Oncologic immunomodulatory agents in patients with cancer and COVID-19.

Corticosteroids, anti-CD20 agents, immunotherapies, and cytotoxic chemotherapy are commonly used in the treatment of patients with cancer. It is unclear how these agents affect patients with cancer who are infected with SARS-CoV-2. We retrospectively investigated associations between SARS-CoV-2-associated respiratory failure or death with receipt of the aforementioned medications and with pre-COVID-19 neutropenia. The study included all cancer patients diagnosed with SARS-CoV-2 at Memorial Sloan Kettering Cancer Center until June 2, 2020 (N = 820). We controlled for cancer-related characteristics known to predispose to worse COVID-19 as well as level of respiratory support during corticosteroid administration. Corticosteroid administration was associated with worse outcomes prior to use of supplemental oxygen; no statistically significant difference was observed in sicker cohorts. In patients with metastatic thoracic cancer, 9 of 25 (36%) and 10 of 31 (32%) had respiratory failure or death among those who did and did not receive immunotherapy, respectively. Seven of 23 (30%) and 52 of 187 (28%) patients with hematologic cancer had respiratory failure or death among those who did and did not receive anti-CD20 therapy, respectively. Chemotherapy itself was not associated with worse outcomes, but pre-COVID-19 neutropenia was associated with worse COVID-19 course. Relative prevalence of chemotherapy-associated neutropenia in previous studies may account for different conclusions regarding the risks of chemotherapy in patients with COVID-19. In the absence of prospective studies and evidence-based guidelines, our data may aid providers looking to assess the risks and benefits of these agents in caring for cancer patients in the COVID-19 era.

Chemotherapy and COVID-19 Outcomes in Patients With Cancer.

PURPOSE: Coronavirus-2019 (COVID-19) mortality is higher in patients with cancer than in the general population, yet the cancer-associated risk factors for COVID-19 adverse outcomes are not fully characterized. PATIENTS AND METHODS: We reviewed clinical characteristics and outcomes from patients with cancer and concurrent COVID-19 at Memorial Sloan Kettering Cancer Center until March 31, 2020 (n = 309), and observed clinical end points until April 13, 2020. We hypothesized that cytotoxic chemotherapy administered within 35 days of a COVID-19 diagnosis is associated with an increased hazard ratio (HR) of severe or critical COVID-19. In secondary analyses, we estimated associations between specific clinical and laboratory variables and the incidence of a severe or critical COVID-19 event. RESULTS: Cytotoxic chemotherapy administration was not significantly associated with a severe or critical COVID-19 event (HR, 1.10; 95% CI, 0.73 to 1.60). Hematologic malignancy was associated with increased COVID-19 severity (HR, 1.90; 95% CI, 1.30 to 2.80). Patients with lung cancer also demonstrated higher rates of severe or critical COVID-19 events (HR, 2.0; 95% CI, 1.20 to 3.30). Lymphopenia at COVID-19 diagnosis was associated with higher rates of severe or critical illness (HR, 2.10; 95% CI, 1.50 to 3.10). Patients with baseline neutropenia 14-90 days before COVID-19 diagnosis had worse outcomes (HR, 4.20; 95% CI, 1.70 to 11.00). Findings from these analyses remained consistent in a multivariable model and in multiple sensitivity analyses. The rate of adverse events was lower in a time-matched population of patients with cancer without COVID-19. CONCLUSION: Recent cytotoxic chemotherapy treatment was not associated with adverse COVID-19 outcomes. Patients with active hematologic or lung malignancies, peri-COVID-19 lymphopenia, or baseline neutropenia had worse COVID-19 outcomes. Interactions among antineoplastic therapy, cancer type, and COVID-19 are complex and warrant further investigation.

Monoclonal antibodies in multiple myeloma: Current and emerging targets and mechanisms of action.

The recent development of monoclonal antibodies (mAbs) has revolutionized the treatment armamentarium for multiple myeloma. The success of daratumumab and elotuzumab in relapsed/refractory patients, has generated tremendous enthusiasm for mAbs in this disease. Combination treatment with other anti-myeloma treatment modalities and clinical evaluation in newly diagnosed patients are expected to fundamentally change the natural history of the disease. Advances in biopharmaceutical engineering together with a robust interest in novel mAb-derivatives, including antibody drug conjugates and poly-specific antibodies are the next rapidly approaching treatment frontier in multiple myeloma. In this review, we comprehensively outline the currently available evidence and the future landscape of mAbs and mAb-derivative therapies in multiple myeloma.

