarily be personalized. This requires the identification of reliable and longitudinally assessable biomarkers of patient-specific progression. Several gastric stem cell (GSC) markers including CD44, CD133, and Lgr5 are upregulated in GC. Here we show a significant stepwise increase in immunohistochemical staining for these markers in biopsies at different stages of the Correa pathway, suggesting GSC fraction to be a promising candidate biomarker for early detection of malignant transformation. We present a mathematical model capable of both simulating clinically observed increases in GSC fraction in longitudinal biopsy samples of individual patients, and forecasting patient-specific disease progression trajectories based only on characteristics identified from immunohistochemistry at initial presentation. From these forecasts, personalized screening schedules may be identified that would allow early stratification of high-risk patients, and potentially earlier detection of dysplasia or early-stage GC.

Cuidado peri-operatorio integral centrado en el paciente: un paso más hacia la ampliación de los horizontes de la anestesiología / Comprehensive patient-centered perioperative care: another step towards expanding horizons in anesthesiology

Abstract We must change the current perioperative care model and expand the horizons of our specialty, as the results are unsatisfactory, health systems are unviable, and an imminent crisis is predicted. Although the contributions made by anesthetists have improved the safety of care and have contributed to increase the life expectancy and the quality of life of the population, it is necessary to adopt a comprehensive, patient-centered care model. This involves adapting to new settings of clinical practice, extending anesthetist intervention times, and rethinking the professional competencies that must be demonstrated by those who will practice in the near future. Therefore, we must identify our training deficiencies and start working immediately on overcoming them. The objective of this article is to reflect on the problems of the current model, the solutions proposed by the new models and the successes, difficulties, and opportunities that have been observed during its implementation.

Resumen Debemos cambiar el modelo de atención perioperatoria actual y ampliar los horizontes de nuestra especialidad, porque los resultados son insatisfactorios, los sistemas sanitarios son inviables y se predice una crisis inminente. A pesar de que los aportes hechos por los anestesiólogos han mejorado la seguridad de la atención y han contribuido a incrementar la calidad y la duración de la vida de la población, se hace necesario adoptar un modelo integral, centrado en el paciente, que implica adaptarse a nuevos escenarios de práctica clínica, ampliar los tiempos de intervención del anestesiólogo y replantear las competencias profesionales que deben demostrar quienes ejercerán en un futuro próximo. Por ello, debemos identificar nuestras deficiencias formativas y empezar de inmediato a superarlas. El objetivo de este artículo es hacer una reflexión sobre los problemas del modelo actual, las soluciones propuestas por los nuevos modelos y los aciertos, dificultades y oportunidades que se han observado durante su implementación.

CD133 Expression as a Helicobacter pylori-independent Biomarker of Gastric Cancer Progression.

BACKGROUND/AIM: Gastric adenocarcinoma is the fourth most common cancer worldwide. While gastric cancer prevalence varies globally and incidence rates are decreasing in the West, many cases continue to be diagnosed at an advanced stage and the 5-year survival rate still falls below 30%. Early treatment of gastric cancer by endoscopic and/or surgical therapy may decrease mortality; yet reliable, universally applicable biomarkers for early detection of gastric cancer have still not been established. MATERIALS AND METHODS: The present work compares the expression of CD133 (prominin-1), a potential biomarker of disease progression in gastric cancer, between independent cohorts of H. pylori (+) and H. pylori (-) patients at each respective stage of carcinogenesis. H. pylori (-) patients (N=45) who underwent gastric biopsy at the Moffitt Cancer Center (MCC) in Tampa, Florida, and H. pylori (+) patients (N=59) who underwent gastric biopsy at the Instituto de Patologia Mejia Jimenez (IPMJ) in Cali, Colombia were evaluated and immunostained for CD133. RESULTS: A statistically significant increase in CD133 expression (in terms of the Allred score) was observed between all stages of progression (normal mucosa, inflammation/metaplasia, low-grade dysplasia and gastric adenocarcinoma) for each respective patient cohort. No statistically significant difference in CD133 expression at each respective stage of disease was observed between the H. pylori-positive and negative-cohorts. CONCLUSION: The observation of distinct stepwise increases in CD133 expression in both patient cohorts, and the lack of any significant difference between groups, suggests that CD133 expression may serve as a biomarker for early detection of gastric cancer independent of bacterial status and strain, and corresponding differences in disease histomorphology and classification. This warrants further validation on larger independent cohorts across multiple geographic regions and incorporating multiple bacterial strain types.

An Isolated TCR αß Restricted by HLA-A*02:01/CT37 Peptide Redirecting CD8+ T Cells To Kill and Secrete IFN-γ in Response to Lung Adenocarcinoma Cell Lines.

