Incidence, risk factors and the prognostic role of thromboembolic events (TEEs) amongst patients with metastatic pancreatic adenocarcinoma (PAAD): a retrospective, single-center analysis.

Background: Thromboembolic events (TEEs) are frequent among patients with pancreatic adenocarcinoma (PAAD). We set out to estimate the incidence and establish predictive risk factors for TEE and estimate the impact of TEEs on the overall survival (OS) of patients with metastatic PAAD. Methods: This is a retrospective, single-center study. We included patients with a pathologically confirmed diagnosis of PAAD with distant metastases treated at AC Camargo Cancer Center from 2016 to 2021. We used the competitive risk survival models to estimate the cumulative incidence of TEE. Risk factors for the development of TEEs were evaluated using the competitive risk and logistic regression models. The impact of TEEs on OS was assessed using both landmark and time-dependent covariate Cox survival analyses. Results: The study population consists of 199 patients. The cumulative incidence of TEEs in 1, 6 and 24 months were 10.1%, 19.3% and 30.2%, respectively. Log10(CA 19-9) was the only factor independently associated with increased risk of TEEs in the logistic regression (Odds ratio = 1.03; 95% confidence interval (95%CI), 1.00-1.06; p = 0.030) and competitive risk survival (Subdistribution hazard ratio = 1.14; 95%CI, 1.02-1.27; p = 0.019) models. In the landmark analysis, early TEEs (within 1 month of diagnosis) were not associated with inferior OS. In the time-dependent covariate Cox proportional hazard model, TEEs were not found to be statistically associated with inferior OS, although there was a trend towards it (Hazard ratio = 1.59; 95%CI, 0.99-2.54; p = 0.051). Conclusion: TEEs occur in a large fraction of patients with metastatic PAAD. Statistical models with higher predictive performance are currently needed. For the time being, consideration for prophylactic anticoagulation should be done on an individual basis.

Short-term survival of patients with advanced pancreatic cancer admitted to intensive care unit: a retrospective cohort study.

Background: Little is known about the outcomes of patients with advanced pancreatic cancer admitted to the intensive care unit (ICU) due to medical complications. We designed a study to evaluate their short-term (30-day) survival, predictors of short-term survival and chances of additional chemotherapy. Methods: We reviewed all patients with advanced (stage III or IV) pancreatic adenocarcinoma admitted to an ICU in a dedicated Brazilian cancer centre from 2009 to 2018 due to medical reasons. We fitted multivariate regression models to identify predictors of 30-day survival and additional systemic chemotherapy. Results: The study population consisted of 171 patients. Ninety-four patients (55.0%) had Eastern Cooperative Oncology Group (ECOG) performance status 2-4 and 146 (85.4%) had metastatic disease. Most patients (N = 75; 43.9%) were admitted to the ICU during first-line treatment. Median overall survival was 32 days (95% confidence interval (95% CI): 20-49). Survival rate at 30 days was 50.6%. ECOG performance status 2-4 was the only variable associated with lower probability of survival at 30 days in multivariate analysis (odds ratio: 0.28; 95% CI: 0.14-0.54; p < 0.001). Overall, 58 patients (33.9%) received additional chemotherapy and among all patients, 13.5% experienced clinical benefit from this treatment. Conclusion: Patients with advanced pancreatic cancer admitted to the ICU for medical reasons have a dismal prognosis. Early palliative care and refined tools to establish those who would benefit from an ICU trial could help improve patients' care.

Anti-PD1 versus anti-PD-L1 immunotherapy in first-line therapy for advanced non-small cell lung cancer: A systematic review and meta-analysis.