Immune-Related Adverse Events Requiring Hospitalization: Spectrum of Toxicity, Treatment, and Outcomes.

PURPOSE: Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs). The proportion of patients who are hospitalized for irAEs and their spectrum, management, and outcomes are not well described. METHODS: We report the proportion of hospitalized patients in an academic center who were treated with ICIs from May to December 2017. Patient characteristics, toxicities, management, and outcomes for confirmed irAE admissions are reported. Associations between patient features and irAE hospitalizations are examined. RESULTS: Twenty-three percent (n = 100) of 443 patients who were admitted to an academic oncology center over 6 months had ever received ICIs. Of these patients, 41% were admitted for suspected irAEs and 23% were confirmed irAEs. IrAEs accounted for 5% of all oncology hospitalizations (n = 23). Ninety-one percent of patients with confirmed irAEs prompted a medicine subspecialist consultation, most commonly gastroenterology (22%). Fifteen patients (65%) had their irAEs improve/resolve, seven (30%) had worsening irAEs, and three (13%) died of their irAEs. The majority of patients (n = 20; 87%) discontinued ICIs after discharge. Among ICI-treated patients who required admission, an increased likelihood of irAE-related hospitalization was associated with patient age older than 65 years (odds ratio, 5.4; 95% CI, 1.6 to 17.8) and receipt of combination immunotherapy (OR, 6.8; 95% CI, 2.0 to 23.2). CONCLUSION: A notable proportion of ICI-treated patients are hospitalized for irAEs, and these patients have a high demand for multidisciplinary management. Older age and combination ICI treatment were associated with an increased risk of irAE-related hospitalization. Whereas these data are from an academic center and include patients in clinical trials, with expanding use of ICIs, these data have important implications for inpatient service planning and risk stratification.

Resumption of Immune Checkpoint Inhibitor Therapy After Immune-Mediated Colitis.

PURPOSE: Immune checkpoint inhibitor (ICI) therapy often is suspended because of immune-mediated diarrhea and colitis (IMDC). We examined the rate of and risk factors for IMDC recurrence after ICI resumption. METHODS: This retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between January 2010 and November 2018. Univariable and multivariable logistic regression analyses assessed the association of clinical covariates and IMDC recurrence. RESULTS: Of the 167 patients in our analysis, 32 resumed an anti-cytotoxic T-cell lymphocyte-4 (CTLA-4) agent, and 135 an anti-programmed cell death 1 or ligand 1 (PD-1/L1) agent. The median age was 60 years (interquartile range [IQR], 50-69 years). The median duration from IMDC to restart of ICI treatment was 49 days (IQR, 23-136 days). IMDC recurred in 57 patients (34%) overall (44% of those receiving an anti-CTLA-4 and 32% of those receiving an anti-PD-1/L1); 47 of these patients (82%) required immunosuppressive therapy for recurrent IMDC, and all required permanent discontinuation of ICI therapy. The median duration from ICI resumption to IMDC recurrence was 53 days (IQR, 22-138 days). On multivariable logistic regression, patients who received anti-PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45; 95% CI, 1.59 to 7.69; P = .002). Risk of IMDC recurrence was higher for patients who required immunosuppression for initial IMDC (OR, 3.22; 95% CI, 1.08 to 9.62; P = .019) or had a longer duration of IMDC symptoms in the initial episode (OR, 1.01; 95% CI, 1.00 to 1.03; P = .031). Risk of IMDC recurrence was lower after resumption of anti-PD-1/L1 therapy than after resumption of anti-CTLA-4 therapy (OR, 0.30; 95% CI, 0.11 to 0.81; P = .019). CONCLUSION: One third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. Recurrence of IMDC was less frequent after resumption of anti-PD-1/L1 than after resumption of anti-CTLA-4.

EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP).

