Dolores Gallardo-Rincón

High frequency of radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent radiotherapy and gemcitabine after induction with gemcitabine and carboplatin.

Introduction: The combination of chemotherapy and thoracic radiation is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). However, most favorable chemotherapy regimen, timing of full-dose chemotherapy, and optimal combination of chemotherapy with radiation remain to be determined. Our primary objective was to evaluate the efficacy and safety of gemcitabine concurrent with radiotherapy after induction chemotherapy with gemcitabine plus carboplatin for locally advanced NSCLC. Patients and Methods: Patients with histologically proven NSCLC stage IIIA and -B received carboplatin (area under the curve of 2.5) and gemcitabine (800 mg/m2) on days 1 and 8, every 21 days for two cycles, followed by conventional fractioned thoracic radiotherapy and concomitant weekly gemcitabine 200 mg/m2, and finally, consolidation chemotherapy. Results: Inclusion was discontinued because of high-grade 3 to 5 radiation-pneumonitis events (6 of 19 patients, 31.6%), including one treatment-related death associated with radiation pneumonitis. Median follow-up was 11.9 months. Most common grades 3/4 hematological side effects comprised anemia, neutropenia 3 of 19 patients, each (15.8%), and thrombocytopenia (4 of 19, 21.1%) during induction. Partial response was observed in 10 patients (52.6%) following induction chemotherapy. After concurrent chemo-radiotherapy, overall response was 68.4%. Four patients (21.1%) underwent surgical resection. Median progression-free survival and overall survival were 12 ± 1 month (95% confidence interval [CI], 9.8–14.1) and 21 ± 3.5 months (95% CI, 14–27.9 months), respectively. Conclusion: Concurrent radiotherapy with gemcitabine after induction with gemcitabine and carboplatin showed a high-response rate; however, it is associated with excessive pulmonary toxicity. Adjustments in gemcitabine dosage during radiotherapy or changes in radiotherapy planning could reduce toxicity.

Phase II study. Concurrent chemotherapy and radiotherapy with nitroglycerin in locally advanced non-small cell lung cancer

BACKGROUND Nitroglycerin, a nitric oxide donor agent, reduces the expression of hypoxia-inducible factor-1α (HIF-1α) and could be a normalizer of the tumor microenvironment. Both factors are associated with chemo-radio-resistance. The aim of this study was to determine the safety profile and efficacy of nitroglycerin administration with chemo-radiotherapy in patients with locally advanced non-small cell lung cancer (NSCLC). METHODS This is a phase II trial of locally advanced NSCLC patients treated with cisplatin and vinorelbine plus concurrent nitroglycerin with radiotherapy. A 25-mg NTG patch was administered to the patients for 5 days (1 day before and 4 days after chemotherapy induction and consolidation) and all day during chemo-radiotherapy. VEGF plasmatic level was determined before and after two cycles of chemotherapy. RESULTS Thirty-five patients were enrolled in this trial. Sixty-three percent of patients achieved an overall response after induction of chemotherapy, and 75% achieved an overall response after chemo-radiotherapy. The median progression-free survival was 13.5 months (95% CI, 8.8-18.2), and the median overall survival was 26.9 months (95% CI, 15.3-38.5). Reduction of VEGF level was associated with better OS. The toxicity profile related to nitroglycerin included headache (20%) and hypotension (2.9%). CONCLUSIONS The addition of nitroglycerin to induction chemotherapy and concurrent chemoradiotherapy in patients with locally advanced NSCLC has an acceptable toxicity profile and supports the possibility to add nitroglycerin to chemotherapy and radiotherapy. A randomized trial is warranted to confirm these findings.

Selection of best candidates for multiorgan resection among patients with T4 gastric carcinoma

Indications for gastrectomy in T4 gastric carcinoma (GC) remain controversial. Our aim was to define prognostic factors to select those patients with best chance to benefit from multiorgan resection.

