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In this article, we discuss the strategy designed by a private oncology group to offer patients access to new technologies and treatments via a recently created research program, and we describe how the patient journey was the motivation for developing standard assistance flows and processes to integrate areas of care. The increase in Brazilians’ life expectancy has raised the incidence of cancer, and it is now the second leading cause of death. Because it is a multifactorial disease, cancer treatment has several challenges. We elected to approach cancer research using a strategic program to obtain national attention and visibility. Starting in 2007, the initial project included three phases: phase I, diagnosis of units in major metropolitan areas; phase II, project design, with a central-office operation model; and phase III, implementation, with launch and integration of research activities at selected units. The foundation of the program was the construction of departmental and interdepartmental flows, standard operating processes, and guidelines (regulatory, ethical, legal, and financial). Recruitment of qualified professionals was another critical, successful determinant. The benefits of an additional central office include improved research-project distribution. Another advantage of the program is attracting and retaining trained professionals with alternative direct or indirect sources of revenue. We increased our corporate and academic partnerships, adhered to deadlines and noted an improvement in turnaround times, and we increased clinical staff engagement and motivation. Some barriers continue to challenge the program's continued expansion, including Brazilian regulatory authority approval, tax inefficiency, and a growing demand for qualified professionals. Research sites offering high-quality care are a reality in Brazil; they offer multiple lines of treatment in the public and private sectors.

Neoadjuvant chemoradiotherapy (neoCRT) followed by surgery is the standard of care for locally advanced rectal cancer (LARC), but the emergence of different drug regimens may result in different response rates. Good clinical response translates into greater sphincter preservation, but quality of life (QOL) may be impaired after treatment due to chemoradiotherapy and surgical side effects.To prospectively evaluate the impact of clinical response and surgical resection on QOL in a randomized trial comparing two different neoCRT regimens.Stage II and III rectal cancer patients were randomized to receive neoCRT with either capecitabine (group 1) or 5-Fu and leucovorin (group 2) concomitant to long-course radiotherapy. Clinical downstaging was accessed using MRI 6-8 weeks after treatment. EORTCs QLQ-C30 and CR38 were applied before treatment (T0), after neoCRT (T1), after rectal resection (T2), early after adjuvant chemotherapy (T3), and 1 year after the end of treatment or stoma closure (T4). The Wexner scale was used for fecal incontinence evaluation at T4. A C30SummaryScore (Geisinger and cols.) was calculated to compare QOL results.Thirty-two patients were assigned to group 1 and 31 to group 2. Clinical downstaging occurred in 70.0% of group 1 and 53.3% of group 2 (p = 0.288), and sphincter preservation was 83.3% in group 1 and 80.0% in group 2 (p = 0.111). No significant difference in QOL was detected when comparing the two treatment groups after neoCRT using QLQ-C30. However, the CR38 module detected differences in micturition problems (15.3 points), gastrointestinal problems (15.3 points), defecation problems (11.8 points), and sexual satisfaction (13.3 points) favoring the capecitabine group. C30SummaryScore detected significant improvement comparing T0 to T1 and deterioration comparing T1 to T2 (p = 0.025). The mean Wexner scale score was 9.2, and a high score correlated with symptoms of diarrhea and defecation problems at T4.QOL was equivalent between groups after neoCRT except for micturition problems, gastrointestinal problems, defecation problems, and sexual satisfaction favoring the capecitabine arm after. The overall QOL using the C30SummaryScore was improved after neoCRT, but decreased following rectal resection, returning to basal levels at late evaluation. Fecal incontinence was high after sphincter preservation.ClinicalTrials.gov Identifier: NCT03428529.

PURPOSE Non–small-cell lung cancer (NSCLC) is the most common type of lung cancer and accounts for 80%-90% of the cases. In Brazil, between 2018 and 2019, lung cancer was ranked as the second most frequent cancer among men and the fourth among women. The primary objectives were to describe the journey and survival rates of patients with advanced NSCLC treated in the Brazilian private health care system (HCS). MATERIALS AND METHODS A retrospective cohort study was based on the search in administrative databases to analyze the Brazilian private HCS. Patients with advanced NSCLC diagnosed between 2011 and 2016 were included. The data on demographics, cancer-related information, treatment-related information, and resources used were collected. Survival analyses were performed using the semiparametric Kaplan-Meier method to assess mortality by NSCLC stage, with NSCLC diagnosis as the index date. RESULTS A total of 5,016 patients were included. Most patients were between 60 and 69 years old (33.6%) and had completed elementary school (52.2%). There was a greater proportion of men (58.1% v 41.9%), and the majority of patients had stage IV NSCLC (67%). It took an average of 31 days, from the first consultation, to have diagnosis. In 44% of the cases, a clinical oncologist was the first specialist in the HCS that the patient was referred to. After the diagnosis, the median time to start of treatment was 35 days. Chemotherapy alone was the most common treatment regimen (32%). The median overall survival was 11.5 months and 6 months for stage II and IV NSCLC, respectively. CONCLUSION This study provides contemporary data on stage III and IV NSCLC in private health care in Brazil, which has shown a high rate of metastatic disease diagnoses, high health care–related costs, and low survival rates.

PURPOSE Stereotactic body radiation therapy (SBRT) is an effective option for patients with both early-stage and oligometastatic non–small-cell lung cancer (NSCLC). However, data from Latin America are limited. Therefore, the aim of this study was to investigate the real-world outcomes of applying SBRT for lung lesions in a Brazilian institution. METHODS This study investigated a consecutive cohort of patients treated with SBRT for lung lesions (primary and metastasis). The study primary outcome was local control rates per lesion. Secondary outcomes included progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS Between 2015 and 2019, a total of 216 patients received SBRT and were included in the study. The median follow-up was 24.5 months (5-70), primary NSCLC corresponded to 70% (n = 151) and nonprimary lung lesions to 30% (n = 65), respectively. Stage I NSCLC represented 56% (85 of 151) of the NSCLC cohort. The average number of fractions and total dose prescribed was 5 (3-10)/59 Gy (50-62 Gy). For stage I NSCLC (all lesions treated with a biologically effective dose [10] > 100 Gy), 2-year local control, OS, and PFS were 93.4%, 81.6%, and 80.7%, respectively. For stage IV lesions, if biologically effective dose (10) > 100 Gy or < 100 Gy, 2-year local control was 95.8/86.4% ( P = .03), 2-year-OS was 81.6/60.5% ( P = .006), and 2-year PFS was 38.9/17.9% ( P = .10). Late toxicity was observed in 16.2% (n = 35) of the total cases. CONCLUSION Our results indicate that SBRT is effective (high local control and acceptable toxicity) for treating malignant lung lesions in a real-world scenario in Latin America.

Lung cancer is the principal cause of cancer-related deaths worldwide; however, there has been controversy as to whether there is a difference in survival rate according to gender in Brazil. The aim of the present study, therefore, was to compare the epidemiologic and clinical profile and the overall survival of patients with lung cancer according to gender.A retrospective cohort study was performed involving 1283 patients diagnosed with lung cancer between 2006 and 2014 at a single cancer center. Survival analysis was conducted using Kaplan-Meier statistics. A log-rank test was used to assess differences between survival curves, and Cox proportional hazards regression analysis was performed to quantitate the relationship between gender and overall survival.Compared with men, women were more frequently younger (P .001), nonsmokers (P = .007), diagnosed with adenocarcinoma (P .001), had early stage disease (P .001), received surgery or surgery in combination with chemotherapy (P .001), and had a better survival rate (P .001). The median overall survival rate was higher in women (14.2 vs. 10.5 months in men; P .001). Cox regression-adjusted analysis shows that women were 16% less likely to die than men (hazard ratio, 0.84; 95% confidence interval, 0.72-0.98; P = .03).A higher overall survival rate was found in women with lung cancer as compared with men with lung cancer in Brazil.