OBJECTIVES: Contrasting other EGFR mutations (EGFRm) in lung adenocarcinomas, insertions in exon 20 (exon20ins) are generally associated with resistance to targeted therapy, limiting therapeutic options and impoverishing the prognosis compared to other EGFRm. We sought to extensively characterize exon20ins from a large cohort of lung adenocarcinomas in Hispanic patients. MATERIALS AND METHODS: This was a region-wide, observational longitudinal cohort study to evaluate characteristics and outcomes of patients with exon20ins in lung adenocarcinoma, based on a secondary analysis of electronic records from the Geno1.2-CLICaP Platform and extended genotype testing. Patients from six Latin-American countries were included (Argentina, Colombia, Costa Rica, Ecuador, Panama, and Mexico). Data obtained included the molecular spectrum (extended genotyping for mutations in BRAF, NRAS, PIK3CA, Her2 and MEK1, as well as for EGFR amplification, ALK and PD-L1 protein expression), clinic-pathologic characteristics, prevalence and outcomes to therapeutic approach. RESULTS AND CONCLUSIONS: 4.005 patients diagnosed with stage III/IV lung adenocarcinoma from 2011 to 2016 were initially screened. Among these, 88 patients had a confirmed exon20 in. and were included; median age was 66-years, 62.5% were females, 64% were never smokers and 39% presented with brain metastases. The H773insH variant was the most frequent, making up 21.6% of cases. A common EGFRm was concomitantly found in 36.4% (del19/L858R), and 8% (G719X/L861Q/S768I) of cases. Five cases had additional mutations in PI3K, KRAS and MEK1, 26% had EGFR amplification and 81.7% had PD-L1 expression 1-50%. Overall response rate to first-line therapy was 28% and overall survival was 16.4 months. Prognosis was positively influenced by the concomitant presence of common EGFRm and response to first-line. Our results suggest that patients with EGFR exon20ins have similar clinical characteristics to those with common EGFRm but a poorer prognosis. Last, the mean PD-L1 expression in this population seems higher than for patients with common EGFRm.

EGFR Amplification and Sensitizing Mutations Correlate with Survival in Lung Adenocarcinoma Patients Treated with Erlotinib (MutP-CLICaP).

BACKGROUND: Non-small cell lung cancer (NSCLC) has a 5-year survival of 5-16%. Epidermal growth factor receptor (EGFR) mutations, in most cases, confer sensitivity to EGFR tyrosine kinase inhibitor (TKI) therapy. Nonetheless, it is still unclear why clinical outcomes vary among patients with identical EGFR mutations. The amplification of the EGFR gene (EGFRamp) may play a significant role. OBJECTIVE: Compare the complete (CR) and partial response (PR) rates, overall survival (OS), and progression-free survival (PFS) in Hispanic patients with lung adenocarcinoma treated with erlotinib with EGFR mutations (L858R or exon 19 deletion [Del19]) with and without concomitant EGFRamp. PATIENTS AND METHODS: Seventy-two EGFR-positive lung adenocarcinoma patients of Hispanic origin, who underwent first-line treatment with erlotinib, were evaluated for EGFRamp by fluorescence in situ hybridization (FISH). The clinical outcomes were analyzed according to EGFR mutations and EGFRamp status. RESULTS: 30.6% of samples showed EGFRamp, more frequently present in patients with Del19 (p = 0.05). Patients with EGFRamp had a longer PFS (in months) [(28.5, 95% CI 22.3-34.6) vs. (11.0, 95% CI 8.2-16.7); p = 0.002] and OS [(37.8, 95% CI 30.9-44.7) vs. (27.1, 95% CI 12.8-41.3); p = 0.009] than those without. EGFRamp significantly influenced the response to erlotinib (p = 0.0001). EGFRamp+/Del19 had a longer OS, 37.8 (95% CI 31.0-44.6), compared to EGFRamp+/L8585R, 27.5 (95% CI 12.4-42.5) (p < 0.001) and longer PFS (p = 0.043). CONCLUSION: Among Hispanic patients, EGFRamp was present in 30% of patients with EGFR mutations. EGFR mutations and EGFRamp are associated with better OS, PFS, CR, and PR to erlotinib and, hence, could aid in the correct selection of patients that benefit from EGFR TKI treatment.

