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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.

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.

Purpose: The SARS-CoV-2 pandemic was declared a global public health emergency. Determinants of mortality in the general population are now clear, but specific data on patients with breast cancer (BC) remain limited, particularly in developing nations. Materials and methods: We conducted a longitudinal, multicenter cohort study in patients with BC and confirmed SARS-CoV-2 infection. The primary end point was the proportion of patients on treatment for severe SARS-CoV-2 infection (defined as need for hospitalization) or early death (within 30 days of diagnosis). Data were evaluated sequentially in the following way: i) univariate Fisher’s exact test; ii) multivariable logistic regression analysis; and iii) multivariable logistic regression. In items i and ii only those with P< 0.1 are considered significant and in stage iii only those with p< 0.05 were the final significant variables. We divided patients’ data into three major variable domains: a) signs and symptoms; b) comorbidities; and c) tumor and treatment characteristics; in item ii each variable domain was tested separately, finally, in item iii the significant variables of all domains were tested together and we called it the integrative step. Results: From April 2020 to June 2021, 413 patients with BC and COVID-19 were retrospectively registered, of which 288 (70%) had an identified molecular subtype and 273 (66%) had stage information. Most patients were on active systemic therapy or radiotherapy (73.2%), most of them in the curative setting (69.5%). The overall rate of severe SARS-CoV-2 was 19.7% (95% CI, 15.3-25.1). In the integrative multivariate analysis, factors associated with severe infection were metastatic setting, chronic pain, acute dyspnea, and cardiovascular comorbidities. Recursive partitioning modeling used acute dyspnea, metastatic setting, and cardiovascular comorbidities to predict non-progression to severe infection, yielding a negative predictive value of 84.9% (95% CI, 78.9%-88.3%). Conclusion: The rate of severe COVID-19 in patients with BC is influenced by prognostic factors that partially overlap with those reported in the general population. High-risk patients should be considered candidates to active preventive measures to reduce the risk of infection, close monitoring in the case of exposure or SARS-CoV-2 -related symptoms and prophylactic treatment once infected. Citation Format: Fanny Cascelli, Matheus Costa e Silva, Rodrigo Dienstmann, Bruno L. Ferrari, Carlos Gil Ferreira, Max S. Mano, Jorge Canedo, Diego Cunha, Daniel Luiz Gimenes, Aline Goncalves. Determinants of severe COVID-19 infection in Patients with Breast Cancer from a Community Oncology Practice in Brazil [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-36.

BACKGROUND Precision oncology has a prominent role in nonsquamous non-small cell lung cancer (nsNSCLC) treatment progress. This study aimed to investigate not-cost-related factors involved in the use of the molecular profile in clinical practice and the influence of its availability on clinical decisions. METHODS nsNSCLC patients who underwent molecular testing in a private referral Brazilian center were identified. The primary endpoint was the interval from the diagnosis of advanced nsNSCLC to the characterization of the molecular profile. Other outcomes, focusing on the biomarker tissue journey, were also assessed, as well as the choice of therapy and changes in the treatment upon the testing results. RESULTS In this cohort (n = 78), the median time between the advanced nsNSCLC diagnosis and biomarker characterization was 40.5 days (range, 29.5–68.5). The median interval between the diagnosis and the test request was longer than the interval between the request and the results (respectively 29.0 versus 12.0 days; p

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.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has caused the coronavirus disease 2019 (COVID-19), first appeared in December 2019 in Wuhan (China) and quickly spread worldwide and has since been assigned a pandemic status. This affected the worlds' social interactions, including within medical practices, thus interfering with routine treatments for a variety of diseases including cancer. Different studies have addressed the fact that patients with cancer are often immunocompromised, making them more susceptible to infections. Since COVID-19 frequently causes respiratory distress, patients with lung cancer are considered to be a high-risk group. Genes that have been indicated to mediate viral entry into host cells such as angiotensin-converting enzyme 2 and transmembrane protease serine 2 are expressed in the lung tissue, a fact that could partially explain COVID-19 pathogenesis and lung involvement. Therefore, the current study offers a disease overview including molecular aspects behind the infection and provide a perspective on already published Chinese data plus recommendations for the management of lung cancer patients according to the two main lung cancer types and stages: non-small cell lung cancer and small cell lung cancer. This review aimed to add to the collective effort of selecting the most appropriate guidelines to follow for the treatment of these patients.