Artificial intelligence (AI)‐based systems applied to histopathology whole‐slide images have the potential to improve patient care through mitigation of challenges posed by diagnostic variability, histopathology caseload, and shortage of pathologists. We sought to define the performance of an AI‐based automated prostate cancer detection system, Paige Prostate, when applied to independent real‐world data. The algorithm was employed to classify slides into two categories: benign (no further review needed) or suspicious (additional histologic and/or immunohistochemical analysis required). We assessed the sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs) of a local pathologist, two central pathologists, and Paige Prostate in the diagnosis of 600 transrectal ultrasound‐guided prostate needle core biopsy regions (‘part‐specimens’) from 100 consecutive patients, and to ascertain the impact of Paige Prostate on diagnostic accuracy and efficiency. Paige Prostate displayed high sensitivity (0.99; CI 0.96–1.0), NPV (1.0; CI 0.98–1.0), and specificity (0.93; CI 0.90–0.96) at the part‐specimen level. At the patient level, Paige Prostate displayed optimal sensitivity (1.0; CI 0.93–1.0) and NPV (1.0; CI 0.91–1.0) at a specificity of 0.78 (CI 0.64–0.89). The 27 part‐specimens considered by Paige Prostate as suspicious, whose final diagnosis was benign, were found to comprise atrophy (n = 14), atrophy and apical prostate tissue (n = 1), apical/benign prostate tissue (n = 9), adenosis (n = 2), and post‐atrophic hyperplasia (n = 1). Paige Prostate resulted in the identification of four additional patients whose diagnoses were upgraded from benign/suspicious to malignant. Additionally, this AI‐based test provided an estimated 65.5% reduction of the diagnostic time for the material analyzed. Given its optimal sensitivity and NPV, Paige Prostate has the potential to be employed for the automated identification of patients whose histologic slides could forgo full histopathologic review. In addition to providing incremental improvements in diagnostic accuracy and efficiency, this AI‐based system identified patients whose prostate cancers were not initially diagnosed by three experienced histopathologists. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Background The treatment of choice for advanced non–small cell lung cancer is selected according to the presence of specific alterations. Patients should undergo molecular testing for relevant modifications and the mutational status of EGFR and translocation of ALK and ROS1 are commonly tested to offer the best intervention. In addition, the tests costs should also be taken in consideration. Therefore, this work was performed in order to evaluate the cost-effectiveness of a unique exam using NGS (next generation sequencing) versus other routinely used tests which involve RT-PCR and FISH. Methods The target population was NSCLC, adenocarcinoma, and candidates to first-line therapy. Two strategies were undertaken, strategy 1 corresponded to sequential tests with EGFR RT-PCR, then FISH for ALK and ROS1. Strategy 2 differed from 1 in that ALK and ROS1 translocation testing were performed simultaneously by FISH. Strategy 3 considered single test next-generation sequencing, a platform that includes EGFR, ALK and ROS1 genes. A decision tree analysis was used to model genetic testing options. From the test results, a microsimulation model was nested to estimate survival outcomes and costs of therapeutic options. Results The use of NGS added 24% extra true cases as well as extra costs attributed to the molecular testing. The ICER comparing NGS with sequential tests was US$ 3479.11/correct case detected. The NGS improved a slight gain in life years and QALYs. Conclusion Our results indicated that, although precise, the molecular diagnosis by NGS of patients with advanced stage NSCLC adenocarcinoma histology was not cost-effective in terms of quality-adjusted life years from the perspective of the Brazilian supplementary health system.

Clear cell carcinoma (CCC) of the cervix (cCCC) is a rare and aggressive type of human papillomavirus (HPV)-negative cervical cancer with limited effective treatment options for recurrent or metastatic disease. Historically, CCCs of the lower genital tract were associated with in utero diethylstilbestrol exposure; however, the genetic landscape of sporadic cCCCs remains unknown. Here we sought to define the molecular underpinning of cCCCs. Using a combination of whole-exome, targeted capture, and RNA-sequencing, we identified pathogenic genetic alterations in the Hippo signaling pathway in 50% (10/20) of cCCCs, including recurrent WWTR1 S89W somatic mutations in 40% (4/10) of the cases harboring mutations in the Hippo pathway. Irrespective of the presence or absence of Hippo pathway genetic alterations, however, all primary cCCCs analyzed in this study (n = 20) harbored features of Hippo pathway deregulation at the transcriptomic and protein levels. In vitro functional analysis revealed that expression of the WWTR1 S89W mutation leads to reduced binding of TAZ to 14-3-3, promoting constitutive nuclear translocation of TAZ and Hippo pathway repression. WWTR1 S89W expression was found to lead to acquisition of oncogenic behavior, including increased proliferation, migration, and colony formation in vitro as well as increased tumorigenesis in vivo, which could be reversed by targeted inhibition of the TAZ/YAP1 complex with verteporfin. Finally, xenografts expressing WWTR1 S89W displayed a shift in tumor phenotype, becoming more infiltrative as well as less differentiated, and were found to be composed of cells with conspicuous cytoplasmic clearing as compared to controls. Our results demonstrate that Hippo pathway alterations are likely drivers of cCCCs and likely contribute to the clear cell phenotype. Therapies targeting this pathway may constitute a new class of treatment for these rare, aggressive tumors. © 2022 The Pathological Society of Great Britain and Ireland.

Background and Objectives: One of the most frequently mutated oncogenes in cancer belongs to the Ras family of proto-oncogenes, which encode distinct key signaling events. RAS gain-of-function mutations are present in ~30% of all human cancers, with KRAS being the most frequently mutated isoform showing alterations in different cancer types including lung cancer. This study aimed to investigate the incidence of KRAS mutations, and concomitant mutations, in advanced non-small cell lung adenocarcinoma patients. Materials and Methods: This was a retrospective study, where genomic DNA extracted from paraffin-embedded tumor tissues from 121 Brazilian advanced non-small cell lung adenocarcinoma patients were analyzed to evaluate via Next Generation Sequencing (NGS) the incidence of KRAS mutations and co-occurring mutations and correlate, when possible, to clinicopathological characteristics. Statistical analyses were performed to calculate the prevalence of mutations and to investigate the association between mutational status, mutation type, and sex. Results: The results showed a prevalence of male (N = 63, 54.8%) compared to female patients (N = 52, 45.2%), and mutant KRAS was present in 20.86% (24/115) of all samples. Interestingly, 33.3% of the mutant KRAS samples showed other mutations simultaneously. Conclusions: This study revealed the presence of rare KRAS concomitant mutations in advanced lung adenocarcinoma patients. Further investigation on the importance of these genomic alterations in patient prognosis and treatment response is warranted.

Challenges of health systems in Latin America and the Caribbean include accessibility, inequity, segmentation, and poverty. These challenges are similar in different countries of the region and transcend national borders. The increasing digital transformation of health care holds promise of more precise interventions, improved health outcomes, increased efficiency, and ultimately reduced health-care costs. In Latin America and the Caribbean, the adoption of digital health tools is in early stages and the quality of cancer registries, electronic health records, and structured databases are problematic. Cancer research and innovation in the region are limited due to inadequate academic resources and translational research is almost fully dependent on public funding. Regulatory complexity and extended timelines jeopardise the potential improvement in participation in international studies. Emerging technologies, artificial intelligence, big data, and cancer research represent an opportunity to address the health-care challenges in Latin America and the Caribbean collectively, by optimising national capacities, sharing and comparing best practices, and transferring scientific and technical capabilities.

PURPOSE Lung cancer is a global health problem, with more than 220,000 new cases and 150,000 deaths per year in the United States. Likewise, in Brazil, lung cancer is the most lethal cancer with 30,200 new cases expected in 2020. Regarding treatment types, radiation therapy (RT) represents an important approach, since 60%-70% of the patients will receive this modality of treatment during the course of their disease. However, access to RT remains challenging because of the socioeconomic inequalities in the Brazilian population, where approximately 100,000 patients/year die without access to RT. This work provides an overview on the availability of high technology RT in Brazil. METHODS A retrospective study was performed using the Brazilian Radiotherapy Census, local public and private databases, and the current literature published in 2019. RESULTS The Brazilian radiotherapy network relies on approximately 363 linear accelerators and 20 cobalt machines that remain operational. Most of these machines are installed at public health facilities. Regarding high technology, intensity-modulated RT is available in 53.7% (n = 130) and volumetric modulated arc therapy in 28.5% (n = 69) of the institutions, although only 19.8% (n = 48) of those facilities are capable of performing image-guided RT using cone beam computed tomography. Considering only the public health care system, the scenario is more restricted, with 40.1% (n = 65) of the institutions offering intensity-modulated RT, 21% (n = 34) volumetric modulated arc therapy, and 14.8% (n = 24) using cone beam computed tomography. Because of these scare resources, only 16% of Radiation Departments offer stereotactic body RT. CONCLUSION Brazil still needs to improve and provide high and safer RT technologies to patients with lung cancer across all Brazilian regions to attend the population needs and obtain better patient outcomes.