Lung cancer is a leading cause of cancer-related death among both men and women in the United States, where non-small cell lung cancer accounts for ∼85% of lung cancer. Lung adenocarcinoma (ADC) is the major histologic subtype. The presence of actionable mutations prompts the use of therapies designed to specifically address the deleterious effects of those cancer-driving mutations; these therapies have already shown promise in cases carrying those actionable mutations (∼30%). Innovative therapeutic approaches are needed for the treatment of 70% of patients suffering from lung ADC. Adoptive transfer of CD8+ T cells specific against cancer/testis (CT) Ags, whose protein expression is restricted to the gonads (testis and ovary) and cancerous cells, is an excellent alternative. In this study, we report the isolation of HLA-A*02:01/CT37 peptide-specific α and ß TCR chains from a CD8+ T cell clone obtained from a patient suffering from lung ADC. We also report the development of an innovative CD3ζ construct. With those TCR chains and the engineered (modified) CD3ζ chain, we produced a construct that when transduced into CD8+ T cells is capable of redirecting transduced CD8+ T cell cytotoxic activity and IFN-γ secretion against peptide-pulsed autologous cells and HLA-A*02:01-positive and CT37-expressing lung ADC cell lines. Our findings will launch the development of innovative adoptive transfer immunotherapies for the treatment of lung ADC, targeting the most prevalent HLA molecules and CT37 peptides restricted by these molecules.

Toward early detection of Helicobacter pylori-associated gastric cancer.

BACKGROUND: Gastric cancer is typically diagnosed at a late stage, leading to poor prognoses. Helicobacter pylori is responsible for 70% of gastric cancers globally, and patients with this bacterial infection often present with early stages of the carcinogenic pathway such as inflammation or gastritis. Although many patients continue to progress to advanced-stage disease after antibacterial treatment, there are no follow-up screening protocols for patients with a history of H. pylori. METHODS: Several biomarkers (Lgr5, CD133, CD44) become upregulated during gastric carcinogenesis. A logistic regression model is developed using clinical data from 59 patients at different stages of the carcinogenic pathway to identify the likelihood of being at an advanced stage of disease for all combinations of age, sex, and marker positivity. Using these likelihood distributions and the observed rate of marker positivity increase, time to high likelihood (probability >0.8) of advanced disease for individual patients is predicted. RESULTS: A strong correlation between marker positivity and disease stage was found for all three markers. Disease stage was accurately classified by the respective regression models for more than 86% of retrospective patients. Highly patient-specific predictions of time to onset of dysplasia were made, allowing the classification of 17 patients initially diagnosed with intestinal metaplasia into high-, intermediate-, or low-risk categories. CONCLUSIONS: We present an approach designed to integrate pathology, mathematics, and statistics for detection of the earliest precancerous, treatable lesion. Given the simplicity and robustness of the framework, such technique has the potential to guide personalized screening schedules to minimize the risk of undetected malignant transformation.

Método clínico en la detección de la enfermedad de Paget de la mama en cuidado primario / Clinical method for detecting Paget disease of the breast in primary care

La enfermedad de Paget de la mama es una manifestación cutánea infrecuente de cáncer de mama que tiene mejor pronóstico cuando se detecta de manera temprana. Se presenta el caso de una mujer de 56 años, que asistió a consulta en cuidado primario en la ciudad de Cali para la evaluación del resultado de una citología cervicouterina. Se le realizó examen mamario preventivo y se encontró una lesión en areola-pezón de características eritematodescamativas de dos años de evolución. Los estudios anatomopatológicos y de inmunotipificación confirmaron enfermedad de Paget. El reporte histológico de la pieza quirúrgica extraída durante la cuadrantectomía con resección del complejo areola-pezón, diagnosticó un carcinoma intraductal subyacente. La utilización del método clínico en cuidado primario, en una paciente sin lesión palpable y con mamografías negativas para malignidad, fue la clave del éxito en la detección temprana y recuperación de la paciente que ha evolucionado de manera favorable. (Acta Med Colomb 2013; 38: 277-281).

Paget's disease of the breast is a rare cutaneous manifestation of breast cancer which has a better prognosis when detected early. We report the case of a 56 year-old woman who attended consultation in primary care in the city of Cali to evaluate the result of uterine cervical cytology. She underwent preventive breast exam and a descamative erythematous nipple-areola lesion of two years of evolution was found. Pathological and immunotyping studies confirmed Paget's disease. The histological report of the surgical specimen removed during lumpectomy with resection of the nipple-areola complex, diagnosed an underlying intraductal carcinoma. The use of the clinical method in primary care in a patient without palpable lesion and malignancy negative mammograms, was the key to success in early detection and recovery of the patient who has performed well. (Acta Med Colomb 2013; 38: 277-281).