Role of liquid biopsies in colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer worldwide, with a global incidence of over 1 million cases. In the era of personalized medicine, tumor sampling is essential for characterizing the molecular profile of individual tumors. This provides pivotal information regarding optimal sequencing of therapy and emergence of drug resistance, allowing for timely therapy adjustment. However, tumor tissue sampling offers static information in a single time point and area of disease at the time of biopsy, which may not entirely represent the heterogeneity of molecular alterations. Moreover, tumor biopsies often involve invasive procedures with potential risks to patients. Less invasive, safer, and real-time methods such as liquid biopsies have generated increasing interest as a surrogate of solid tumor biopsies. Liquid biopsy allows for noninvasive survey with detection of cell-free circulating tumor DNA (ctDNA) or circulating tumor cells. Blood-based assays are the most widely studied. Additionally, the quantity of ctDNA detected has been shown to correlate with tumor burden and enables assessment of tumor heterogeneity. In this article, we discuss the concept of liquid biopsies including ctDNA and circulating tumor cell, and their current application in the diagnosis and management of CRC. We suggest that liquid biopsies can be successfully used to characterize the molecular profile of CRC, monitor disease, detect minimal residual disease after surgery, and identify therapeutic targets and mechanisms of drug resistance. This strategy could potentially imply an early change in treatment, sparing unnecessary side effects, and minimizing health costs. Combined radiological and liquid biopsy assessments will likely become more standard in CRC oncology. However, large prospective studies are needed to definitively establish the role of liquid biopsy.

Treatment of Complications from Immune Checkpoint Inhibition in Patients with Lung Cancer.

OPINION STATEMENT: Immune checkpoint inhibitors have revolutionized the management of advanced NSCLC. With the intention of generating an anti-tumor immune response, ICIs can also lead to inflammatory side effects involving a wide variety of organs in the body, termed immune-related adverse events. Although no prospective clinical trial exists to guide recommendations for optimal and more specific immunosuppressive treatments rather than corticosteroids, further studies may lead to a more mechanistic-based approach towards these toxicities in the future. In relation to current practice, we recommend adherence to the recent published guidelines which emphasize the importance of early recognition and administration of temporary immunosuppressive therapy with corticosteroids in most cases, depending on the organ system involved, and the severity of toxicity. Recognition of these toxicities is increasingly important as the use of these agents expand within different indications for patients with lung cancers, and to other tumor types.

Valvuloplastia mitral percutánea de emergencia en un paciente con edema pulmonar refractario / Emergency percutaneous mitral valvuloplasty in a patient with refractory pulmonary oedema

Resumen La estenosis mitral usualmente es causada por fiebre reumática. A pesar de ser una patología poco frecuente en los países desarrollados, es prevalente en los países en vía de desarrollo, donde aproximadamente dos tercios de la población mundial vive, haciendo de esta condición, una enfermedad valvular común. Es importante considerar la estenosis mitral en el diagnóstico diferencial de los pacientes con edema agudo de pulmón cardiogénico refractario y la valvuloplastia mitral percutánea de emergencia como el tratamiento definitivo. Se presenta el caso de un paciente femenino de 21 años, con edema agudo de pulmón cardiogénico refractario, secundario a estenosis mitral muy severa de origen reumático, tratado con valvuloplastia percutánea con balón de urgencia. Se realiza una revisión sobre la estenosis mitral y se examina el tratamiento con especial énfasis en los casos publicados en la literatura de valvuloplastia mitral percutánea de emergencia.

Abstract Mitral valve stenosis is usually caused by rheumatic fever. Although it is an uncommon disease in developed countries, it is prevalent in developing countries where approximately two-thirds of the world population lives, making this condition a common valve disease. It is important to consider mitral stenosis in the differential diagnosis of patients with acute refractory cardiogenic pulmonary oedema, and emergency percutaneous mitral valvuloplasty as the definitive treatment. The case is presented of a 21 year-old female with acute refractory cardiogenic pulmonary oedema, secondary to a very severe mitral stenosis of rheumatic origin, and who was treated with an urgent percutaneous balloon valvuloplasty. A review of mitral stenosis is presented, and the treatment is examined, with special emphasis on cases of emergency percutaneous mitral valvuloplasty published in the literature.