BACKGROUND: Due to the increasing number of trials with immune checkpoint inhibitors (ICIs) in the first-line therapy of non-small cell lung cancer (NSCLC) patients, we performed a systematic review and meta-analyses to investigate the difference between anti PD-1 and PD-L1 antibodies, used alone or in combination with chemotherapy, through adjusted indirect analysis to minimize the potential bias regarding overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and grade 3-5 adverse events (AEs). METHODS: A systematic review of studies reporting clinical outcomes and toxicity associated with first-line therapy employing anti-PD1 or anti-PD-L1 antibodies alone, or in combination with chemotherapy, to treat metastatic, treatment-naïve NSCLC patients was performed. Primary outcomes were OS, PFS, ORR and grade 3-5 AEs. We used a random-effects model to generate pooled estimates for proportions. Meta-analyses using pooled risk ratios were performed for binary outcomes from comparative studies with the random effects model. RESULTS: A total of 13 eligible studies met our eligibility criteria, including 7673 patients. In the ICI-chemotherapy combination subgroup, we observed that anti-PD1 therapy was associated with better OS (p = 0.022) and PFS (p = 0.029) compared with anti-PD-L1 therapy. In the monotherapy subgroup, there was no statistical difference between the use of anti-PD-1 and anti-PD-L1 for OS and PFS. With regard to ORR and toxicity, in the ICI-chemotherapy combination subgroup, we observed a trend of better ORR (p = 0.12) with the use of anti-PD1 therapy and less frequent grade 3-5 AEs compared to the use of anti-PD-L1 therapy (p = 0.0302). In the monotherapy subgroup, there was no statistical difference between the use of anti-PD-1 and anti-PD-L1 regarding ORR and toxicity. CONCLUSIONS: Our study suggests that PD-1 drug plus chemotherapy is superior to anti-PD-L1 plus chemotherapy for NSCLC; nevertheless, as monotherapy, both strategies appear to be similar.

Disease-Free Survival and Time to Complete Response After Definitive Chemoradiotherapy for Squamous-Cell Carcinoma of the Anus According to HIV Infection.

BACKGROUND: The standard treatment for localized squamous-cell carcinoma of the anal canal is definitive chemoradiotherapy. A meta-analysis of published studies conducted by our group showed significantly lower rates of disease-free survival (DFS) and overall survival at 3 years among HIV-positive patients. We aimed to compare detailed treatment outcomes between the groups of HIV-positive and -negative patients. PATIENTS AND METHODS: We performed a retrospective multicenter study of a comparative cohort of consecutive patients with histologic diagnosis of localized squamous-cell carcinoma of the anal canal who received definitive chemoradiotherapy. Patients' characteristics and outcomes were compared according to HIV status. The primary end points were time to complete response (CR) and DFS time. RESULTS: From June 2001 to September 2018, a total of 185 patients were included; 43 (30.2%) were HIV positive and 142 (69.8%) were HIV negative. The overall CR rates were 67.4% and 91.5% for HIV-positive and -negative patients, respectively (P < .001). The median follow-up was 47.8 months and the median time to experience CR was 7.8 months (95% confidence interval [CI], 5.7-10.5) for HIV-positive versus 4.89 months (95% CI, 4.54-5.25) for HIV-negative (P < .001) patients. The median DFS times were 79.7 months (95% CI, 56.8-102.6) and 127.9 months (95% CI, 112.6-143.2) for HIV-positive and -negative patients, respectively (P = .02). There was a trend toward greater grade 3/4 toxicity in the HIV-positive group. CONCLUSION: HIV-positive patients take longer to experience CR and present worse DFS. These findings have clinical implications because waiting longer to define CR among these patients may prevent unnecessary anorectal amputations.

Characteristics and survival of older patients with metastatic pancreatic cancer: a retrospective analysis of the AC Camargo Cancer Center experience.