PURPOSEThe COVID-19 pandemic remains a public health emergency of global concern. Determinants of mortality in the general population are now clear, but specific data on patients with cancer remain limited, particularly in Latin America.MATERIALS AND METHODSA longitudinal multicenter cohort study of patients with cancer and confirmed COVID-19 from Oncoclínicas community oncology practice in Brazil was conducted. The primary end point was all-cause mortality after isolation of the SARS-CoV-2 by Real-Time Polymerase Chain Reaction (RT-PCR) in patients initially diagnosed in an outpatient environment. We performed univariate and multivariable logistic regression analysis and recursive partitioning modeling to define the baseline clinical determinants of death in the overall population.RESULTSFrom March 29 to July 4, 2020, 198 patients with COVID-19 were prospectively registered in the database, of which 167 (84%) had solid tumors and 31 (16%) had hematologic malignancies. Most patients were on active systemic therapy or radiotherapy (77%), largely for advanced or metastatic disease (64%). The overall mortality rate was 16.7% (95% CI, 11.9 to 22.7). In univariate models, factors associated with death after COVID-19 diagnosis were age ≥ 60 years, current or former smoking, coexisting comorbidities, respiratory tract cancer, and management in a noncurative setting ( P < .05). In multivariable logistic regression and recursive partitioning modeling, only age, smoking history, and noncurative disease setting remained significant determinants of mortality, ranging from 1% in cancer survivors under surveillance or (neo)adjuvant therapy to 60% in elderly smokers with advanced or metastatic disease.CONCLUSIONMortality after COVID-19 in patients with cancer is influenced by prognostic factors that also affect outcomes of the general population. Fragile patients and smokers are entitled to active preventive measures to reduce the risk of SARS-CoV-2 infection and close monitoring in the case of exposure or COVID-19-related symptoms.

Early diagnosis when melanoma is still small and thin is essential for improving mortality and morbidity. However, the diagnosis of small size melanoma might be particularly difficult, not only clinically but also dermoscopically. This study aimed to define clinical and dermatoscopic parameters in the diagnosis of suspicious pigmented cutaneous lesions with a diameter of ≤ 6mm and determine the sensitivity, specificity, positive and negative predictive values as well as the accuracy of each clinical and dermatoscopic criterion. This is a transversal, descriptive and analytical study of dermatoscopic analysis with the gold standard being the pathologic examination obtained from the excisional biopsy of suspicious melanocytic lesions with a diameter of ≤ 6mm. Trunk and limb lesion data from a public health service and a private clinic were prospectively collected from 2011 to 2017 by a unique observer. In total, 481 melanocytic lesions were included, with 73.8% being ≤ 4mm in diameter. Overall, 123 were diagnosed as melanoma, 56.0% in situ and 22.0% as thin melanomas (Breslow index 0.1 to 1.0mm). Melanoma presented symmetry in 53.7% of cases, regular borders in 54.5% and a single color in 60.2%. Regarding evolution, 13.8% of melanomas versus 10.9% of benign lesions (p = 0.116) were new by comparing photos from baseline with photos from the follow-up. The majority of melanomas (65%) were found on the limbs compared to 37.2% of the benign lesions at this location (p

The objective of this review is to address the barriers limiting access to next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) for metastatic nonsquamous non-small cell lung cancer in Brazil and to propose its implementation in practice. A selected panel of lung cancer experts was provided with relevant prompts to address at a conference; a paper was then compiled on the topic. The authors propose specific and realistic recommendations for implementing access to ctDNA NGS. Further, the authors address all barriers and impediments mentioned within this review. There is a great need to increase ctDNA NGS for cancer care in Brazil. Adapting the current cancer testing framework is essential to expanding the use of this tool.

Oral mucositis is an acute toxicity that occurs in patients submitted to chemoradiotherapy to treat head and neck squamous cell carcinoma. In this study, we evaluated differences in gene expression in the keratinocytes of the oral mucosa of patients treated with photobiomodulation therapy and tried to associate the molecular mechanisms with clinical findings. From June 2009 to December 2010, 27 patients were included in a randomized double-blind pilot study. Buccal smears from 13 patients were obtained at days 1 and 10 of chemoradiotherapy, and overall gene expression of samples from both dates were analyzed by complementary DNA (cDNA) microarray. In addition, samples from other 14 patients were also collected at D1 and D10 of chemoradiotherapy for subsequent validation of cDNA microarray findings by qPCR. The expression array analysis identified 105 upregulated and 60 downregulated genes in our post-treatment samples when compared with controls. Among the upregulated genes with the highest fold change, it was interesting to observe the presence of genes related to keratinocyte differentiation. Among downregulated genes were observed genes related to cytotoxicity and immune response. The results indicate that genes known to be induced during differentiation of human epidermal keratinocytes were upregulated while genes associated with cytotoxicity and immune response were downregulated in the laser group. These results support previous clinical findings indicating that the lower incidence of oral mucositis associated with photobiomodulation therapy might be correlated to the activation of genes involved in keratinocyte differentiation.

Background The impact of low-level laser therapy (LLLT) to prevent oral mucositis in patients treated with exclusive chemoradiation therapy remains unknown. This study evaluated the overall, disease-free and progression-free survival of these patients. Methods: Overall, disease-free and progression-free survival of 94 patients diagnosed with oropharynx, nasopharynx, and hypopharynx cancer, who participated on a phase III study, was evaluated from 2007 to 2015. The patients were subjected to conventional radiotherapy plus cisplatin every 3 weeks. LLLT was applied with an InGaAlP diode (660 nm–100 mW–1 J–4 J/cm 2 ). Results With a median follow-up of 41.3 months (range 0.7–101.9), patients receiving LLLT had a statistically significant better complete response to treatment than those in the placebo group (LG = 89.1%; PG = 67.4%; p = 0.013). Patients subjected to LLLT also displayed increase in progression-free survival than those in the placebo group (61.7% vs. 40.4%; p = 0.030; HR:1:93; CI 95%: 1.07–3.5) and had a tendency for better overall survival (57.4% vs. 40.4%; p = 0.90; HR:1.64; CI 95%: 0.92–2.91). Conclusion This is the first study to suggest that LLLT may improve survival of head and neck cancer patients treated with chemoradiotherapy. Further studies, with a larger sample, are necessary to confirm our findings.

Hyalinizing trabecular tumors (HTTs) of the thyroid are rare and mostly benign epithelial neoplasms of follicular cell origin, which have recently been shown to be underpinned by the PAX8-GLIS3 fusion gene. In this study we sought to investigate the potential oncogenic mechanisms of the PAX8-GLIS3 fusion gene. Forced expression of PAX8-GLIS3 was found to increase proliferation, clonogenic potential and migration of human non-malignant thyroid (Nthy-ori 3–1) and embryonic kidney (HEK-293) cells. Moreover, in xenografts, Nthy-ori 3–1 PAX8-GLIS3 expressing cells generated significantly larger and more proliferative tumors compared to controls. These oncogenic effects were found to be mediated through activation of the Sonic Hedgehog (SHH) pathway. Targeting of smoothened (SMO), a key protein in the SHH pathway, using the small molecule inhibitor Cyclopamine partially reversed the increased proliferation, colony formation and migration in PAX8-GLIS3 expressing cells. Our data demonstrate that the oncogenic effects of the PAX8-GLIS3 fusion gene are, at least in part, due to an increased activation of the SHH pathway.