58 Background: Regorafenib and trifluridine/tipiracil (TAS-102) are the only therapeutic options for patients with chemorefractory metastatic colorectal cancer (mCRC) with demonstrated benefit in overall survival (OS). However, they are not accessible worldwide. In Brazil, they have been recently approved, but they have not yet been provided by public health system or private health insurances. We aimed to describe the treatment patterns and clinical outcomes of that population in a setting with limited access to those drugs. Methods: Retrospective study evaluating 510 patients with mCRC who were treated at five Oncoclinicas centers in Brazil from January 2011 to December 2019. Demographic and clinical data were retrieved from electronic medical records. The median OS was calculated by Kaplan-Meier method and prognostic factors were evaluated via multivariable Cox Regression, calculating the Hazard Ratio (HR) and the confidence interval (CI95%). Results: A total of 163 patients (33% of the overall population) received third-line and 73 (15%) fourth-line systemic therapy. Median age was 62 years, 59% were male. Tumors were right-sided in 19%, RAS mutated 44%, BRAF mutated 3%, and high-frequency microsatellite instability 3%. Metastasectomy prior to third-line was performed in 62% of the patients. From the start of third-line therapy, median follow-up was 9.0 months, with 67% of deaths, and median OS was 13.7 months (CI95% 11.8m–20.0m). Most adopted regimens in third-and fourth-line were (1) rechallenge with oxaliplatin-based therapy (39% and 26%, respectively); (2) rechallenge with irinotecan-based therapy (32% and 34%); (3) rechallenge with anti-EGFR monoclonal antibodies (20% and 29%); (4) regorafenib (13% and 25%); and (5) TAS-102 (2% and 4%). In multivariable model including clinical and molecular variables, prior metastasectomy was the only significant prognostic factor for OS (HR 0.51, CI95% 0.31–0.83, p=0.007). Conclusions: In real-world, a meaningful proportion of patients with mCRC are eligible for third and later lines of therapy. Rechallenge with chemotherapy and anti-EGFR agents is overused in a setting of limited access to therapies with demonstrated OS benefit, such as regorafenib and TAS-102. Barriers to drug access impair the adoption of the best evidence-based continuum of care and strategies to overcome them are urgently needed. Refractory patients in later lines of therapy derive survival benefit from prior metastasectomy.

Immuno-therapeutics have revolutionized the field of oncology. The Brazilian cancer population would unquestionably benefit from an increase in the availability of cost-effective immuno-oncologic drugs. The challenge is how to incorporate these into the toolbox of health professionals, given the complexity and inequities of the Brazilian healthcare system, limiting financial resources and numerous health needs. We provide a series of recommendations that are likely to improve access and reduce the cost of these important medications. Nonetheless, there are numerous challenges that must be overcome if the entire Brazilian cancer population is to benefit from this remarkable advancement in health care.

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.

The present study describes the geographical and sectorial profile of chemical and biotechnological patents, regarding prevention, diagnosis, and treatment for the most frequent cancer types in Brazil that are currently registered in the Brazilian National Institute of Industrial Property – INPI, from 1998 until 2013. The steps taken to generate competitive advantage in the Brazilian oncological drug market are discussed and an analytic sectional survey was performed using the INPI database. In addition, a literature review on technology and scientific development was conducted using the Porter's Diamond of National Advantage model. From 503 requests for patents, 41.4% corresponded to breast cancer, 13.7% lung cancer, 38.6% prostate, and 6.4% cervical cancer. Regarding the sectors and countries involved, the vast majority (74.4%) came from the pharmaceutical industry: mainly from the USA and Switzerland. According to the analysis and the Porter Diamond Model, we concluded that Brazil is uncompetitive in cancer R&DI.

