Correlation between PD-L1 expression (clones 28-8 and SP263) and histopathology in lung adenocarcinoma.

Lung cancer is the leading cause of cancer-related death worldwide. Recent advances in the management of non-small cell carcinoma are focused on the discovery of targeted therapies and novel immunotherapy strategies for patients with advanced disease. Treatment with anti PD-(L)1 immune checkpoint inhibitors requires the development of predictive biomarkers to select those patients that can most benefit from these therapies. Several immunohistochemical biomarkers have been developed in different technological platforms. However, the most useful and accessible for the daily clinical practice need to be selected. The objective of this study was to compare PD-L1 expression by automated immunohistochemistry in lung adenocarcinoma (ADC) FFPE samples with clones 28-8 and SP263 performed with the BenchMark GX automated staining instrument. To further determine interobserver agreement between two pathologists, and to correlate the results with histologic and pathology variables. FFPE tissue from 40 samples obtained from patients with lung ADC were reviewed retrospectively. Among all studied specimens, 53% of samples presented <1% of positive tumor cells with the 28-8 clone and 50% had <1% of PD-L1 expression in tumor cells with the SP263 clone; PD-L1 expression between ≥1 and <5% was observed in 18% and 24%; ≥5 and <50% PD-L1 expression in 18% and 21%; and ≥50% PD-L1 expression in 11% and 5% of samples, respectively. Similar results between antibodies were observed in 84% of cases for each of the four PD-L1 cutoff groups (Pearson's score 0.90, p < 0.00001). The interobserver degree of agreement calculated with Kappa was 0.75 (95%CI: 0.57-0.93), z = 7.08; p < 0.001. Lepidic, acinar and mucinous patterns had predominantly <1% PD-L1 expression, and the solid pattern subtype had high levels of PD-L1 staining using both clones. PD-L1 expression in less than 1% of tumor cells was similar in stages I/II compared to III/IV. No significant differences were observed in PD-L1 staining and quantification pattern between IHC antibodies 28-8 and SP263.

Tobacco smoking is an independent factor associated with retinal damage in systemic lupus erythematosus: a cross-sectional and retrospective study.

To analyze the influence of tobacco smoking on systemic lupus erythematosus (SLE) clinical features and damage. Cross-sectional and retrospective, case-control study comparing SLE patients with and without tobacco exposure. Cumulative clinical data and comorbidities were collected, and severity (Katz index) and damage (SLICC/ACR damage index) (SDI) indices were calculated. Pack-years (PY) was used to estimate lifetime tobacco exposure. A logistic regression was carried out to explore the impact of tobacco use on retinal damage. 216 patients were included. The mean age was 49 years (± 12.7), 93% were females, and median disease duration was 17 years [interquartile range (IQR):9-25]. Fifty-three percent of patients were smokers at some point. The median PY was 13 (IQR: 6-20.5). Only 54.8% of active smokers recalled having been informed of the negative effects of smoking, versus 83.3% of never smokers (< 0.001). In a bivariant analysis, an association between tobacco use at any time and discoid lupus [OR: 3.5(95%CI 1.5-8.9); p = 0.002] photosensitivity [OR: 2.06(95%CI 1.16-3.7); p = 0.01] and peripheral arteriopathy (p = 0.007) was found. Considering SDI item by item, a significant association with retinal damage, adjusted for age [OR: 1.03(95%CI 1-1.07); p = 0.04], was found. Using PYs, an association was found with discoid lupus (p = 0.01), photosensitivity (p = 0.03) and peripheral arteriopathy (p = 0.01), global SDI > 0 (p = 0.002) and retinal damage (p = 0.02). In a multivariate analysis exploring factors associated with retinal damage, any previous smoking history and SDI remained associated with retinal damage. Tobacco smoking is associated with cutaneous manifestations and damage and is an independent predictor of retinal damage in SLE patients.

Distribution of molecular subtypes of advanced lung adenocarcinoma and clinical outcomes in a center of Argentina.