Integrins and haptoglobin: Molecules overexpressed in ovarian cancer

Integrins are adhesion molecules whose expression is upregulated during different cellular processes such as adhesion, growth, proliferation, migration, survival and differentiation, all of which are involved in neoplastic development. Several reports have linked the overexpression of integrins with epithelial ovarian cancer (EOC). Furthermore, fucosylated haptoglobin (Hp) isoforms with antioxidant activity and synthesized primarily in the liver have also been associated with various types of cancer, including ovarian cancer. Here, we determined the level of expression of three integrin heterodimers (α5β1, α6β4, and αVβ3) and fucosyltated Hp in two different settings: cell cultures and biopsies from ovarian cancer patients. On the one hand, integrin heterodimers were analyzed in the ovarian cancer cell line (SKOV-3), two primary cultures (INCan017 and INCan019) and a tumor derived from INCan017 (T-017) by Western blot. Statistical analysis was performed using one-way ANOVA. The SKOV-3 cell line, INCan017 and INCan019 primary cultures, and the T-017 tumor showed increased expression patterns of the α5, αV, β1, β3, and β4 integrin subunits when compared with healthy ovary tissue. We then analyzed the expression pattern of the integrin subunits as well as the fucosylated Hp in biopsies from patients with different histotypes of EOC by immunofluorescence. α5β1 and α6β4 integrins were expressed by 90% of the samples, whereas 80% expressed the αVβ3 integrin. Furthermore, Hp, fucosylated or not, was present at high levels in most biopsies. In fact, there was a statistical correlation between the expression of integrins or Hp and the presence of the disease given that α5β1, α6β4, and αVβ3 integrins, Hp, fucosylated Hp and additional fucosylation state of proteins were highly expressed in biopsies of EOC histotypes when compared with healthy ovarian tissue. However, the statistical analysis showed no association of the presence of integrins, Hp or fucosylation with clinical or pathological characteristics of EOC patients. These results suggest that increased expression of these molecules and of the fucosylation modification are characteristics of the malignant process itself. Therefore, these molecules may be promising therapeutic targets in patients with this type of neoplasia.

Proteomic identification of fucosylated haptoglobin alpha isoforms in ascitic fluids and its localization in ovarian carcinoma tissues from Mexican patients

BackgroundOvarian cancer is the most lethal gynecologic disease due to delayed diagnosis, and ascites production is a characteristic of patients in advanced stages. The aim of this study was to perform the proteomic analysis of ascitic fluids of Mexican patients with ovarian carcinoma, in order to detect proteins with a differential expression pattern in the continuing search to identify biomarkers for this disease.MethodsSamples were collected from 50 patients from the Instituto Nacional de Cancerología of México under informed consent and with approval of the bioethics and scientific committees. After elimination of abundant proteins (Albumin/IgGs) samples were processed for 2D electrophoresis and further protein identification by Mass Spectrometry (MALDI-TOF). Molecules of interest were followed by western blot and lectin binding assays, and their tissue location by histo-immunofluorescence and confocal analysis.Results and discussionAn area with a differential expression pattern among samples was located in the 2D gels. Identified proteins were 6 alpha 1 isoforms and 1 alpha 2 isoform of Haptoglobin, and 2 isoforms of Transthyretin. While Transthyretin isoforms were constitutively expressed in all samples, clear differences in the expression pattern of Haptoglobin alpha isoforms were found. Moreover, increased levels of fucosylation of Haptoglobin alpha isoforms analyzed in 40 samples by Aleuria aurantia lectin binding by 1D overlay assay showed a positive correlation with advanced stages of the disease. Tissue detection of Haptoglobin and its fucosylated form, by histo-immunofluorescence in biopsies of ovarian cancer, also showed a correlation with ovarian cancer progression. Moreover, results show that fucosylated Haptoglobin is produced by tumor cells.ConclusionsIncreased numbers of highly fucosylated Haptoglobin alpha isoforms in ascitic fluids and the presence of fucosylated Haptoglobin in tumor tissues of ovarian cancer Mexican patients associated with advanced stages of the disease, reinforce the potential of fucosylated Haptoglobin alpha isoforms to be characterized as biomarkers for disease progression.