The enzyme cyclooxygenase 2 (COX-2) is known to be involved in tumorigenesis and metastasis in certain types of cancer. Nevertheless, the prognostic value of COX-2 overexpression and its polymorphisms in patients with non-small cell lung cancer (NSCLC) have yet to be fully elucidated. The aim of the present study was to investigate the association between the three most commonly studied COX-2 gene polymorphisms (−1195 G/A, −765 G/C and 8473 T/C) with COX-2 expression and lung cancer risk in a Brazilian cohort. In the present hospital based, case-control retrospective study, 104 patients with NSCLC and 202 cancer free control subjects were genotyped for −1195 G/A, −765 G/C and 8473 T/C polymorphisms using allelic discrimination with a reverse transcription quantitative polymerase chain reaction method. COX-2 mRNA expression was analyzed in surgically resected tumors from 34 patients with NSCLC. The results revealed that COX-2 expression levels were higher in tumor tissue compared with normal lung tissue. However, this overexpression of COX-2 was not associated with the patient outcome, and furthermore, none of the analyzed polymorphisms were associated with the risk of developing lung cancer, COX-2 overexpression, or the overall survival of the patients with NSCLC. Taken together, the findings described in the present study do not support a major role for COX-2 polymorphisms and COX-2 overexpression in lung carcinogenesis within the Brazilian population.

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.

1558 Background: COVID-19 is a challenge for clinical decision-making in cancer patients and the allocation of healthcare resources. An accurate prognosis prediction to effectively triage patients is needed, especially in the community oncology practice. Methods:Nationwide cohort from Oncoclínicas Brazil was used to validate previously developed multivariable logistic regression (mLR) model (Ferrari et al, JCO GO 2021) and to construct a machine learning Random Forest (RF) algorithm as predictor of 30-day mortality after SARS-CoV-2 detection by RT-PCR in cancer patients diagnosed in an outpatient setting. To find the most important baseline clinical determinants of early COVID-19-related death via Gini index, a RF with 100,000 trees was trained in 75% of the dataset, and the performance was assessed in the remaining 25%. We then compared the accuracy of different models in terms of sensitivity, specificity and area under the receiver operating characteristics curves (AUC). Results:From March to December 2020, 533 patients with COVID-19 were prospectively registered in the database. Median age was 60 years (19-93) and 67% were female. Most frequent cancers were breast in 34%, hematological in 16%, and gastrointestinal in 15%. Comorbidities were common (52%), as was current/former smoking history (17%). Most patients were on active systemic therapy or radiotherapy (84%) in the advanced or metastatic disease setting (55%). The overall mortality rate was 15% (CI95% 12%-18%). We validated the original mLR model trained in the first 198 patients: management in a non-curative setting (odds ratio [OR] 3.7), age ≥ 60 years (OR 2.3), and current/former smoking (OR 1.9) were significant predictors of death in the expanded cohort. Presence of comorbidities (OR 1.9) also defined poor outcome in the updated mLR model, which yielded low sensitivity (74%), specificity (68%) and AUC (0.78). With RF modeling, the most significant predictors of 30-day death after COVID-19 (in decreasing order) were older age, treatment of advanced or metastatic disease, tumor type (respiratory tract, brain and unknown primary cancers had higher mortality), COVID-related symptom burden at baseline evaluation and treatment regimen (immunotherapy combinations had higher mortality). The RF model demonstrated high sensitivity (89%), specificity (88%) and AUC (0.96). Conclusions:The results highlight the possibility that machine learning algorithms are able to predict early mortality after COVID-19 in cancer patients with high accuracy. The proposed prediction model may be helpful in the prompt identification of high-risk patients based on clinical features alone, without having to wait for the results of additional tests such as laboratory or radiologic studies. It can also help prioritize medical resources and redefine vaccination strategies. A web-based mortality risk calculator will be created for clinical decision support.

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.

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.

e13597 Background: Lung cancer is the principal cause of death from cancer worldwide. However, little is known of the clinic and histological profile from former smokers patients with lung cancer. Objectives: To characterize the clinical and histological profile and to identify independent factors associated with smoking status (former versus current) in patients with lung cancer in Brazil between 2010 and 2016. Methods: An ecological study was conducted using data from Brazilian hospital-based cancer registries between 2010 and 2016. Data with p-value < 0.20 in the univariate analysis were included in the logistic regression analysis by using the stepwise forward method, in order to control for potential confounders. Results: This study evaluated 23,462 patients with lung cancer diagnosed between 2010 and 2016 in Brazil. In general, the average age of all patients was 63.7 + 10.7 years old. Never smokers, former smokers and current smokers corresponded to 18.9 %, 35.2% and 45.9% of cases in the moment of the diagnosis, respectively. Current smokers were the most frequent smoking status, albeit its frequency decreased significantly during the period. Male and female former smokers had its frequency increasing over the period and male former smokers became more frequent than males current smokers since 2015. In multivariate analysis, comparing former versus smokers, the follow variables were statistically significant: former drinkers, older age group, higher schooling, married or living married, from non-public (private) health system insurance, living in region North, Northeast and West Center and more recent year of diagnosis. Conclusions: Recently, former smokers with lung cancer is increasing and became the most frequent smoking status, as a result of the very effective policies against to smoking in Brazil since 1990’s. The increase in that specific population discloses some interesting challenges and opportunities in clinical and translational settings.