BACKGROUND: Advanced age is the most important risk factor for pancreatic cancer and about half of patients are diagnosed with metastatic disease. In the first-line setting, multidrug chemotherapy regimens were shown to be more effective than gemcitabine alone. However, the older population was under-represented in randomized clinical trials. We aimed to describe the clinical profile of older patients with metastatic pancreatic cancer and their survival outcomes. MATERIALS AND METHODS: This was a retrospective, unicentric study that included patients diagnosed with metastatic pancreatic cancer (non-neuroendocrine), aged 65 years and over. RESULTS: The study population comprised 196 patients. The median age was 73 years; 67% of these patients presented Eastern Cooperative Oncology Group performance status (ECOG) ⩽ 1 and the median Charlson Comorbidity score was 10. Chemotherapy was given to 89% of the patients. The most frequently used chemotherapy regimens were gemcitabine (44%), 5-fluorouracil and oxaliplatin [FOLFOX; 26%], and 5-fluorouracil, oxaliplatin and irinotecan (FOLFIRINOX; 20%). Patients treated with FOLFIRINOX were younger and they presented better performance status. After a median follow up of 19.8 months, the median overall survival (OS) was of 7.2 months and the median time to first-line-treatment failure was 4.6 months. Among patients treated with chemotherapy, the median OS was highest for those treated with FOLFIRINOX (13.8 months), as compared with FOLFOX (7.0 months) or gemcitabine (6.7 months); p = 0.004. Nonetheless, treatment with FOLFIRINOX was associated with increased risk of severe toxicity (p = 0.008). CONCLUSION: Older patients with metastatic pancreatic cancer benefit from palliative chemotherapy, and FOLFIRINOX is a therapeutic option in rigorously selected older patients.

Treatment outcomes of patients with localized anal squamous cell carcinoma according to HIV infection: systematic review and meta-analysis.

BACKGROUND: Definitive chemoradiation (CRT) is the standard treatment for localized squamous cell carcinoma of the anus (SCCA). Because most phase III trials in SCCA have excluded patients with HIV, the evidence on treatment outcomes of these patients is lacking. We performed a systematic review and meta-analysis on the efficacy and toxicity profiles of HIV-positive SCCA patients treated with definitive CRT. METHODS: The systematic search was conducted Embase, Medline, Cochrane Libary, Scopus, Lilacs and Opengrey, from inception until September 2017. Eligible studies were clinical trials, prospective or retrospective cohort studies. The main outcome variables were 3-year disease-free survival (DFS) and overall survival (OS) rates and frequency of grade 3 or 4 (G3/4) treatment-related toxicities, according to HIV status. Meta-analyses using pooled risk ratios were performed for binary outcomes from comparative studies from the antiretroviral therapy (HAART) era with the fixed effects model. RESULTS: Out of 3,951 studies, 40 were deemed eligible, with a total of 3,720 patients. One third (N=1,298; 34%) were HIV-positive and their median pre CRT CD4 count was 347 µm/L. HIV-positive patients presented higher risk of G3/4 cutaneous toxicities [risk ratio (RR) =1.34; 95% CI, 1.10-1.64; P=0.004; I2=77.7%], worse 3-year DFS rate (RR =1.32; 95% CI, 1.01-1.74; P=0.043; I2=52.19%), and 3-year OS rate (RR =1.77; 95% CI, 1.35-2.32; P<0.001; I2=6%). CONCLUSIONS: Patients with localized SCCA and HIV infection treated with CRT tend to experience higher risk of toxicities and worse DFS and OS rates. Our findings suggest that future trials should be tailored to HIV-positive patients.

Retrospective analysis of efficacy and safety of Gemcitabine-based chemotherapy in patients with metastatic pancreatic adenocarcinoma experiencing disease progression on FOLFIRINOX.

BACKGROUND: Metastatic pancreatic adenocarcinoma (MPA) represents a highly lethal condition. Despite the improvements seen with FOLFIRINOX, there is no randomized data to guide treatment selection beyond this regimen. We aimed to evaluate the outcomes of patients with MPA progressing on FOLFIRINOX who were treated with Gemcitabine-based chemotherapy afterwards. METHODS: We included patients aged 18 years or older, treated for MPA with FOLFIRINOX in the first-line setting and who experienced disease progression, with Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and treated with at least one cycle of Gemcitabine-based chemotherapy in second or further lines of treatment. We used descriptive statistics to characterize the study population and Cox proportional-hazards models to describe factors associated with survival. As an exploratory analysis, we compared the outcomes of patients treated with single-agent Gemcitabine with those of patients undergoing Gemcitabine-based polychemotherapy. RESULTS: The study population consisted of 42 patients. Median age was 59 years and 78.6% of patients presented ECOG 0-1. Thirty-three patients (78.6%) were treated with Gemcitabine-based chemotherapy in the second-line setting and 27 patients (64.3%) were treated with single-agent Gemcitabine. Objective response rate and disease control rate were 2.4% and 33.4%, respectively. Median progression-free survival (PFS) and median overall survival (OS) were 2.9 and 5.5 months, respectively. Six-month PFS and OS rates were 19.2% and 46.2%, respectively. We observed no significant difference in OS according to the type of Gemcitabine-based chemotherapy, despite numerically improved disease control rate and PFS for those treated with Gemcitabine-based polychemotherapy. In multivariate analysis, ECOG 2 (vs. ECOG 0-1) was the only factor significantly associated with inferior PFS and OS. CONCLUSIONS: a subgroup of patients with MPA derives benefit from treatment with Gemcitabine-based regimens after FOLFIRINOX. There is a suggestion that Gemcitabine-based combinations, in particular Gemcitabine plus Nab-Paclitaxel, provide superior outcomes compared to single-agent Gemcitabine. Additionally, treatment in this setting should be offered carefully to patients with ECOG 2, as they present shorter survival and increased risk of toxicity.