Efficacy and safety of Levetiracetam vs. other antiepileptic drugs in Hispanic patients with glioblastoma.

Epilepsy is a common symptom in patients with glioblastoma (GB). 213 patients with GB from RedLANO follow-up registry were included. All patients underwent surgery, if feasible, followed by chemoradiation based on temozolomide (Stupp platform). Information was recorded regarding demographics, seizure timing, anti-epileptic drugs (AEDs), dosage, time to next seizure, total seizures in 6 months, and main side effects of AEDs. The relationship between epilepsy treatment and overall survival (OS) was evaluated. Mean age was 53 years old and 56.8% were male. Seventy-eight patients (37%) were treated with levetiracetam (LEV), 27% were given another AED and 36% did not require any AED. Choice of AED was not associated with age (p = 0.67), performance status (p = 0.24) or anatomic tumor site (p = 0.34). Seizures and AED requirement were greater in those having primary GB (p = 0.04). After starting an AED, the mean time until next crisis was 9.9 days (SD ± 6.3), which was shorter in those receiving LEV (p = 0.03); mean number of seizures during the first 3 and 6 months were 2.9 and 4, respectively. Most patients treated with LEV (n = 46) required less than two medication adjustments compared to those treated with other AEDs (p = 0.02). Likewise, less patients exposed to LEV required a coadjuvant drug (p = 0.04). Additionally, patients receiving LEV had significantly less adverse effects compared to patients treated with another AED. OS was significantly higher in the group treated with LEV compared to other AEDs (25.5 vs. 17.9 months; p = 0.047). Patients treated with LEV had better seizure control and longer OS compared to other AEDs.

An international epidemiological analysis of young patients with non-small cell lung cancer (AduJov-CLICaP).

BACKGROUND: A proportion of patients with NSCLC is diagnosed at 40 years or younger. These patients tend to be never-smokers, usually present with stage IV adenocarcinoma, and have somatic genomic alterations. Few studies have documented and analyzed epidemiological characteristics of this population. MATERIALS AND METHODS: We performed an international epidemiological analysis of 389 young patients with NSCLC. Data was collected from centers participating in the Latin American Consortium for Lung Cancer Research (AduJov-CLICaP). Patients were identified and data was retrospectively collected from different Latin American countries and Canada (Argentina=6, Canada=19, Colombia=29, Costa Rica=9, Mexico=219, Nicaragua=2, Panama=19, Perú=76 and Venezuela=10). The period of study was from 2012 to 2017. Inclusion criteria were: age 40 years or less and a histologically confirmed NSCLC. Clinical data was obtained, and EGFR mutation status and EML4-ALK translocation were collected. RESULTS: NSCLC patients aged 40 years or less accounted for approximately 4% of the total NSCLC population. Female patients accounted for 54.5%, while median age was of 37 years. Adenocarcinoma accounted for 86.1% (n=335/389), 72.5% (n=282/389; unknown=5) of patients were non-smokers, and 90.3% (n=351/389) had stage IV disease. Site of metastasis was obtained from 260/351 (unknown=91) stage IV patients (lung metastasis=40.0%, CNS metastasis=35.7%, and bone metastasis=31.5%). OS for the total population was 17.3 months (95%CI=13.9-20.7). OS for EGFRm(+)=31.4months (95%CI=11.6-51.3), EGFRm(-)=14.5months (95%CI=11.0-17.9) (p=0.005). OS for alk(+)=9.8months (95%CI=3.1-16.5) and alk(-)=5.6months (95%CI=3.9-7.3) (p=0.315). CONCLUSIONS: Patients aged 40 years or less account for a small but important proportion of NSCLC cases. Younger patients may have different characteristics compared to the older population. EGFRm and EML4-alk translocation frequency is higher than that of the general population.

Survival Outcomes According to TIMP1 and EGFR Expression in Heavily Treated Patients with Advanced Non-small Cell Lung Cancer who Received Biweekly Irinotecan Plus Bevacizumab.