e14076 Background: The most common approach to diagnose prostate cancer is the “whole gland biopsy procedure,” in which numerous cores (≥12) are taken from different regions of the gland to maximize the chances of detecting small cancers; the presence of cancer in any of these cores is significant to the patient. If concerning features that are not fully diagnostic of cancer are identified, the pathologist may defer the final diagnosis until additional studies (e.g. immunohistochemistry) have been performed. We recently developed an artificial intelligence (AI)-based system for the assessment of cancer in prostate biopsies. Here, we investigated the performance of this test in an independent dataset of prostate cancers consecutively accrued. Methods: Two board-certified pathologists retrospectively reviewed 600 digitized hematoxylin-and-eosin (H&E) stained diagnostic prostate core needle biopsy slides from 100 consecutive patients, originally diagnosed at an independent hospital. Pathologists’ assessments were based on the H&E image alone; if further testing would be preferred, it was noted in the review notes. All images were assessed by Paige Prostate 1.0, an AI-based diagnostic tool; based on its outputs (either suspicious for cancer or not), the discordant images were re-reviewed by the pathologists and, in parallel, adjudicated with additional testing (e.g. ancillary immunohistochemical markers). Results: Paige Prostate's slide-level sensitivity was 98.9% and its specificity was 93.3% (100% and 78.0%, respectively, at the subject-level). The pathologists' average slide-level sensitivity and specificity without Paige Prostate was 90.9% and 98.6%, respectively. The sensitivity with their consensus read and Paige Prostate increased by 5.7% to 96.6% with only 0.8% decrease in specificity. In addition to new slide-level findings, benefits were also observed at the subject-level; with Paige, three new prostate cancer cases were discovered that were initially missed. Conclusions: The study reflects the potential benefits of the Paige Prostate system in the hands of experienced pathologists and validates the algorithm in a completely independent dataset. Paige Prostate can improve pathologists' sensitivity when reviewing digitized H&E prostate needle biopsy images with a minor impact on specificity.

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.

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.

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.

A 14-year-old boy was referred to our hospital with a 1-year evolving productive cough and hemoptysis.A Positron-emission-tomography scan (PET/CT) revealed a 17cm hypermetabolic right lower-lobe lung mass in contact with mediastinal structures as well as multiple bilateral pulmonary nodules. Percutaneous lung biopsy identified an invasive mucinous adenocarcinoma (IMA; formerly mucinous BAC) associated with Type I Congenital Cystic Adenomatoid Malformation (CCAM).Genomic profiling was performed and detected a KRAS mutation (G12D). NSCLC can be rarely seen in young patients. In the pediatric population, the incidence is approximately 0.0002% and it is usually associated with a congenital malformation. CCAM is a group of rare lung congenital malformations. The estimated incidence is 1 in 25.000 to 1 in 35.000 pregnancies and it represents 25% of all congenital lung malformations. Type I is the most common subtype of CCAM. It is characterized by the presence of large cysts lined by pseudostratified ciliated cells that are often interspersed with rows of mucous cells.It has been largely recognized that some cases of type I CCAM show malignant transformation to mucinous adenocarcinoma. Recent data clearly demonstrated that the occurrence of mucinous adenocarcinoma in type I CCAM is associated with KRAS mutation. This case highlights the relationship between type I CCAM and lung mucinous adenocarcinoma/KRAS mutant. Moreover, demonstrated that the clinical outcome was consistent with the molecular feature of a KRAS mutant patient.

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.