Estabilidad enzoótica de babesiosis bovina en la región de Puerto Berrío, Colombia / Enzootic Stability of Bovine Babesiosis at Puerto Berrio Region, Colombia

En Colombia, la industria ganadera representa el tercer renglón de importancia económica después de la explotación petrolera y la agricultura. Este recurso económico se encuentra afectado por enfermedades hemoparasitarias como la babesiosis bovina. Su transmisión se encuentra determinada por la relación vector-parásito- hospedador y está condicionada por factores bióticos y abióticos. El estado de equilibrio entre el proceso infeccioso y la adquisición de inmunidad por parte de los hospedadores bovinos es conocido como estabilidad enzoótica. Para la determinación de la estabilidad enzoótica en la babesiosis bovina se ha utilizado como indicador anticuerpos tipo IgG específicos para cada especie de Babesia en bovinos entre 3 y 9 meses de edad. Así, una zona es estable para babesiosis cuando al menos 75% de los bovinos entre 3 y 9 meses de edad son serorreactivos para Babesia spp. Se diseñó un estudio descriptivo prospectivo de corte transversal, con una n de 282 bovinos, para evaluar el nivel de estabilidad enzoótica en nueve hatos ganaderos de la región de Puerto Berrío, a través de un muestreo probabilístico aleatorio simple, estratificado por género y pareado por edad. Se utilizó la técnica de inmunofluorescencia indirecta (IFI) para la detección de anticuerpos tipo IgG específicos contra Babesia bovis y Babesia bigemina. Se obtuvo un nivel de serorreactividad por hato para B. bovis superior al 75% en la población estudiada en cuatro de los nueve hatos. En los hatos con estabilidad enzoótica se encontró una relación positiva entre la frecuencia del tratamiento garrapaticida y la serorreactividad. En particular, cuando la frecuencia de baños es de 90 días o más, el nivel de serorreactividad es el doble frente a la frecuencia de baños de 60 días o menos.

In Colombia, cattle industry is the third level of economic importance after oil and agriculture exploitation systems. This economic resource is affected by hemoparasitic diseases like bovine babesiosis. Transmission of babesiosis is determined by the vector-parasitic-host relation and biotic and abiotic conditional factors. Equilibrium between infection and acquired immunity on bovine hosts is called enzootic stability. To determine enzootic stability levels of bovine babesiosis it has been used the detection of IgG specific antibodies for bovine babesias in calves between 3 and 9 months of age. Thus, a geographic region has enzootic stability when 75% or more of calves between 3 and 9 months of age are seroreactive for Babesia spp. A descriptive prospective cross sectional study was carried out. A sample of 282 calves was tested to determine enzootic stability level in cattle ranches of Puerto Berrio Region. A simple random probabilistic sampling was designed, stratified by sex and age. The sample was distributed in nine cattle ranches and was evaluated by indirect immunofluorescence antibodies technique to detection of IgG specific antibodies against Babesia bovis and Babesia bigemina. A level of seroreactivity higher than 75% to B. bovis in four of nine cattle farms was obtained. In the cattle farms with enzootic stability, a positive relation between acaricide treatment frequency and seroreactivity was found. Specifically, 90 days or more of acaricide treatment frequency induce a double level of seroreactivity than 60 days or less frequency.

Phase I study of prolonged-infusion gemcitabine combined with cyclophosphamide in patients with metastatic carcinoma of the breast: tolerability of an optimal dose schedule.

BACKGROUND: A phase I study was initiated to determine the maximum tolerated dose (MTD) of prolonged-infusion gemcitabine combined with cyclophosphamide in patients with metastatic breast carcinoma (MBC). METHODS: Patients with MBC were treated with gemcitabine infusion at 10 mg/m2/min and cyclophosphamide by intravenous piggyback injection, 4 h after initiation of the infusion. We treated 3-6 patients at a particular dose level until the MTD was determined. RESULTS: Overall, 44 patients received a total of 197 courses of therapy. Both drugs were given on days 1, 8 and 15 to 14 patients (68 courses). Delayed white blood cell recovery necessitated first protocol amendment to drop cyclophosphamide on days 8 and 15 in 9 patients (43 cycles). A second amendment was needed to drop gemcitabine on day 15 because of thrombocytopenia in 21 patients (86 courses). The dose-limiting toxicity was thrombocytopenia. The MTD of an optimal dose schedule was 800 mg/m2 gemcitabine infused at a rate of 10 mg/m2/min on days 1 and 8, and 400 mg/m2 cyclophosphamide, by intravenous piggyback injection, on day 1, 4 h after initiation of the gemcitabine infusion. CONCLUSIONS: The MTD can be given safely every 4 weeks to patients with MBC. Phase II studies are warranted to evaluate the clinical activity of this therapy.

Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer.