The prevalence of relevant oncogenic drivers in lung adenocarcinoma varies in our region and data on clinical outcomes is scarce. The objective of the study was to describe the prevalence of KRAS, BRAF and EGFR mutations and ALK translocations in patients with advanced lung adenocarcinoma, and to depict the clinical outcome according to treatment strategies. Patients with adequate tumor biopsy sampling were included. KRAS, BRAF and EGFR mutations were studied by Sanger sequencing. ALK translocations were studied by fluorescent in situ hybridization (FISH) and immunohistochemistry (IH) with antibodies against ALK with clones D5F3 and 5A4. Informed consent was signed by 118 patients and 84 (72%) with complete molecular analysis were included. KRAS mutations were detected in 16 samples (19%), EGFR in 11 (13%), 9 of them conferring sensitivity to EGFR inhibitors, and BRAF mutations in 1 (1%). ALK translocations were detected in 3 samples (4%). Median follow-up was 42.4 [interquartile range (IQR): 27.0-64.2] months. Globally, median overall survival was 10.3 [IQR: 5.6-20.2] months. Median survival was 10.8 [IQR: 6.0-20.3] months in the group of patients without detectable molecular alteration, 9.6 [IQR: 3.7-16.1] months in KRAS mutant population (HR: 1.08; p = 0.82) and 32.5 [IQR: 19.6-38.4] months in patients with ALK translocations or sensitizing EGFR mutated tumors treated with tyrosine kinase inhibitors (HR: 0.27; p = 0.03). In conclusion, the prevalence of molecular alterations and outcomes in our population is similar to that reported in other studies in Western countries.

Distribution of molecular subtypes of advanced lung adenocarcinoma and clinical outcomes in a center of Argentina

The prevalence of relevant oncogenic drivers in lung adenocarcinoma varies in our region and data on clinical outcomes is scarce. The objective of the study was to describe the prevalence of KRAS, BRAF and EGFR mutations and ALK translocations in patients with advanced lung adenocarcinoma, and to depict the clinical outcome according to treatment strategies. Patients with adequate tumor biopsy sampling were included. KRAS, BRAF and EGFR mutations were studied by Sanger sequencing. ALK translocations were studied by fluorescent in situ hybridization (FISH) and immunohistochemistry (IH) with antibodies against ALK with clones D5F3 and 5A4. Informed consent was signed by 118 patients and 84 (72%) with complete molecular analysis were included. KRAS mutations were detected in 16 samples (19%), EGFR in 11 (13%), 9 of them conferring sensitivity to EGFR inhibitors, and BRAF mutations in 1 (1%). ALK translocations were detected in 3 samples (4%). Median follow-up was 42.4 [interquartile range (IQR): 27.0-64.2] months. Globally, median overall survival was 10.3 [IQR: 5.6-20.2] months. Median survival was 10.8 [IQR: 6.0-20.3] months in the group of patients without detectable molecular alteration, 9.6 [IQR: 3.7-16.1] months in KRAS mutant population (HR: 1.08; p = 0.82) and 32.5 [IQR: 19.6-38.4] months in patients with ALK translocations or sensitizing EGFR mutated tumors treated with tyrosine kinase inhibitors (HR: 0.27; p = 0.03). In conclusion, the prevalence of molecular alterations and outcomes in our population is similar to that reported in other studies in Western countries.

La prevalencia de alteraciones en oncogenes en adenocarcinoma de pulmón varía en nuestra región. El objetivo fue describir la prevalencia de mutaciones en KRAS, BRAF y EGFR y las translocaciones de ALK en pacientes con adenocarcinoma de pulmón y estudiar la supervivencia de acuerdo a subtipos moleculares. Se incluyeron pacientes con biopsias adecuadas para el estudio. Se evaluó el estado mutacional de KRAS, BRAF y EGFR por secuenciación con la técnica de Sanger. Las translocaciones de ALK se estudiaron por hibridación in situ por fluorescencia (FISH) e inmunohistoquimica (IHQ) contra ALK (clones D5F3 y 5A4). De 118 pacientes evaluados, se incluyeron 84 (72%) con análisis molecular completo. Se detectaron mutaciones de KRAS en 16 muestras (19%), EGFR en 11 (13%), y BRAF en 1 muestra (1%). Se detectaron rearreglos de ALK en 3 muestras (4%). La mediana de seguimiento de los pacientes fue de 42.4 [rango intercuatilo (RIC): 27.0-64.2] meses. Globalmente, la mediana de supervivencia en la población fue 10.3 [RIC: 5.6-20.2] meses y fue de 10.8 [RIC: 6.0 20.3] meses en pacientes sin alteraciones moleculares detectables. La mediana de supervivencia de los pacientes con mutación en KRAS fue de 9.6 [RIC: 3.7-16.1] meses (HR: 1.08; p = 0.82) y 32.5 [RIC: 19.6-38.4] meses en el grupo con rearreglos de ALK o mutaciones en EGFR tratados con inhibidores de tirosina quinasa (HR: 0.27; p = 0.03). En conclusión, la prevalencia de alteraciones moleculares en nuestra población fue similar a otros países occidentales.

Correction to: Musculoskeletal infections caused by Aerococcus urinae: a case-based review.

The presentation of the Table 1 of the original version of this article was incorrectly published. The Table is now presented correctly in this article.

Optimizing the treatment of metastatic castration-resistant prostate cancer: a Latin America perspective.