Currently, there is no established guidance on how to process and evaluate resected lung cancer specimens after neoadjuvant therapy in the setting of clinical trials and clinical practice. There is also a lack of precise definitions on the degree of pathologic response, including major pathologic response or complete pathologic response. For other cancers such as osteosarcoma and colorectal, breast, and esophageal carcinomas, there have been multiple studies investigating pathologic assessment of the effects of neoadjuvant therapy, including some detailed recommendations on how to handle these specimens. A comprehensive mapping approach to gross and histologic processing of osteosarcomas after induction therapy has been used for over 40 years. The purpose of this article is to outline detailed recommendations on how to process lung cancer resection specimens and to define pathologic response, including major pathologic response or complete pathologic response after neoadjuvant therapy. A standardized approach is recommended to assess the percentages of (1) viable tumor, (2) necrosis, and (3) stroma (including inflammation and fibrosis) with a total adding up to 100%. This is recommended for all systemic therapies, including chemotherapy, chemoradiation, molecular-targeted therapy, immunotherapy, or any future novel therapies yet to be discovered, whether administered alone or in combination. Specific issues may differ for certain therapies such as immunotherapy, but the grossing process should be similar, and the histologic evaluation should contain these basic elements. Standard pathologic response assessment should allow for comparisons between different therapies and correlations with disease-free survival and overall survival in ongoing and future trials. The International Association for the Study of Lung Cancer has an effort to collect such data from existing and future clinical trials. These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as suggestion for good clinical practice outside of clinical trials, to improve consistency of pathologic assessment of treatment response.

The process of lung carcinogenesis is still not well understood and involves different levels of regulation of several genes. The search for molecular biomarkers, which can be applicable to clinical practice, has been the focus of various studies. XIAP-associated factor 1 (XAF1) was previously shown to be downregulated in many types of tumors, including squamous cell lung cancer. XAF1 is a pro-apoptotic protein and its restoration was found to sensitize cancer cells to apoptotic stimuli; however, the precise mechanism involved in the downregulation of XAF1 in tumors is unknown and promoter hypermethylation or heat-shock transcription factor 1 (HSF1) may be involved. Therefore, the aim of the present study was to evaluate the expression of XAF1 in tumors and adjacent non-tumor specimens from non-small cell lung cancer (NSCLC) patients, and its potential association with various factors including clinicopathological characteristics and other genes involved in NSCLC. Our results indicated that XAF1 expression was markedly altered in NSCLC tumor samples when compared to that found in normal lung tissues. Predominantly, XAF1 was downregulated in the tumors, except in never-smoker patients. In addition, XAF1 may also be important in the whole cell stress mechanism where the p53 status is crucial.

Oligodendrocytes produce and maintain the myelin sheath of axons in the central nervous system. Because misassembled myelin sheaths have been associated with brain disorders such as multiple sclerosis and schizophrenia, recent advances have been made towards the description of the oligodendrocyte proteome. The identification of splice variants represented in the proteome is as important as determining the level of oligodendrocyte-associated proteins. Here, we used an oligodendrocyte proteome dataset deposited in ProteomeXchange to search against a customized protein sequence file containing computationally predicted splice variants. Our approach resulted in the identification of 39 splice variants, including one variant from the GTPase KRAS gene and another from the human glutaminase gene family. We also detected the mRNA expression of five selected splice variants and demonstrated that a fraction of these have their canonical proteins participating in direct protein-protein interactions. In conclusion, we believe our findings contribute to the molecular characterization of oligodendrocytes and may encourage other research groups working with central nervous system disorders to investigate the biological significance of these splice variants. The splice variants identified in this study may encode proteins that could be targeted in novel treatment strategies and diagnostic methods.Several disorders of the central nervous system (CNS) are associated with misassembled myelin sheaths, which are produced and maintained by oligodendrocytes (OL). Recently, the OL proteome has been explored to identify key proteins and molecular functions associated with CNS disorders. We developed an innovative approach to select, with a higher level of confidence, a relevant list of splice variants from a proteome dataset and detected the mRNA expression of five selected variants: EEF1D, KRAS, MFF, SDR39U1, and SUGT1. We also described splice variants extracted from OL proteome data. Among the splice variants identified, some are from genes previously linked to CNS and related disorders. Our findings may contribute to oligodendrocyte characterization and encourage other research groups to investigate the biological role of splice variants and to improve current treatments and diagnostic methods for CNS disorders.

Colorectal cancer (CRC) is a multifactorial disease resulting from lifestyle, genetic, and environmental factors. There are hereditary and non-hereditary CRC types; however, the majority are non-hereditary and mainly caused by somatic mutations in response to environmental factors. In past years, researchers have focused their attention on the mechanisms behind these factors and the methods of improving disease prevention and treatment. Improving the awareness of the population with regard to the benefits of a healthy lifestyle, including a balanced diet associated with exercise, could globally reduce CRC risk. The present review aims to address the current knowledge on CRC, taking into consideration the common molecular alterations upon different environmental and non-environmental factors, current and promising treatment interventions, and how all these factors may interact to positively or negatively influence CRC risk.

Objectives Regarding the fatality rates stemming from various existing forms of cancers worldwide, lung cancer (LC) is ranked as the main cause of death amongst those who suffer from cancer. Although the epidemiological, clinical, and histological profile of patients with this type of cancer is largely unknown, Brazil has made tremendous efforts to generate data for supporting healthcare policies concerning lung cancer. Taking these factors into account, this study aims to analyse the epidemiological, clinical, and histological profiles of patients with non-small-cell lung cancer (NSCLC) in Brazil. Material and methods For this study, a cross-sectional epidemiological study was conducted to nationally analyse patient’s data within the cancer hospital registries found in the National Cancer Institute (INCA) and the Sao Paulo Cancer Foundation (FOSP) between 2000 and 2011. Results A total of 35,018 patients diagnosed with NSCLC in Brazil between 2000 and 2011 were analysed. The analysis demonstrated the occurrence of an epidemiological shift, related to the most prevalent histological type of NSCLC in the study population from 2003. The shift resulted in a higher percentage of adenocarcinoma (43.3%) over squamous cell carcinoma (36.5%). Additionally, there was a significant increase in both the number of cases of LC in women and in the rates of patients diagnosed with metastatic disease. Conclusion The use of filtered cigarettes since the 60’s and the increase in the number of LC cases in women, were one of the causes for the switch in the histological profile of NSCLC in Brazil. Consequently, adenocarcinoma is now the predominant type of cancer detected. Late diagnosis is a hallmark sign.

Activating mutations of K-ras are the most common oncogenic alterations found in lung cancer. Unfortunately, attempts to target K-ras–mutant lung tumors have thus far failed, clearly indicating the need for new approaches in patients with this molecular profile. We have previously shown NF-κB activation, release of IL6, and activation of its responsive transcription factor STAT3 in K-ras–mutant lung tumors, which was further amplified by the tumor-enhancing effect of chronic obstructive pulmonary disease (COPD)-type airway inflammation. These findings suggest an essential role for this inflammatory pathway in K-ras–mutant lung tumorigenesis and its enhancement by COPD. Therefore, here we blocked IL6 using a monoclonal anti-IL6 antibody in a K-ras–mutant mouse model of lung cancer in the absence or presence of COPD-type airway inflammation. IL6 blockade significantly inhibited lung cancer promotion, tumor cell–intrinsic STAT3 activation, tumor cell proliferation, and angiogenesis markers. Moreover, IL6 inhibition reduced expression of protumor type 2 molecules (arginase 1, Fizz 1, Mgl, and IDO), number of M2-type macrophages and granulocytic myeloid-derived suppressor cells, and protumor T-regulatory/Th17 cell responses. This was accompanied by increased expression of antitumor type 1 molecule (Nos2), and antitumor Th1/CD8 T-cell responses. Our study demonstrates that IL6 blockade not only has direct intrinsic inhibitory effect on tumor cells, but also reeducates the lung microenvironment toward an antitumor phenotype by altering the relative proportion between protumor and antitumor immune cells. This information introduces IL6 as a potential druggable target for prevention and treatment of K-ras–mutant lung tumors. Cancer Res; 76(11); 3189–99. ©2016 AACR.