BACKGROUND: Heavily treated patients with non-small cell lung cancer (NSCLC) have few treatment options, while irinotecan and bevacizumab have proven synergistic action in preclinical studies. PATIENTS AND METHODS: A total of 49 patients with heavily treated NSCLC were enrolled from 2011-2014 and treated with irinotecan and bevacizumab. Treatment response along with mutational status of epidermal growth factor receptor (EGFR), and tissue inhibitor of metalloproteinases-1 (TIMP1) and EGFR expression were evaluated. Progression-free (PFS) and overall (OS) survival were monitored. RESULTS: Median follow-up was 13.2 months. Twenty-three patients had received three or more prior therapy lines. Overall response rate was 32% [95% confidence interval (CI)=22%-39%] and 26% of patients achieved stable disease. Median PFS was 4.4 (95% CI=2.8-8.3) months and median OS 18.0 (95% CI=16.2-30.7) months. Nine patients harboring EGFR mutations had a long-lasting partial response. A shorter OS was found in patients with a higher TIMP1 expression (p=0.006). CONCLUSION: Irinotecan combined with bevacizumab had favorable antitumor activity in heavily pretreated patients with NSCLC. These results suggest this is a reasonable strategy, particularly for patients with low TIMP1 expression.

Acquired Resistance to Erlotinib in EGFR Mutation-Positive Lung Adenocarcinoma among Hispanics (CLICaP).

BACKGROUND: Lung cancer harboring epidermal growth factor receptor (EGFR) mutations and treated with EGFR tyrosine kinase inhibitors (TKIs) all eventually develop acquired resistance to the treatment, with half of the patients developing EGFR T790M resistance mutations. OBJECTIVE: The purpose of this study was to assess histological and clinical characteristics and survival outcomes in Hispanic EGFR mutated lung cancer patients after disease progression. PATIENTS AND METHODS: EGFR mutation-positive lung cancer patients (n = 34) with acquired resistance to the EGFR-TKI erlotinib were identified from 2011 to 2015. Post-progression tumor specimens were collected for molecular analysis. Post-progression interventions, response to treatment, and survival were assessed and compared among all patients and those with and without T790M mutations. RESULTS: Mean age was 59.4 ± 13.9 years, 65% were never-smokers, and 53% had a performance status 0-1. All patients received erlotinib as first-line treatment. Identified mutations included: 60% DelE19 (Del746-750) and 40% L858R. First-line erlotinib overall response rate (ORR) was 61.8% and progression free survival (PFS) was 16.8 months (95% CI: 13.7-19.9). Acquired resistance mutations identified were T790M mutation (47.1%); PI3K mutations (14.7%); EGFR amplification (14.7%); KRAS mutation (5.9%); MET amplification (8.8%); HER2 alterations (5.9%, deletions/insertions in e20); and SCLC transformation (2.9%). Of patients, 79.4% received treatment after progression. ORR for post-erlotinib treatment was 47.1% (CR 2/PR 14) and median PFS was 8.3 months (95% CI: 2.2-36.6). Median overall survival (OS) from treatment initiation was 32.9 months (95% CI: 30.4-35.3), and only the use of post-progression therapy affected OS in a multivariate analysis (p = 0.05). CONCLUSIONS: Hispanic patients with acquired resistance to erlotinib continued to be sensitive to other treatments after progression. The proportion of T790M+ patients appears to be similar to that previously reported in Caucasians.

BIM deletion polymorphisms in Hispanic patients with non-small cell lung cancer carriers of EGFR mutations.

BACKGROUND: Germline alterations in the proapoptotic protein Bcl-2-like 11 (BIM) can have a crucial role in diverse tumors. To determine the clinical utility of detecting BIM deletion polymorphisms (par4226 bp/ par363 bp) in EGFR positive non-small-cell lung cancer (NSCLC) we examined the outcomes of patients with and without BIM alterations. RESULTS: BIM deletion was present in 14 patients (15.7%). There were no significant differences between patients with and without BIM-del in clinical characteristics or EGFR mutation type; however, those with BIM-del had a worse overall response rate (ORR) to erlotinib (42.9% vs. 73.3% in patients without BIM-del; p=0.024) as well as a significantly shorter progression-free survival (PFS) (10.8 BIM-del+ vs. 21.7 months for patients without BIM-del; p=0.029) and overall survival (OS) (15.5 BIM-del+ vs. 34.0 months for patients without BIM-del; p=0.035). Multivariate Cox regression analysis showed that BIM-del+ was an independent indicator of shorter PFS (HR 3.0; 95%CI 1.2-7.6; p=0.01) and OS (HR 3.4; 95%CI 1.4-8.3; p=0.006). METHODS: We studied 89 NSCLC Hispanic patients with EGFR mutation who were treated with erlotinib between January 2009 and November 2014. BIM deletion polymorphisms (BIM-del) was analyzed by PCR in formalin-fixed paraffin-embedded (FFPE) tissues of tumor biopsies. We retrospectively analyzed clinical characteristics, response rate, toxicity, and outcomes among patients with and without BIM-del. CONCLUSIONS: The incidence of BIM-del found in Hispanic patients is similar to that previously described in Asia. This alteration is associated with a poor clinical response to erlotinib and represents an independent prognostic factor for patients who had NSCLC with an EGFR mutation.