Prostate cancer is a significant burden and cause of mortality in Latin America. This article reviews the treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) and provides consensus recommendations to assist Latin American prostate cancer specialists with clinical decision making. A multidisciplinary expert panel from Latin America reviewed the available data and their individual experience to develop clinical consensus opinions for the use of life-prolonging agents in mCRPC, with consideration given to factors influencing patient selection and treatment monitoring. There is a lack of level 1 evidence for the best treatment sequence or combinations in mCRPC. In this context, consensus recommendations were provided for the use of taxane-based chemotherapies, androgen receptor axis-targeted agents and targeted alpha therapy, for patients in Latin America. Prostate-specific antigen (PSA) changes alone, during treatment, should be treated with caution; PSA may not be a suitable biomarker for radium-223. Bone scans and computed tomography are the standard imaging modalities in Latin America. Imaging should be prompted during treatment where symptomatic decline and/or significant worsening of laboratory evaluations are reported, or where a course of therapy has been completed and another antineoplastic agent is under consideration. Recommendations and guidance for treatment options in Latin America are provided in the context of country-level variable access to approved agents and technologies for treatment monitoring. Patients should be treated with the purpose of prolonging overall survival and preserving quality of life through increasing the opportunity to administer all available life-prolonging therapies when appropriate.

Musculoskeletal infections caused by Aerococcus urinae: a case-based review.

Aerococcus are Gram-positive bacteria that have been historically misidentified using standard techniques. We report a case of a 63-year-old man with septic oligoarthritis caused by Aerococcus urinae (isolated in two ankle synovial fluid cultures and in two blood cultures). Due to the lack of evidence found in a search performed to identify similar cases, a systematic review was conducted with the objective to identify and analyze all documented cases of musculoskeletal infections caused by Aerococcus urinae. A total of 8 cases were selected: 6 spondylodiscitis, 1 periarticular hip abscess, and 1 prosthetic hip infection. Similarly, as in other Aerococcus urinae invasive infections, these were presented predominantly in older males with history of urinary tract disease, being identified mostly by sequencing of the 16S rRNA or by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), with an increasing incidence in the last years and generally with good sensitivity to beta-lactams (aminoglycosides were associated in some cases due to its synergistic effect). Additionally, 4 cases of musculoskeletal infections caused by Aerococcus viridans and 4 cases of Aerococcus urinae with ammoniacal and pervasive malodorous urine were identified; the last was a symptom also present in our case. In this review, we identify a recent increase of musculoskeletal infections caused by Aerococcus urinae, which as well as in series of other invasive infections could be well correlated with an increasing use of more sensible diagnosis methods in clinical laboratories. Therefore, we suggest that these probably will be more frequently diagnosed in the future.

Spectrum of BRCA1/2 variants in 940 patients from Argentina including novel, deleterious and recurrent germline mutations: impact on healthcare and clinical practice.

BRCA1/2 mutations in Latin America are scarcely documented and in serious need of knowledge about the spectrum of BRCA pathogenic variants, information which may alter clinical practice and subsequently improve patient outcome. In addition, the search for data on testing policies in different regions constitutes a fundamental strength for the present study, which analyzes BRCA1/2 gene sequences and large rearrangements in 940 probands with familial and/or personal history of breast/ovary cancer (BOC). In non-mutated DNA samples, Multiplex Ligation-dependent Probe Amplification assays (MLPA) were used for the analysis of large rearrangements. Our studies detected 179 deleterious mutations out of 940 (19.04%) probands, including 5 large rearrangements and 22 novel mutations. The recurrent mutations accounted for 15.08% of the total and only 2.87% of the probands analyzed, very different from a Hispanic panel previously described. IN CONCLUSION: a) this first comprehensive description of the spectrum in BRCA1/2 sheds light on the low frequency of recurrent mutations; b) this information is key in clinical practice to select adequate sequencing studies in our population, subsequently improve patient outcome and prevent damage associated to false normal reports resulting from the use of invalid population panels; c) panels of mutations from other populations should be cautiously validated before imported, even those of apparently similar origin, a concept to be considered beyond significance in Argentina.

What is the Current Role of Immunotherapy for Colon Cancer?

Colon cancer is a leading cause of cancer related mortality. Until very recently the only existing options that medical oncologists had to treat metastatic colon cancer were a combination of chemotherapy, anti-EGFR and anti-angiogenic agents. We currently have the first proof that immune therapies could be an effective approach to battle colorectal cancers that carry a mismatch repair machinery deficient phenotype. It is expected that as our knowledge of the different mechanisms of immune-resistance grows, this therapeutic modality might soon be applicable to all patients. However, due to the continuous increase in the cost of oncological drugs, some treatment overheads may soon become prohibitive for many. In this review we will examine the current evidence related to this topic with the objective to provide the reader with concise but practical information about the potential role of immunotherapy in CRC.