Cervical carcinomas are almost universally associated with high-risk human papillomavirus (HPV) infections, and are a leading cause of cancer death in women worldwide. Since the late 1990s, when a spate of studies reported the benefit of cisplatin-based chemotherapy, there had been a dearth of clinical trials in cervical cancer (CC). More effective therapies in locally advanced and recurrent or metastatic CC are an urgent clinical need. In the era of molecular oncology one should look beyond conventional chemoradiation and chemotherapy for locally advanced and advanced CC. The fact that the initiating oncogenic insult, infection with a high-risk HPV and viral oncoprotein expression is common to almost all CC offers unique opportunities for disease control. Diverse biologic pathways with an implication in the development and progression of CC are being explored. For the first time, increase in overall survival has recently been obtained for advanced CC patients with a target drug, the antiangiogenic agent bevacizumab, and durable complete responses after HPV-targeted adoptive T cell therapy in metastatic CC patients were achieved. In this review, we will summarize molecular aspects of HPV infection focusing on potential targets to stop the carcinogenic process, present updated drug development data, and discuss challenges and prospects for the future.

For many decades, cancer treatment has been strongly directed toward the development of cytotoxic and cytostatic drugs, quite often leading to disappointing results due to the inter- and intra-tumoral heterogeneity. Lately, this intra-cellular look has given way to the understanding of the tumor microenvironment, thus enabling modification of the immunological dynamics between tumor cells and their host. An era of new drugs aiming to unlock the host immune system against tumor cells is steadily increasing. Strategies involving adoptive cell therapy, therapeutic vaccines, immune checkpoint inhibitors and so on have provided spectacular clinical responses and increased survival in previously refractory settings and "hard-to-treat" cancers. Based on a comprehensive search in the main scientific databases, annals of recent renowned oncology congresses and platforms of ongoing trials, the clinical pharmacology characteristics of the main classes of immunotherapeutic agents, as well as the new treatment strategies related to immunotherapy in solid tumors, are carefully discussed throughout this review.

Background Scientific and professional development opportunities for early career scientists in low- and middle- income countries (LMICs) are limited and not consistent. There is a disproportionately low number of biomedical and clinical researchers in LMIC’s relative to their high burden of disease, a disparity that is aggravated by emigration of up to 70% of scientists from their countries of birth for education and employment elsewhere. To help address this need, a novel University-accredited, immersive fellowship program was established by a large public-academic-private network. We sought to describe the program and summarize progress and lessons learned over its first 7-years. Methods Hallmarks of the program are a structured learning curriculum and bespoke research activities tailored to the needs of each fellow. Research projects expose the scientists to state-of-the-art methodologies and leading experts in their fields while also ensuring that learnings are implementable within their home infrastructure. Fellows run seminars on drug discovery and development that reinforce themes of scientific leadership and teamwork together with practical modules on addressing healthcare challenges within their local systems. Industry mentors achieve mutual learning to better understand healthcare needs in traditionally underserved settings. We evaluated the impact of the program through an online survey of participants and by assessing research output. Results More than 140 scientists and clinicians from 25 countries participated over the 7-year period. Evaluation revealed strong evidence of knowledge and skills transfer, and beneficial self-reported impact on fellow’s research output and career trajectories. Examples of program impact included completion of post-graduate qualifications; establishment and implementation of good laboratory- and clinical- practice mechanisms; and becoming lead investigators in local programs. There was a high retention of fellows in their home countries (> 75%) and an enduring professional network among the fellows and their mentors. Conclusions Our experience demonstrates an example for how multi-sectoral partners can contribute to scientific and professional development of researchers in LMICs and supports the idea that capacity-building efforts should be tailored to the specific needs of beneficiaries to be maximally effective. Lessons learned may be applied to the design and conduct of other programs to strengthen science ecosystems in LMICs.

Objective: To characterize the clinical and histological profile, as well as treatment patterns, of patients with early-stage, locally advanced (LA), or advanced/metastatic (AM) lung cancer, diagnosed between 2000 and 2014, in Brazil. Methods: This was an analytical cross-sectional epidemiological study employing data obtained for the 2000-2014 period from the hospital cancer registries of two institutions in Brazil: the José Alencar Gomes da Silva National Cancer Institute, in the city of Rio de Janeiro; and the São Paulo Cancer Center Foundation, in the city of São Paulo. Results: We reviewed the data related to 73,167 patients with lung cancer. The proportions of patients with early-stage, LA, and AM lung cancer were 13.3%, 33.2%, and 53.4%, respectively. The patients with early-stage lung cancer were older and were most likely to receive a histological diagnosis of adenocarcinoma; the proportion of patients with early-stage lung cancer remained stable throughout the study period. In those with LA lung cancer, squamous cell carcinoma predominated, and the proportion of patients with LA lung cancer decreased significantly over the period analyzed. Those with AM lung cancer were younger and were most likely to have adenocarcinoma; the proportion of patients with AM lung cancer increased significantly during the study period. Small cell carcinoma accounted for 9.2% of all cases. In our patient sample, the main treatment modality was chemotherapy. Conclusions: It is noteworthy that the frequency of AM lung cancer increased significantly during the study period, whereas that of LA lung cancer decreased significantly and that of early-stage lung cancer remained stable. Cancer treatment patterns, by stage, were in accordance with international guidelines.

The development of therapies that restore or activate the host immune response – the socalled “immuno-oncologic” therapy – has improved the survival of some cancer patients harboring specific tumor types. These drugs, however, are very expensive which has greatly limited their use and consequently reduced the number of patients who could likely benefit. Not to mention, the proportion of patients who display a clinical benefit from therapy is limited. Thus, from a clinical and health economics perspective, there is a pressing need to identify and treat those patients for whom a given immuno- oncologic therapy is most likely to be beneficial. At this end, the identification, validation and use of biomarkers emerge as an important therapeutic tool. Here, we briefly review the state of immunologic biomarker development and utilization and make suggestions for interested clinicians, health policy makers and other stakeholders to prepare for the broader use of biomarkers associated with immuno-oncologic therapy in routine practice. The biomarker field is clearly in its earliest stages and there is no doubt that continued research will identify new biomarkers with valuable clinical indications. Of course, the clinical utility of a biomarker must consider patient preferences and perspectives. In addition, health economic analyses are crucial to better define the value of immunotherapy based on precision medicine strategies and promote value-based pricing.

Lung cancer is the principal cause of death from cancer worldwide. However, little is known of its epidemiological and histological profile and of the incidence and mortality rates in Brazil according to sex.To evaluate the incidence, morbidity and mortality rates of lung cancer in Brazil from 2000 to 2014, as well as the epidemiological, clinical and morphological profile of women with lung cancer in Brazil is described.An ecological study was conducted using three reliable sources of secondary data: population-based cancer registries, hospital-based cancer registries and the national mortality database.The incidence rate in women increased from 7.92/100,000 in 2000 to 9.12/100,000 in 2012, while mortality increased from 6.02/100,000 in 2000 to 8.29/100,000 in 2014. In men, the incidence decreased from 23.40/100,000 in 2000 to 18.47/100,000 in 2012 and mortality also fell from 16.12/100,000 to 15.11/100,000 in 2014. There was a reduction in the male-to-female ratio from 2.54 in 2000 to 1.46 in 2014. Women tended to be younger (p 0.001), black (p 0.001), non-smokers (p 0.001), to have adenocarcinoma or small-cell lung cancer (p 0.001), and to have metastatic disease (p 0.001). In addition, the time between diagnosis and the start of cancer treatment was longer in women (p 0.001). In relation to treatment, women were more likely to have undergone chemotherapy, surgery or surgery in combination with chemotherapy (p 0.001) and to have response to the initial treatment (p 0.001).Incidence, morbidity and mortality rates of lung cancer in women of Brazil increased in the most recent years.