BACKGROUND: Previous studies have evaluated 3-week and weekly docetaxel schedules in patients with metastatic breast cancer (MBC). The varying efficacy results and toxicity profiles noted in these earlier studies led to a comparison of the schedules to determine which was safer and more efficacious. METHODS: A phase 3 clinical trial was conducted in patients with MBC who were treated with docetaxel either every 3 weeks or once weekly to determine and compare response rate and duration, time to disease progression, progression-free survival (PFS), overall survival (OS), and toxicity. Patients were randomized to receive docetaxel at a starting dose of either 75 mg/m(2) every 3 weeks or 35 mg/m(2) weekly for 3 consecutive weeks followed by 1 week of rest. RESULTS: A total of 118 patients underwent efficacy analysis; 59 patients were randomized to the every-3-week treatment arm and 59 to the weekly arm. The response rate was 35.6% (95% confidence interval [95% CI], 23.6-49.1%) for the every-3-week arm versus 20.3% (95% CI, 11.0-32.8%) for the weekly arm. There was no statistical difference between the every 3-week and the weekly treatment arms with regard to median PFS (5.7 months vs 5.5 months; P= .46) or OS (18.3 months vs 18.6 months, respectively; P= .34). There was a higher overall toxicity rate (grades 3 and 4, according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) in the every-3-week treatment arm versus the weekly treatment arm (88.1% vs 55.9%, respectively; P= .0001). CONCLUSIONS: Compared with patients who received weekly docetaxel, those who received docetaxel every 3 weeks had a higher response rate but experienced similar PFS and OS and a more pronounced toxicity.

Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC. PATIENTS AND METHODS: Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC. RESULTS: Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates (P < .0001) and 3-year overall survival (OS) rates (P < .0001). TNBC was associated with increased risk for visceral metastases (P = .0005), lower risk for bone recurrence (P = .027), and shorter postrecurrence survival (P < .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival (P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC (P < .0001). CONCLUSION: Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.

CD40 signaling predicts response to preoperative trastuzumab and concomitant paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide in HER-2-overexpressing breast cancer.

INTRODUCTION: We performed gene expression analysis to identify molecular predictors of resistance to preoperative concomitant trastuzumab and paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide (T/FEC). METHODS: Pretreatment fine-needle aspiration specimens from 45 patients with HER-2-overexpressing stage II to IIIA breast cancer were subjected to transcriptional profiling and examined for differential expression of various genes and gene sets. The primary endpoint for tumor response was pathologic complete response (pCR). Correlations between pCR and gene expression were sought. RESULTS: The overall pCR rate was 64%. Age, nuclear grade, tumor size, nodal status, quantitative expression of estrogen and HER-2 receptor mRNA, and HER-2 gene copy number showed no correlation with pCR. Results of gene set enrichment analysis suggested that the lower expression of genes involved with CD40 signaling is associated with a greater risk of residual cancer after the preoperative chemotherapy that includes trastuzumab. CONCLUSION: CD40 signaling may play a role in determining response to trastuzumab-plus-T/FEC therapy in patients with HER-2-overexpressing breast cancer.

Microtubule-associated protein-tau is a bifunctional predictor of endocrine sensitivity and chemotherapy resistance in estrogen receptor-positive breast cancer.

PURPOSE: The clinical outcome for patients with breast cancer is influenced by the metastatic competence of the cancer and its sensitivity to endocrine therapy and chemotherapy. A molecular marker may be prognostic of outcome or predictive of response to therapy, or a combination of both. EXPERIMENTAL DESIGN: We examined separately the prognostic and predictive values of tau mRNA expression in estrogen receptor (ER)-positive primary breast cancers in three patient cohorts. We used gene expression data from 209 untreated patients to assess the pure prognostic value of tau, data from 267 patients treated with adjuvant tamoxifen to assess predictive value for endocrine therapy, and data from 82 patients treated with preoperative paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide (paclitaxel/FAC) to assess predictive value for chemotherapy response. Wilcoxon rank sum test was used to compare tau expression between different outcome groups. RESULTS: Higher tau mRNA expression showed borderline nonsignificant association with better prognosis in the absence of systemic adjuvant therapy. Higher tau mRNA expression was significantly associated with no recurrence (at 5 and 10 years, P = 0.005 and P = 0.05, respectively) in patients treated with tamoxifen, indicating a predictive value for endocrine therapy. Tau expression was significantly lower in patients who achieved pathologic complete response to paclitaxel/FAC chemotherapy (P < 0.001). CONCLUSION: This study suggests that high tau mRNA expression in ER-positive breast cancer indicates an endocrine-sensitive but chemotherapy-resistant disease. In contrast, low tau expression identifies a subset of ER-positive cancers that have poor prognosis with tamoxifen alone and may benefit from taxane-containing chemotherapy.