Epithelial-mesenchymal transition, proliferation, and angiogenesis in locally advanced cervical cancer treated with chemoradiotherapy.

We evaluated the association between epithelial-mesenchymal transition (EMT)-derived markers and expression of proteins associated with cell proliferation and tumor growth, as well as their prognostic roles, in 61 patients (mean age 52 ± 10 years) with locally advanced cervical cancer, all of whom were treated with chemoradiation and intracavitary brachytherapy. We used immunohistochemical analysis to assess the expression of proteins targeted in our investigation. Various statistical analyses were then conducted to assess protein marker associations with survival outcomes. Forty-six percent of the patients were positive for human papilloma virus. Median progression-free survival (PFS) was 6.6 months (95% confidence interval [CI]: 4.0-9.1, whereas overall survival (OS) was 30.0 months (95% CI: 11-48). Multivariate analysis demonstrated that vascular endothelial growth factor (VEGF) (P = 0.002), epidermal growth factor receptor (EGFR) (P = 0.001), and TWIST2 (P = 0.001) expression levels, as well as a tumor size <6 cm (P = 0.02), influenced OS. Changes in TWIST2 levels and loss of E-cadherin expression were correlated with VEGF and EGFR levels; furthermore, patients with high TWIST2 expression had shorter OS (P = 0.0001), as those with loss of E-cadherin (P = 0.02). OS was even shorter when positive EGFR or VEGF expression was related with EMT markers (positive EGFR + negative E-cadherin: median 14 months, 95% CI: 3-24; negative EGFR + positive E-cadherin: median 31 months, 95% CI: 14-NA; P = 0.02.). The presence of EMT markers was associated with proliferative and pro-angiogenic protein expression and influenced the prognosis of locally advanced cervical cancer.

Pemetrexed/Carboplatin/Bevacizumab followed by Maintenance Pemetrexed/Bevacizumab in Hispanic Patients with Non-Squamous Non-Small Cell Lung Cancer: Outcomes according to Thymidylate Synthase Expression.

OBJECTIVE: To evaluate the efficacy and safety of pemetrexed, carboplatin and bevacizumab (PCB) followed by maintenance therapy with pemetrexed and bevacizumab (PB) in chemotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer (NSCLC) through the influence of thymidylate synthase (TS) protein and mRNA expression on several outcomes. The primary endpoints were the overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). METHODS: A cohort of 144 patients were administered pemetrexed (500 mg/m2), carboplatin (AUC, 5.0 mg/ml/min) and bevacizumab (7.5 mg/kg) intravenously every three weeks for up to four cycles. Maintenance PB was administered until disease progression or unacceptable toxicity. RESULTS: One hundred forty-four Colombian patients with a median follow-up of 13.8 months and a median number of 6 maintenance cycles (range, 1-32) were assessed. The ORR among the patients was 66% (95% CI, 47% to 79%). The median PFS and (OS) rates were 7.9 months (95% CI, 5.9-10.0 months) and 21.4 months (95% CI, 18.3 to 24.4 months), respectively. We documented grade 3/4 hematologic toxicities, including anemia (14%), neutropenia (8%), and thrombocytopenia (16%). The identified grade 3/4 non-hematologic toxicities were proteinuria (2%), venous thrombosis (4%), fatigue (11%), infection (6%), nephrotoxicity (2%), and sensory neuropathy (4%). No grade >3 hemorrhagic events or hypertension cases were reported. OS was significantly higher in patients with the lowest TS mRNA levels [median, 29.6 months (95% CI, 26.2-32.9)] compared with those in patients with higher levels [median, 9.3 months (95% CI, 6.6-12.0); p = 0.0001]. TS expression (mRNA levels or protein expression) did not influence the treatment response. CONCLUSION: Overall, PCB followed by maintenance pemetrexed and bevacizumab was effective and tolerable in Hispanic patients with non-squamous NSCLC. This regimen was associated with acceptable toxicity and prolonged OS, particularly in patients with low TS expression. We found a role for Ki67 and TS expression as prognostic factors.