Summary Background Oral mucositis is a major event increasing treatment costs of head and neck squamous cell carcinoma (HNSCC) patients treated with chemoradiation (CRT). This study was designed to estimate the cost-effectiveness of low-level laser therapy (LLLT) to prevent oral mucositis in HNSCC patients receiving CRT. Methods From June 2007 to December 2010, 94 patients with HNSCC of nasopharynx, oropharynx, and hypopharynx entered a prospective, randomized, double blind, placebo-controlled, phase III trial. CRT consisted of conventional radiotherapy (RT: 70.2 Gy, 1.8 Gy/d, 5 times/wk) + concurrent cisplatin (100 mg/m2) every 3 weeks. An InGaAlP (660 nm–100 mW–4 J/cm2) laser diode was used for LLLT. Results From the perspective of Brazil’s public health care system (SUS), total costs were higher in Placebo Group (PG) than Laser Group (LG) for opioid use (LG = US$ 9.08, PG = US$ 44.28), gastrostomy feeding (LG = US$ 50.50, PG = US$ 129.86), and hospitalization (PG = US$ 77.03). In LG, the cost was higher for laser therapy only (US$ 1880.57). The total incremental cost associated with the use of LLLT was US$ 1689.00 per patient. The incremental cost-effectiveness ratio (ICER) was US$ 4961.37 per grade 3–4 OM case prevented compared to no treatment. Conclusions Our results indicate that morbidity was lower in the Laser Group and that LLLT was more cost-effective than placebo up to a threshold of at least US$ 5000 per mucositis case prevented. Clinical trial information: NCT01439724.

Objective Pemetrexed plus carboplatin offers survival advantage in first line treatment of advanced lung cancer patients with performance status of 2. We estimated the cost-effectiveness of this combined regimen compared to pemetrexed alone in a Brazilian population. Methods A cost-effectiveness analysis was conducted based on a randomized phase III trial in patients with advanced non-small cell lung cancer (NSCLC) and ECOG performance status of 2 (PS2), comparing doublet regimen pemetrexed plus carboplatin with pemetrexed alone. The perspective adopted was the public health care sector over a three-year period. Direct medical costs and survival time were calculated from patient-level data and utility values were extracted from the literature. Sensitivity analyses were performed to evaluate uncertainties in the results. Results and conclusion The combined regimen pemetrexed plus carboplatin yielded a gain of 0.16 life year (LY) and 0.12 quality-adjusted life year (QALY) compared to pemetrexed alone. The total cost was 17,674.31 USD for the combined regimen and 15,722.39 USD for pemetrexed alone. The incremental cost-effectiveness ratio (ICER) was $12,016.09 per LY gained and $15,732.05 per QALY gained. The factors with the greatest impact on the ICER are pemetrexed price and the time to progression utility value. The cost-effectiveness acceptability curve showed an upper 90% probability of pemetrexed plus carboplatin being cost-effective with a threshold between two and three GDP per capita. Our study suggests superiority of the combined pemetrexed plus carboplatin regimen in terms of efficacy as well as cost-effectiveness in advanced NSCLC patients with a poor performance status of 2.

Aim: To show additional prognostic information about the mutational profile and new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification of adenocarcinoma (ADC) in patients without epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatments. Methods: In human lung ADC patients (n = 125), including 24 lepidic, 67 acinar, 23 papillary, and 11 solid predominant subtypes, EGFR and KRAS were sequenced, and anaplastic lymphoma kinase (ALK) rearrangements were screened using fluorescence in situ hybridization (FISH). Results:EGFR was mutated in 21.6% of patients with 19.57% showing a mean expression. The most frequent EGFR mutation was a deletion in exon 19, followed by an L858R amino acid substitution in exon 21. KRAS was mutated in 26.4% of patients with 50% displaying mean expression. ALK rearrangement was detected in 6 patients (4.8%). Predominant acinar ADC was strongly associated with EGFR and KRAS mutation. Clinical stage, lymph node metastases, and EGFR mutation in exon 18 showed a significant difference in disease-free and overall survival, but only a trend significance for EGFR and KRAS mutations. Multivariate analysis revealed that men aged >71 years, with a history of smoking (72 packs/year), and having a predominant solid ADC and EGFR mutation in exon 18. Conclusions: These results indicate that the mutational profile and new IASLC/ATS/ERS classification provide additional prognostic information about lung ADC.

Objectives Mammalian cells differently express 4 RAS isoforms: H-RAS, N-RAS, K-RAS4A and K-RAS4B, which are important in promoting oncogenic processes when mutated. In lung cancer, the K-RAS isoform is the most frequently altered RAS protein, being also a difficult therapeutic target. Interestingly, there are two K-RAS splice variants (K-RAS4A and K-RAS4B) and little is known about the role of K-RAS4A. Most studies targeting K-RAS, or analysing it as a prognostic factor, have not taken into account the two isoforms. Consequently, the in-depth investigation of them is needed. Methods The present study analysed 98 specimens from advanced non-small cell lung cancer (NSCLC) adenocarcinoma patients originated from Brazil. The alterations present in K-RAS at the DNA level (Sanger sequencing) as well as the expression of the splicing isoforms at the RNA (qRT-PCR) and protein levels (immunohistochemistry analysis), were evaluated. Possible associations between clinicopathological features and the molecular findings were also investigated. Results Our results showed that in the non-smoking population, the cancer incidence was higher among women. In contrast, in smokers and former smokers, the incidence was higher among men. Regarding sequencing results, 10.5% of valid samples presented mutations in exon 2, being all wild-type for exon 3, and the most frequently occurring base change was the transversion G → T. Our qRT-PCR and immunohistochemical analysis showed that both, K-RAS4A and K-RAS4B, were differently expressed in NSCLC tumour samples. For example, tumour specimens showed higher K-RAS4A mRNA expression in relation to commercial normal lung control than did K-RAS4B. In addition, K-RAS4B protein expression was frequently stronger than K-RAS4A in the patients analysed. Conclusion Our results highlight the differential expression of K-RAS4A and K-RAS4B in advanced adenocarcinoma NSCLC patients and underline the need to further clarify the enigma behind their biological significance in various cancer types, including NSCLC.

Objective Cervical cancer is a global public health challenge. Since 1999, platin based chemoradiation (CRT) is the standard treatment for those patients with locally advanced disease. However, this population still has a dismal prognosis and, alternatives approaches such as adjuvant chemotherapy are controversial, especially because of increased toxicity. Neoadjuvant chemotherapy (NACT) could be an option for more intensive treatment with manageable toxicity. Methods A phase II, prospective, non-randomized trial was conducted at a reference center in Recife, Brazil. Locally advanced cervical cancer patients (Ib2–IVa) were treated with neoadjuvant cisplatin 35mg/m 2 and gemcitabine 1000mg/m 2 D1 and D8, for 2cycles. Then, they received CRT (50.4Gy) with weekly cisplatin 40mg/m 2 followed by brachytherapy. Response rate (RR) and toxicity were the primary endpoints. Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Results Between Sep/2013 and Oct/2015, 50 patients were initiated on NACT and CRT. RR was 81% at the end of treatment. Hematological and gastrointestinal toxicity were most common. Grade 3/4 toxicity was 20% during NACT and 44% during CRT. Late adverse events were present in 20% of patients. PFS at 1 and 3-years were 73.4% (IC 58.7–83.6) and 53.9% (IC 36.9–68.3), respectively; and, OS at 1 and 3-years were 93.9% (IC 82.4–98.0) and 71.3% (IC 53.3–83.3), respectively. Conclusion In our hands NACT in locally advanced cervical cancer patients did not show a meaningful improvement in ORR. Nevertheless, we believe it should be further explored in prospective trials.

Lung cancer is one of the most incident types of cancer and a leading cause of cancer mortality in Brazil. We reviewed the current status of lung cancer by searching relevant data on prevention, diagnosis, and treatment in the country. This review highlights several issues that need to be addressed, including smoking control, patient lack of awareness, late diagnosis, and disparities in the access to cancer health care facilities in Brazil. We propose strategies to help overcome these limitations and challenge health care providers, as well as the society and governmental representatives, to work together and to take a step forward in fighting lung cancer. RESUMO O câncer de pulmão é um dos tipos de câncer com maior incidência e uma das principais causas de mortalidade por câncer no Brasil. Revisamos a situação atual do câncer de pulmão por meio de pesquisa de dados relevantes a respeito de prevenção, diagnóstico e tratamento no país. Esta revisão mostra várias questões que precisam de atenção, tais como controle do tabagismo, educação dos pacientes, desconhecimento por parte dos pacientes, diagnóstico tardio e desigualdade de acesso ao tratamento de câncer no Brasil. Propomos estratégias para ajudar a superar essas limitações e desafiamos os profissionais de saúde, a sociedade e os representantes do governo a trabalhar em conjunto e dar um passo à frente na luta contra o câncer de pulmão.