Immunotherapy for Non-Small Cell Lung Cancer - Finally a Hint of Hope.

Lung cancer is a major public health problem worldwide and the leading cause of cancerrelated mortality in developed countries. Significant advances have been made especially with the discovery of targeted agents. However, only a small proportion of patients carry activating mutations; until recently conventional chemotherapy and angiogenesis inhibitors were the preferred treatment for the vast majority of patients. Now, the successful experience of anti-PD-1 agents may have opened the door to a novel and previously unexplored dimension in the treatment of lung cancer: immunotherapy. In this mini-review we will discuss the current applications and future consequences related this topic, paying special attention to the clinical studies that constitute the scientific evidence to supports its use.

Anti-Hormonal Therapies for Premenopausal Patients--What did we Learn from the TEXT/SOFT Trials?

Between 20-25% of all breast cancers are diagnosed in patients younger than 50 years of age, most of whom are still premenopausal. Currently, tamoxifen is considered the standard of care for adjuvant treatment in these cases. However, in postmenopausal women, aromatase inhibitors (AIs) are a better choice. Given the superiority of AIs over tamoxifen in postmenopausal women, multiple investigators explored the potential role of AIs in premenopausal patients receiving ovarian suppression. Until very recently, available data derived from the ABCSG-12 clinical trial argued against the combination of AIs and ovarian suppression. This idea, however, may have changed with the release of the combined analysis of two clinical trials: SOFT and TEXT which evaluated the use of ovarian suppression in combination therapy. Clinicians will soon reconsider the possibility of using this strategy for premenopausal patients. Given the availability of this new data this review will analyze the consequences derived from this study, contextualize this new information within the vast available literature of anti-hormonal therapy, and discuss potential arguments in favor of and against the use of this approach.

Therapeutic options for HER-2 positive breast cancer: Perspectives and future directions.

During the last 15 years we have witnessed an unprecedented expansion in the drugs developed to target human epidermal growth factor receptor-2 (HER-2) positive breast cancer. Trastuzumab, pertuzumab, ado-trastuzumab emtansine and lapatinib are currently food and drug administration (FDA)-approved for the treatment of breast cancer patients with HER-2 over-expressed. However, given the amount of information gathered from years of uninterrupted clinical research, it is essential to have periodic updates that succinctly recapitulate what we have learnt over these last years and help us to apply that information in our daily practice. This review will pursue that objective. We will summarize the most relevant and updated information related to the state of the art management of HER-2 positive breast cancer in all the clinical scenarios including the adjuvant, neoadjuvant and metastatic settings. But we will also critically appraise that literature in order to highlight some key clinical concepts that should not be overlooked. Lastly, this review will also point out some of the most promising strategies that are currently being tested and may soon become available.

Advances and new perspectives in the treatment of metastatic colon cancer.

During the last decade we have witnessed an unprecedented outburst of new treatment approaches for the management of metastatic colon cancer. Anti-angiogenic drugs, epidermal growth factor receptor blockers and multi-kinase inhibitors have all resulted in small but consistent improvement in clinical outcomes. However, this progress has paradoxically leaded us into new challenges. In many cases the clinical development was done in parallel and the lack of head-to-head comparison evolved into circumstances where several valid new "standards of care" are available. Even though desirable in essence, the availability of many options as well as different possible combinations frequently leaves the busy clinician in the difficult situation of having to choose between one or the other, sometimes without solid evidence to support each decision. In addition, progress never stops and new agents are continuously tested. For these reason this review will try to summarize all the clinical trials that constitute the theoretical framework that support our daily practice but will also procure the reader with rational answers to common clinical dilemmas by critically appraising the current literature. Lastly, we will provide with a compilation of promising new agents that may soon become our next line of defense against this deadly disease.

[Limphomatous meningitis as recurrence site in Hodgkin's disease]. / Meningitis linfomatosa como sitio de recaída en la enfermedad de Hodgkin.

Intracraneal manifestations of Hodgkin's Disease (HD) are extremely rare, with an estimated incidence rate of approximately 0.5%. They can be classified as: 1) treatment-related leucoencephalopathy, 2) central nervous system infections, 3) paraneoplasic syndromes and 4) intracraneal lymphomas, which could be sub-classified into intraparenchymal or intradural masses. We describe a case of a 40 year-old male with mixed cellularity type HD who developed neurological manifestations as relapsed disease. Magnetic resonance imaging suggested leptomeningeal metastases and atypical cells were found in cerebrospinal fluid. The patient died from progressive disease refractory to third line chemotherapy. There are less than 50 similar cases reported in the literature. We review the clinical features and differential diagnosis of leptomeningeal metastases in Hodgkin's disease.