Pericarditis postraumática como manifestación del síndrome de lesión postcardiaca: Post-traumatic pericarditis as a manifestation of post cardiac injury syndrome / Post-traumatic pericarditis as a manifestation of post cardiac injury syndrome

La pericarditis constrictiva ocurre cuando el pericardio engrosado y calcificado impide el llenado ventricular adecuado y en consecuencia ocasiona una limitación del volumen cardiaco total. En la actualidad, una de las causas más comunes es el trauma cardiaco. Los cuadros de pericarditis secundarios a daño del pericardio constituyen el síndrome de lesión postcardiaca, el cual incluye pericarditis postinfarto o síndrome de Dressler, síndrome postpericardiotomía y pericarditis postraumática. Se ha decidido utilizar este nuevo término en la medida en que es más incluyente puesto que la lesión inicial también puede estar en el miocardio y no sólo en el pericardio. Su fisiopatología no se conoce por completo, pero cree que puede tener un componente tanto inflamatorio como autoinmune. Usualmente es un diagnóstico de exclusión que requiere tratamiento definitivo con pericardiectomía. A continuación se reporta el caso de una paciente con pericarditis constrictiva posterior a un trauma cerrado de tórax.

Constrictive pericarditis occurs when thickened and calcified pericardium prevents adequate ventricular filling and consequently causes a limitation of the total cardiac output. Currently, one of its most common causes is cardiac trauma. Clinical conditions of pericarditis secondary to pericardial injury constitute the post cardiac injury syndrome which includes post-infarction pericarditis or Dressler syndrome, post-pericardiotomy syndrome and post-traumatic pericarditis. It was decided to use this new term to the extent that is more inclusive, since the initial injury may also be in the myocardium and not only in the pericardium. Its pathophysiology is not completely understood, but is believed to have both an inflammatory and an autoimmune component. Usually it is a diagnosis of exclusion that requires definitive treatment with pericardiectomy. The case of a patient with constrictive pericarditis subsequent to a closed chest trauma is reported.

Inhibición dual de la neprilisina y del receptor de la angiotensina (ARNI): una alternativa en los pacientes con falla cardiaca / Dual angiotensin receptor and neprilysin inhibition (ARNI): an alternative for patients with cardiac failure

La falla cardiaca (FC) es la causa más común de admisión hospitalaria en adultos en el mundo. Además, de su importante prevalencia la FC tiene un alta tasa de mortalidad, se estima que aproximadamente el 50% de los pacientes con FC mueren a los 5 años posterior al egreso hospitalario. Esto ha motivado el desarrollo de nuevas terapias seguras y efectivas para el manejo de esta entidad. El LCZ696 es un inhibidor dual de la neprilisina y del receptor de angiotensina II que demostró en estudios de fase III disminuir el desenlace primario de muerte cardiovascular y hospitalización por empeoramiento de la FC y muerte global. Probablemente el LCZ696 se convertirá en la piedra angular del manejo en pacientes con FC con fracción de eyección deprimida.

Cardiac failure (CF) is the most common cause of hospital admission in adults all over the world. In addition to its important prevalence, CF presents a high mortality rate. It is estimated that approximately 59% of patients with CF die within 5 years after the admission. This has been the motivation for the development of new, safe and effective therapies aimed at the management of this disease. LCZ696 is an angiotensin II receptor-neprilysin inhibitor; phase III studies have shown it decreases the primary outcome of cardiovascular death and admission due to worsening of the CF and global death. LCZ696 could probably become the cornerstone of the management of patients with CF with depressed ejection fraction.