The mechanism of alternative splicing in the transcriptome may increase the proteome diversity in eukaryotes. In proteomics, several studies aim to use protein sequence repositories to annotate MS experiments or to detect differentially expressed proteins. However, the available protein sequence repositories are not designed to fully detect protein isoforms derived from mRNA splice variants. To foster knowledge for the field, here we introduce SpliceProt, a new protein sequence repository of transcriptome experimental data used to investigate for putative splice variants in human proteomes. Current version of SpliceProt contains 159 719 non-redundant putative polypeptide sequences. The assessment of the potential of SpliceProt in detecting new protein isoforms resulting from alternative splicing was performed by using publicly available proteomics data. We detected 173 peptides hypothetically derived from splice variants, which 54 of them are not present in UniprotKB/TrEMBL sequence repository. In comparison to other protein sequence repositories, SpliceProt contains a greater number of unique peptides and is able to detect more splice variants. Therefore, SpliceProt provides a solution for the annotation of proteomics experiments regarding splice isofoms. The repository files containing the translated sequences of the predicted splice variants and a visualization tool are freely available at http://lbbc.inca.gov.br/spliceprot.

Purpose To compare single-agent pemetrexed (P) versus the combination of carboplatin and pemetrexed (CP) in first-line therapy for patients with advanced non–small-cell lung cancer (NSCLC) with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2. Patients and Methods In a multicenter phase III randomized trial, patients with advanced NSCLC, ECOG PS of 2, any histology at first and later amended to nonsquamous only, no prior chemotherapy, and adequate organ function were randomly assigned to P alone (500 mg/m2) or CP (area under the curve of 5 and 500 mg/m2, respectively) administered every 3 weeks for a total of four cycles. The primary end point was overall survival (OS). Results A total of 205 eligible patients were enrolled from eight centers in Brazil and one in the United States from April 2008 to July 2011. The response rates were 10.3% for P and 23.8% for CP (P = .032). In the intent-to-treat population, the median PFS was 2.8 months for P and 5.8 months for CP (hazard ratio [HR], 0.46; 95% CI, 0.35 to 0.63; P < .001), and the median OS was 5.3 months for P and 9.3 months for CP (HR, 0.62; 95% CI, 0.46 to 0.83; P = .001). One-year survival rates were 21.9% and 40.1%, respectively. Similar results were seen when patients with squamous disease were excluded from the analysis. Anemia (grade 3, 3.9%; grade 4, 11.7%) and neutropenia (grade 3, 1%; grade 4, 6.8%) were more frequent with CP. There were four treatment-related deaths in the CP arm. Conclusion Combination chemotherapy with CP significantly improves survival in patients with advanced NSCLC and ECOG PS of 2.

The era of personalized medicine has come to the treatment of non-small cell lung cancer, and now molecular testing is part of the daily clinical decision, at least for patients with adenocarcinoma. Nevertheless, access to those tests is still very limited in the developing world. Developing countries must adapt their health care system to address that and grant access of patients with lung cancer to those tests. Because of several differences among developing countries, strategies will certainly vary from country to country. Issues such as generation of local molecular epidemiology data, quality control, education of health care professionals, development of innovative local and regional strategies, interconnection between regulatory pathways for the approval of drugs, and companion molecular tests are required.

Lung cancer is one of the most frequent types of cancer worldwide. Most patients are diagnosed at advanced stage and thus have poor prognosis. Smoking is a risk factor for lung cancer, however most smokers do not develop lung cancer while 20% of women with lung adenocarcinoma are non-smokers. Therefore, it is possible that these two groups present differences besides the smoking status, including differences in their gene expression signature. The altered expression patterns of non-coding RNAs in complex diseases make them potential biomarkers for diagnosis and treatment. We analyzed data from differentially and constitutively expressed PIWI-interacting RNAs and small nucleolar RNAs from publicly available small RNA high-throughput sequencing data in search of an expression pattern of non-coding RNA that could differentiate these two groups. Here, we report two sets of differentially expressed small non-coding RNAs identified in normal and tumoral tissues of women with lung adenocarcinoma, that discriminate between smokers and non-smokers. Our findings may offer new insights on metabolic alterations caused by tobacco and may be used for early diagnosis of lung cancer.

Cervix cancer (CC) represents the fourth most common cancer in women. Treatment involving cisplatin and radiotherapy has been the standard for locally advanced disease. Everolimus inhibits the aberrant activity of mTOR that is part of carcinogenesis in CC. Further everolimus inactivates the HPV E7 oncoprotein and inhibits its proliferation. Preclinical models have suggested that everolimus sensitizes tumoral cells and vasculature to cisplatin and radiotherapy. In a 3 + 3 design, the trial aimed to treat three dose levels of at least three patients with daily doses of everolimus (2.5, 5 and 10 mg/day), cisplatin and radiotherapy delivered in a 9-week interval in CC patients, stage IIB, IIIA or IIIB. Patients received everolimus from day −7 up to the last day of brachytherapy. Primary objective was to evaluate safety, toxicity and the maximum-tolerated dose (MTD) of everolimus in association with cisplatin and radiotherapy. Pharmacokinetic (PK) parameters and response rates were analyzed as secondary objectives. Thirteen patients were enrolled, 6 at 2.5 mg, 3 at 5 mg and 4 at 10 mg. Four patients did not complete the planned schedule, 1 at 2.5 mg presented grade 4 acute renal failure interpreted as dose-limiting toxicity (DLT) and 3 at 10 mg: 1 with disease progression, and 2 with DLTs—1 grade 3 rash and 1 grade 4 neutropenia. PK results were characterized by dose-dependent increases in AUC and C max. The MTD of everolimus in combination with cisplatin and radiotherapy has been defined as 5 mg/day. The data regarding safety and response rates support further studies.

ObjectiveCervical cancer is a public health problem. A large proportion of patients have locally advanced (LA) disease at presentation and for this group, neoadjuvant chemotherapy (NACT) has an undefined role in the era of chemoradiotherapy. In countries with restricted access to radiotherapy, NACT may precipitate patients’ access to an effective treatment approach. We carried out a systematic review to evaluate available data about NACT followed by chemoradiation.MethodsStudies evaluated the use of NACT followed by chemoradiotherapy. Search strategy was performed in MEDLINE, LILACS, and Cochrane Library from 2003 to 2013. Conference proceedings of American Society of Clinical Oncology annual meeting, International Journal of Gynecological Cancer Society biennial meeting, and European Society of Gynecological Oncology biennial meeting were also reviewed. Key words used were “cervical uterine cancer,” “cervical uterine neoplasm,” “neoadjuvant therapy,” “neoadjuvant treatment,” and “locally advanced.” Data collected included author information, year of publication, study design, number of participants, eligibility criteria, treatment, response rate (RR), disease-free survival, overall survival, and toxicities.ResultsInitial searches retrieved 7670 references. There were 7 eligible trials. Only 2 studies were published and a total of 323 participants were recruited. Patients with LA disease were eligible in most of them. Neoadjuvant chemotherapy consisted of paclitaxel combined with a platinum compound. Compliance was more than 90% in published trials. Response rate to NACT ranged from 67.8% to 70%. Major toxicity was hematological. Survival was evaluated in different points in time. Overall survival was up to 93% in 2 years, and in a poor prognostic group, 81% of patients were alive after 22 months. However, we must interpret these results with caution because of data limitation.ConclusionsOur result raises the possibility of NACT as an alternative upfront treatment for these patients with a small risk of disease progression. In countries where radiotherapy network is limited, randomized clinical trials should clarify its role.