Effect of ovarian cancer ascites on SKOV-3 cells proteome: new proteins associated with aggressive phenotype in epithelial ovarian cancer

BackgroundEpithelial ovarian cancer is the second most lethal gynecological cancer worldwide. Ascites can be found in all clinical stages, however in advanced disease stages IIIC and IV it is more frequent and could be massive, associated with worse prognosis. Due to the above, it was our interest to understanding how the ascites of ovarian cancer patients induces the mechanisms by which the cells present in it acquire a more aggressive phenotype and to know new proteins associated to this process.MethodsA proteomic analysis of SKOV-3 cells treated with five different EOC ascites was performed by two-dimensional electrophoresis coupled to MALDI-TOF. The level of expression of the proteins of interest was validated by RT-PCR because several of these proteins have only been reported at the messenger level.ResultsAmong the proteins identified that increased their expression in ascites-treated SKOV-3 cells, were Ran GTPase, ZNF268, and Synaptotagmin like-3. On the other hand, proteins that were negatively regulated by ascites were HLA-I, HSPB1, ARF1, Synaptotagmin 1, and hnRNPH1, among others. Furthermore, an interactome for every one of these proteins was done in order to identify biological processes, molecular actions, and cellular components in which they may participate.ConclusionsIdentified proteins participate in cellular processes highly relevant to the aggressive phenotype such as nuclear transport, regulation of gene expression, vesicular trafficking, evasion of the immune response, invasion, metastasis, and in resistance to chemotherapy. These proteins may represent a source of information which has the potential to be evaluated for the design of therapies directed against these malignant cells that reside on ovarian cancer ascites.

Advancing clinical research globally: Cervical cancer research network from Mexico

Cervical cancer is the fourth most common cancer in women with 85% of the mortality burden occurring in less-developed regions of the world. The Cervix Cancer Research Network (CCRN) was founded by the Gynecologic Cancer InterGroup (GCIG) with a mission to improve outcomes in cervix cancer by increasing access to high-quality clinical trials worldwide, with particular attention to less-developed, underrepresented sites. The CCRN held its second international educational symposium in Mexico City with ninety participants from fifteen Latin America countries in January 2017. The purpose of this symposium was to advance knowledge in cervix cancer therapy, promote recruitment to CCRN clinical trials, and to identify relevant future CCRN clinical trial concepts that could improve global care standards for women with cervical cancer.

Abstract A77: Validation of the EORTC QLQ-OV28 instrument for the assessment of quality of life in women with ovarian carcinoma in Mexico.

Objective: Health-related quality of life (HRQL) is an important outcome measurement in Oncology. Our aim was to validate the Mexican-Spanish version of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-OV28 questionnaire to assess HRQL in patients with Ovarian cancer (OC). Patients and Methods: The QLQ-C30 and QLQ-OV28 instruments were applied to Mexican patients with OC at a cancer referral centre. Reliability and validity tests were performed, and test-retest analysis was carried out in a subgroup of patients. Results: Two hundred fifty-two women were included in this cohort. Questionnaire compliance rates were high and the instrument was well accepted; internal consistency tests demonstrated good convergent and divergent validity. Cronbach9s α; coefficients of 8 of 9 multi-item scales of the QLQ-C30 and of 6 of 8 scales of the QLQ-OV28 instruments were >0.7 (range, 0.22 to 0.89). Scales of the QLQ-C30 and QLQ-OV28 instruments distinguished among clinically distinct groups of patients; some were highly sensitive to change over time after the use of induction chemotherapy, and some were associated to overall survival. Conclusion: The Mexican-Spanish version of the QLQ-OV28 questionnaire is reliable and valid for the assessment of HRQL in patients with OC and can be broadly used in clinical trials. Citation Format: Dolores Gallardo-Rincon, Wendy Munoz-Montano, David Cantu de Leon, Jaime Coronel-Martinez, Flavia Morales, Luis F. Onate-Ocana. Validation of the EORTC QLQ-OV28 instrument for the assessment of quality of life in women with ovarian carcinoma in Mexico. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A77.