Retrospective comparison of the efficacy and the toxicity of standard and modified FOLFIRINOX regimens in patients with metastatic pancreatic adenocarcinoma.

BACKGROUND: FOLFIRINOX stands a major breakthrough in the management of metastatic pancreatic adenocarcinoma (MPA). Nonetheless, significant side-effects have been reported using standard FOLFIRINOX. We aimed to compare survival outcomes, response rates and toxicity of patients treated with standard or modified FOLFIRINOX in MPA. METHODS: We included patients aged ≥18 years old, with pathologically confirmed MPA, treated with FOLFIRINOX in the first-line setting. Patients submitted to at least one cycle of full-dose FOLFIRINOX were grouped in the standard FOLFIRINOX group. RESULTS: Patients treated with standard FOLFIRINOX were younger and had less comorbidity. We observed no differences in overall survival or in progression-free survival between the two treatment arms. The only variable independently associated with OS was log10[neutrophil-to-lymphocyte ratio (NLR)]. Modified FOLFIRINOX was associated with a lower dose reduction rate, but a slightly increased incidence of severe toxicity. CONCLUSIONS: Modified FOLFIRINOX presents the same activity against MPA as standard FOLFIRINOX. We found no significant differences in toxicity, possibly due to patient selection and a higher dose reduction rate in the standard FOLFIRINOX arm. NLR stood as an important prognostic marker and further research is needed to comprehend its biological meaning in pancreatic cancer.

The roles of PTEN, cMET, and p16 in resistance to cetuximab in head and neck squamous cell carcinoma.

There is no established biomarker for cetuximab efficacy in recurrent head and neck squamous cell carcinoma (HNSCC). The aim of the present study was to evaluate the prognostic and predictive impact of PTEN, cMET, and p16 expression in recurrent HNSCC. In this retrospective study, 112 patients with recurrent HNSCC received chemotherapy (CT) alone (n = 37) or chemotherapy with cetuximab (n = 75). PTEN, cMET, and p16 protein expression were evaluated by immunohistochemistry. The median overall survival (mOS) for the patients treated with cetuximab + CT versus CT alone was 11.4 months and 7.0 months, (p = 0.949). The median progression-free survival (mPFS) was 6.2 months versus 3.0 months (p = 0.154). Patients with PTEN loss exhibited a mOS of 5.8 months versus 10.5 months (p = 0.002) and a mPFS of 3.2 months versus 4.7 months (p = 0.019). A multivariate analysis identified an independent association between PTEN loss and OS (HR 2.27; 95% confidence 95% CI 1.27-4.08; p = 0.006) and with PFS (HR 1.85; 95% CI 1.09-2.99; p = 0.022). A negative prognostic impact of PTEN loss was observed in the patients treated with cetuximab + CT, and not in the CT only group. Expression of cMET and p16 showed no impact on OS or PFS. The present findings confirm that PTEN is a prognostic factor for metastatic HNSCC and they support further studies of PTEN expression to evaluate its predictive value to cetuximab response.