A growing understanding of the molecular pathology of tumours combined with a surge of new drugs and associated diagnostic technologies (ie, precision medicine) has translated into substantial improvements in survival for patients with cancer. However, to achieve the promise that precision medicine has to offer will require overcoming hurdles within a national health-care system in which it is to be implemented. Brazil is one such nation, an emerging middle-income country with a very complex health-care system. To address the challenges associated with implementing precision medicine into a country such as Brazil, a group of experts convened (Nov 16-18, 2015, Miami) to discuss challenges related to precision medicine within an oncology setting. Complex regulatory hurdles, a shortage of human and technical resources, and the complexities of a two-tiered health-care delivery system were all identified as the main shortcomings to effectively implementing this new field of medicine. A path forward was proposed that relies on active collaboration between clinicians, private organisations, and government. It seems entirely possible that, despite many intrinsic economic and political problems, Brazil can readily emerge as a model for other countries in Latin America for the potential benefits of precision medicine and companion diagnostics.

Small cell lung cancer (SCLC) is an aggressive malignancy but with a high response rate to chemotherapy. Eastern Cooperative Oncology Group performance status (ECOG PS) has been recognized as one of the main prognostic factors in SCLC. There are few data about risk-benefit ratio of chemotherapy over exclusive best supportive care in ECOG PS 3 and 4 patients. This study was performed to assess the outcome of poor ECOG PS SCLC patients that received chemotherapy in our institution.A retrospective review of medical records from patients with ECOG PS 3-4 SCLC, who received systemic chemotherapy, was performed between January 2001 and December 2006 at the Instituto Nacional do Câncer, Rio de Janeiro, Brazil.A total of 40 patients were included. Extensive disease was observed in 85% of patients and 25% had PS 4. The median overall survival was 53 days (64 days for ECOG PS 3 and 7 days for ECOG PS 4). There were 30% of early deaths. On univariate analysis, lactate dehydrogenase value, need for hospital admission, and exposure to radiotherapy had impact on survival. ECOG PS 3 patients had better survival than PS 4 patients, even when adjusted for stage. On multivariate analysis, ECOG PS, combined with stage, sustained a major influence on survival.Median survival for ECOG PS 4 patients treated with chemotherapy in our series was extremely short with a high rate of early deaths. ECOG PS 3 patients also showed a poor survival. These data suggest that we need a more comprehensive approach and further studies, regarding the palliative care of this high-risk population.

Intron splicing is one of the most important steps involved in the maturation process of a pre-mRNA. Although the sequence profiles around the splice sites have been studied extensively, the levels of sequence identity between the exonic sequences preceding the donor sites and the intronic sequences preceding the acceptor sites has not been examined as thoroughly. In this study we investigated identity patterns between the last 15 nucleotides of the exonic sequence preceding the 5' splice site and the intronic sequence preceding the 3' splice site in a set of human protein-coding genes that do not exhibit intron retention. We found that almost 60% of consecutive exons and introns in human protein-coding genes share at least two identical nucleotides at their 3' ends and, on average, the sequence identity length is 2.47 nucleotides. Based on our findings we conclude that the 3' ends of exons and introns tend to have longer identical sequences within a gene than when being taken from different genes. Our results hold even if the pairs are non-consecutive in the transcription order.

Some proteins, canonically not associated with amyloid diseases, can aggregate into amyloid-like fibrils under special conditions. Our group hypothesized that stressful cancer microenvironment might induce the formation of insoluble deposits of p53 mutant protein. A cohort of 28 non-small cell lung cancer (NSCLC) patients was used to test the aforementioned hypothesis. Tumor specimens were assessed for TP53 mutations using DNA sequencing and for amyloid formation by Congo red staining. TP53 mutations were present in 57% of patients, whereas no amyloid deposits were detected in tissue sections under polarized light microscopy. Mutant p53 proteins are not associated with the appearance of amyloid-like fibrils in NSCLC samples, and DNA sequencing remains the standard method to detect such abnormality.

Purpose: To evaluate the long-term efficacy of concurrent radiotherapy with mitomycin-C (MMC)-based or cisplatin (CP)-based combinations in a cohort of patients with locally advanced anal canal carcinoma. Methods and Materials: Between 1988 and 2000, 179 patients with locally advanced anal canal carcinoma were treated at the Instituto Nacional de Cancer with two cycles of chemotherapy during Weeks 1 and 5 of radiotherapy. 5-Fluorouracil (750 mg/m{sup 2} 120-hour infusion or 1,000 mg/m{sup 2} 96-hour infusion) plus CP (100 mg/m{sup 2}) on the first day of each cycle or MMC (10-15 mg/m{sup 2}) on the first day of Cycle 1 was administered concurrent with radiotherapy (total dose, 55-59.4 Gy). Of the 179 patients, 60% were included from a randomized trial initiated at the Instituto Nacional de Cancer in 1991 that compared concurrent chemoradiotherapy with MMC vs. CP. Results: The median follow-up for the whole chemoradiotherapy group was 83 months. The median patient age was 58 years, 57% had Stage T3-T4 tumors, and 35% had N-positive disease. The 5-year cumulative colostomy rate was not significantly different between the CP group (22%) and MMC group (29%; p = .28). The actuarial 10-year overall survival and disease-free survival rate for the CP group was 54%more » and 49% and for the MMC group was 52% and 53%, respectively (p = .32 and p = .92, respectively). On multivariate analysis, male gender (p = .042) and advanced Stage T3-T4 disease (p

Purpose Erlotinib, an oral tyrosine kinase inhibitor, is active against head-and-neck squamous cell carcinoma (HNSCC) and possibly has a synergistic interaction with chemotherapy and radiotherapy. We investigated the safety and efficacy of erlotinib added to cisplatin and radiotherapy in locally advanced HNSCC. Methods and Materials In this Phase I/II trial 100 mg/m 2 of cisplatin was administered on Days 8, 29, and 50, and radiotherapy at 70 Gy was started on Day 8. During Phase I, the erlotinib dose was escalated (50 mg, 100 mg, and 150 mg) in consecutive cohorts of 3 patients, starting on Day 1 and continuing during radiotherapy. Dose-limiting toxicity was defined as any Grade 4 event requiring radiotherapy interruptions. Phase II was initiated 8 weeks after the last Phase I enrollment. Results The study accrued 9 patients in Phase I and 28 in Phase II; all were evaluable for efficacy and safety. No dose-limiting toxicity occurred in Phase I, and the recommended Phase II dose was 150 mg. The most frequent nonhematologic toxicities were nausea/vomiting, dysphagia, stomatitis, xerostomia and in-field dermatitis, acneiform rash, and diarrhea. Of the 31 patients receiving a 150-mg daily dose of erlotinib, 23 (74%; 95% confidence interval, 56.8%–86.3%) had a complete response, 3 were disease free after salvage surgery, 4 had inoperable residual disease, and 1 died of sepsis during treatment. With a median 37 months' follow-up, the 3-year progression-free and overall survival rates were 61% and 72%, respectively. Conclusions This combination appears safe, has encouraging activity, and deserves further studies in locally advanced HNSCC.

Purpose The aim of this study was to investigate whether mRNA expression of the apoptosis-associated genes, XAF1 and XIAP, in bladder cancer patients correlates with response to neoadjuvant treatment. Methods Gene expression was analyzed by a real-time quantitative PCR method in paired samples from 14 bladder cancer patients treated with a combination of neoadjuvant gemcitabine and cisplatin. The prognostic significance of XAF1 and XIAP mRNA expression as well as the correlation with several clinical and pathological findings were evaluated. Results The clinical response in the XAF1-high subset ( n = 5) was remarkably higher compared with the XAF1-low subset ( n = 9) (100% vs. 44.4%; P = 0.038). These results translated into a notably improvement of progression-free survival (PFS) in the XAF1-high subset (log-rank P = 0.012). In addition, patients in the XAF1-high subset had a 3.9-fold decreased chance of dying from the disease (hazard ratio for death (HR), 0.257; (CI 95%), 0.043–1.536, P = 0.036). When we evaluated the expression of XIAP, although an inverse correlation was found between expression and pathological response, there were no statistically significant associations with the clinical response, the length of PFS, and OS. Conclusions This is one of the few studies to address the role of XAF1 in a clinical setting. The data presented here identify XAF1 as a novel predictive and prognostic factor in bladder cancer patients. Furthermore, our observations are in line with previous studies, which point towards XAF1 as a tumor-suppressor gene. Nonetheless, additional studies, both mechanistic and translational, are warranted and may help not only in corroborating the role of XAF1 as a prognostic marker, but also as a potential target for anticancer therapy.