Who are the best candidates for multiorgan resection among patients with T4 gastric carcinoma

Results 718 patients were included (gastrectomy performed in 169). The clinical and pathological characteristics of the cohort depending on the residual status after the surgery was recorded. Presence of metastasis (Hazard ratio = 1.68 [HR], 95% confidence interval [CI] 1.19–2.36), albumin <3 g/dL plus lymphocytes <1000 cells/mm3 (HR = 2.9, 95% CI 1.8–4.6), presence of ascites (HR = 2.1, 95% CI 1.06–4.2), 50 years old or more (HR = 1.37, 95% CI 1.02– 1.8) and absence of surgical resection (HR = 2.6, 95% CI 1.7–4.1) define patients with the worst prognosis (model p = 0.00001). Including only patients underwent surgical resection, presence of metastases, extent of gastrectomy, serum albumin level and R1–R2 residual were determinants of poor survival (model p = 0.00001). Surgical morbidity and mortality were 39% and 10.7%, respectively. The significant determinants of surgical morbidity were extent of gastrectomy, age, serum albumin and lymphocyte count (model p = 0.0001).

The prognostic value of serum carcinoembryonic antigen in colorectal carcinoma

AbstractBackground. Carcinoembryonic antigen (CEA) is a non-specific tumor marker, however some clinical applications have been reported. Aims. Our aim is to define the role of pretherapeutic serum CEA level (SCEAL) as prognostic factor and to describe the usefulness of serial SCEAL in the follow-up of Mexican patients with completely resected colorectal carcinoma (CRC). Patients and methods. A retrospective cohort study of 580 patients with CRC treated in Mexico City in a 12-year period. The Cox’s model was used to evaluate prognostic factors predicting survival and the logistic regression model was used to test recurrence determinants in completely resected CRC. Sensitivity and specificity for SCEAL as diagnostic aid of recurrence after complete resection is reported and receiver-operating characteristic curve (ROC) analysis was performed to choose the best cutoff point. Results. Histologic grade, Dukes’ stage, curative resection and age were independent factors determining survival. Preoperative SCEAL was not found to be significant, however a bivariate correlation between preoperative SCEAL and Dukes’ stage was found. Dukes’ stage and specially lymph node metastasis were significant recurrence determinants in completely resected CRC. The sensitivity and specificity of serial SCEAL as diagnostic aid for recurrence after complete resection was 58% and 91%, respectively, using 10 ng/ml as cutoff point. Conclusions. Preoperative SCEAL is neither a significant prognostic factor nor a significant determinant of recurrence. Serial SCEAL has a limited role in the follow-up of patients with completely resected CRC. However, the high specificity for diagnosis of recurrences supports its use in CEA-based second-look surgery.ResumenFundamento. El antígeno carcinoembrionario (ACE) es un marcador tumoral inespecífico, sin embargo se han reportado algunas aplicaciones clínicas. Objetivos. Nuestro objetivo es difinir el papel de la determinación preterapéutica de ACE sérico como factor predictivo y describir su utilidad de la determinación seriada del ACE sérico en el seguimiento de pacientes mexicanos con carcinoma colorrectal (CCR) completamente resecado. Pacientes y métodos. Es un estudio retrospectivo de cohortes de 580 pacientes con CCR tratados en la ciudad de México durante un período de 12 años. Se usó el modelo de Cox para evaluar los factores predictivos de supervivencia y se usó el modelo de regresión logística para probar los determinantes de recurrencia en CCR completamente resecado. Se evaluó la sensibilidad y especificidad del ACE sérico como prueba diagnóstica de recurrencia y el mejor punto de corte se calculó mediante análisis de característica operativa del receptor (ROC). Resultados. Los determinantes independientes de la supervivencia fueron el grado histológico, la etapa clínica de Dukes, la resección curativa y la edad. El nivel de ACE sérico preoperatorio no fue un factor significativo, sin embargo, se encontró una asociación entre el ACE sérico y la etapa clínica de Dukes. La etapa clínica de Dukes y especialmente la presencia de ganglios linfáticos con metástasis fueron los más importantes determinantes de recurrencia en CCR completamente resecado. La sensibilidad y especificidad de las determinaciones seriadas del ACE sérico como prueba diagnóstica de recurrencia fue de 58% y 91%, respectivamente, usando 10 ng/ml como punto de corte. Conclusiones. El ACE sérico preoperatorio no es ni factor predictivo ni determinante de recurrencia. La determinación seriada de ACE sérico tiene un papel limitado en el seguimiento de pacientes con CCR completamente resecado. Sin embargo, su alta especificidad en el diagnóstico de recurrencias apoya su uso en cirugía de segunda mirada basada en ACE.