FOXP3 expression in papillary thyroid carcinoma with and without Hashimoto's thyroiditis / Expressão do FOXP3 no carcinoma papilífero da tireoide com e sem tireoidite de Hashimoto

INTRODUCTION: The forkhead box P3 (FOXP3) plays a role in cell development and control. In the presence of abnormal FOXP3 expression, tumor cells may evade the immunosurveillance of lymphoid cells, the first step for the maintenance of cancer cells in the thyroid tissue. OBJECTIVE: To identify the presence of FOXP3 in papillary thyroid carcinoma (PTC) with and without Hashimoto's Thyroiditis (HT). METHODS: We conducted a series study of cases collected from 2000 to 2008, when 1,438 thyroidectomies were performed. We selected those diagnosed with PTC, comprising 466 cases. 30 patients were randomly selected for purposes of immunohistochemistry with antibodies against FOXP3. RESULT: FOXP3 revealed high positivity for PTC and positive immunostaining was present in 21 (72.4%) from all analyzed cases. There was no difference regarding coexistent HT or not. DISCUSSION AND CONCLUSION: In the present study, it was evidenced that the focal or diffuse FOXP3 expression was commonly observed in neoplastic cells from PTC, hence indicating that the assessment of this molecule expression in suspected cases of thyroid cancer may contribute to its diagnosis.

INTRODUÇÃO: O forkhead box P3 (FOXP3) tem o seu papel no desenvolvimento e no controle celular. Na presença de alterações da sua expressão, células tumorais podem escapar da imunovigilância das células linfoides, sendo o primeiro passo para perpetuação das células cancerígenas no tecido tireoidiano. OBJETIVO: Identificar a presença do FOXP3 no carcinoma papilífero da tireoide (CPT), com e sem tireoidite de Hashimoto (TH). MÉTODOS: Foi realizado um estudo de série de casos coletados no período de 2000 a 2008, quando foram realizadas 1.438 tireoidectomias. Destes, foram selecionados aqueles que apresentaram diagnóstico de CPT, perfazendo um total de 466 casos. Desse total, 30 casos de CPT foram selecionados aleatoriamente para fins de exame imuno-histoquímico com o anticorpo contra o FOXP3. RESULTADO: O FOXP3 apresentou alta positividade no CPT; a marcação positiva na imuno-histoquímica esteve presente em 21 (72,4%) de todos os casos analisados. Não houve diferença com relação à coexistência ou não de TH. DISCUSSÃO E CONCLUSÃO: No presente estudo, foi documentado que a expressão difusa ou focal de FOXP3 foi intensamente observada nas células neoplásicas do CPT, indicando que a avaliação da expressão dessa molécula em casos suspeitos de neoplasia da tireoide pode contribuir para o seu diagnóstico.

Carcinoma papilífero da tireóide associado à tireoidite de Hashimoto: uma série de casos / Hashimoto disease linked to thyroid papillary carcinoma: a number of cases

Estudo que teve como objetivo quantificar a coexistência da tireoidite de Hashimoto no carcinoma papilífero da tireoide, correlacionando-a com os dados demográficos, informações clínicas e diagnósticos anatomopatológicos prévios. Realizou-se um estudo de série de 347 casos de pacientes com diagnóstico anatomopatológico de carcinoma papilífero da tireoide no serviço de Anatomia Patológica e Citopatologia do Hospital São Rafael, de janeiro de 2000 a dezembro de 2007. Foram feitas aplicações de formulários aos casos, visando a coletar os dados demográficos e as informações clínicas; os exames anatomopatológicos foram diagnosticados pelos dois patologistas deste estudo.O estudo apresentou uma coexistência de 31,4 por cento de tireoidite de Hashimoto em pacientes com carcinoma papilífero da tireoide. No sexo feminino houve um total de 96 casos (88,1 por cento), o que demonstra maior frequência quando comparado com os casos sem a coexistência. A série de casos apresentada mostrou uma frequência de 31,4 por cento de tireoidite de Hashimoto nos casos de carcinoma papilífero da tireoide, sugerindo uma associação não apenas casual, mas que levanta a possibilidade de uma relação de causa e efeito entre a tireoidite e o desenvolvimento do carcinoma. No entanto, necessita-se de mais estudos, seccionais ou de coorte, para essa comprovação.