SUMMARY Substantial advances have been made in understanding critical molecular and cellular mechanisms driving tumor initiation; these findings have led to the discovery of a variety of novel drug targets and the development of new treatment strategies. The treatment of non-small-cell lung cancer patients harboring gain-of-function hotspot mutations in EGFR gene or an ALK gene rearrangement, has provided an impressive clinical benefit and changed the management of this disease. The standard of care with cytotoxic chemotherapy empirically based on a patient’s clinicopathologic features is no longer acceptable. Nevertheless, chemotherapy still bears a crucial role in all subsets of patients diagnosed with non-small-cell lung cancer. This article aims to describe the emergence of these new treatment strategies and update the role of chemotherapy in the current setting.

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.

BACKGROUND This study sought to determine the feasibility and recommended phase 2 dose (RP2D) of the combination of cetuximab with chemoradiotherapy based on 5-fluorouracil (5-FU) and cisplatin (CP) in locally advanced anal canal carcinoma. METHODS Cetuximab was administered on days 1, 8, 15, 29, 36, 43, and 50 (400 mg/m2 initial dose, then 250 mg/m2/week) concurrent with total dose radiation of 55 to 59 Gy, both starting on day 1. Escalating doses of 5-FU (96-hour infusion) and CP (2-hour infusion), both on days 1 and 29, were administered according to the following design: starting dose level (0) 5-FU/CP = 800/60 mg/m2/day and up to dose level (+2) 5-FU/CP = 1000/80 mg/m2/day. RESULTS Dose-limiting toxicity (DLT) events (uncontrolled diarrhea or febrile neutropenia) occurred in 3 of 14 assessable patients receiving escalated dose of 5-FU/CP, with 1 in dose level (0) and 2 in dose level (+2). The RP2D was 5-FU/CP = 800/80 mg/m2/day. Because of unexpected non-DLT treatment-related grade 3 (G3) adverse events (AEs) such as thrombosis/embolism, syncope, and infection occurring in ≥ 20% of patients, a safety expansion cohort with an additional 9 patients was investigated with the RP2D. The most frequent G3/G4 AEs evaluated in 23 patients were radiation dermatitis (12 patients), diarrhea (10 patients), thrombosis/embolism (6 patients), and infection (5 patients). The study was closed due to these severe AEs, although no G5 AEs occurred. Twenty of 21 patients (95%) achieved pathological complete response at primary tumor. With a median follow-up of 43.4 months, the 3-year locoregional control rate was 64.2%. CONCLUSIONS Cetuximab could not be integrated with chemoradiotherapy-cisplatin–based therapy due to the high toxicity rate. However, efficacy is encouraging and further investigation of an epidermal growth factor receptor–targeted agent (other than cetuximab) concurrent with chemoradiation should be pursued. Cancer 2013;119:2973—2980. © 2013 American Cancer Society.

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.

The aim of the present systematic review was to analyze the potential impact of mammalian target of rapamycin (mTOR) inhibitors on the treatment of cervical squamous cell carcinoma (CSCC). A systematic literature search was conducted in PubMed, PMC, Scopus, Cochrane Library, LILACS, Web of Science, Google Scholar and ScienceDirect on January 19, 2015, without time and language restrictions. Studies that evaluated women of any age with CSCC and who received mTOR inhibitors alone or in association with other treatments were considered. Randomized and non-randomized clinical trials were included, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist was followed. Selected studies were methodologically appraised according to the Grades of Recommendation, Assessment, Development and Evaluation method to assess the quality of evidence. Of 642 identified citations, 43 studies were fully reviewed; however, only 3 studies met the inclusion criteria and were used for qualitative analysis. Of these, two studies were phase 1 and one was a phase 2 clinical trial. The studies included were not conclusive with regard to the association between mTOR inhibitor treatment and cervical cancer. The main analysis of secondary endpoints revealed that individuals treated with other drugs in association with mTOR inhibitors achieved partial responses (15.4-33.3%) or stable disease (17.6-28%). Treatment with mTOR inhibitors in general was well tolerated in patients with metastatic disease. The predominant toxicities were grade 1 and 2. The phase 1 trials included in this review demonstrated that mTOR inhibitor treatments are feasible and safe. However, the currently available evidence is insufficient to determine the effect of mTOR inhibitors on CSCC, and further investigation in high-quality, randomized clinical trials is required.