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OBJECTIVES: The impact of diabetes mellitus (DM) on colorectal cancer (CRC) outcomes remains unknown. We studied this by conducting a meta-analysis to evaluate (1) CRC outcomes with and without DM and (2) treatment patterns. METHODS: We searched PubMed, EMBASE, Google Scholar, and CINAHL for full-text English studies from 1970 to 12/31/2017. We searched keywords, subject headings, and MESH terms to locate studies of CRC outcomes/treatment and DM. Studies were evaluated by two oncologists. Of 14,332, 48 met inclusion criteria. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method, we extracted study location, design, DM definition, covariates, comparison groups, outcomes, and relative risks and/or hazard ratios. We utilized a random-effects model to pool adjusted risk estimates. Primary outcomes were all-cause mortality (ACM), disease-free survival (DFS), relapse-free survival (RFS), and cancer-specific survival (CSS). The secondary outcome was treatment patterns. RESULTS: Forty-eight studies were included, 42 in the meta-analysis, and 6 in the descriptive analysis, totaling > 240,000 patients. ACM was 21% worse (OR 1.21, 95% CI 1.15-1.28) and DFS was 75% worse (OR 1.75, 95% CI: 1.33-2.31) in patients with DM. No differences were detected in CSS (OR 1.10, 95% CI 0.98-1.23) or RFS (OR 1.12, 95% CI 0.91-1.38). Descriptive analysis of treatment patterns in CRC and DM suggested potentially less adjuvant therapy use in cases with DM and CRC. CONCLUSIONS: Our meta-analysis suggests that patients with CRC and DM have worse ACM and DFS than patients without DM, suggesting that non-cancer causes of death in may account for worse outcomes.
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Neoplasias Colorretais , Diabetes Mellitus , Neoplasias Colorretais/terapia , Diabetes Mellitus/epidemiologia , Intervalo Livre de Doença , Humanos , Recidiva Local de Neoplasia , Modelos de Riscos ProporcionaisRESUMO
INTRODUCTION: Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. The optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown. METHODS: In this multi-institutional, international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary end point) and overall survival (secondary end point). Treatment-related adverse events (trAEs) during consolidation treatment were defined using Common Terminology Criteria for Adverse Events version 5.0. Multivariable Cox regression analysis was used. RESULTS: Of 136 patients with stage III EGFRmut NSCLC treated with definitive concurrent CRT, 56 received consolidation durvalumab, 33 received consolidation osimertinib, and 47 was on observation alone. Baseline characteristics were similar across the three cohorts. With a median follow-up of 46 months for the entire cohort, the median duration of treatment was not reached (NR) for osimertinib (interquartile range: NR-NR) and was 5.5 (interquartile range: 2.4-10.8) months with durvalumab. After adjusting for nodal status, stage III A/B/C, and age, patients treated with consolidation osimertinib had significantly longer 24-month rwPFS compared to those treated with durvalumab or in the observation cohorts (osimertinib: 86%, durvalumab: 30%, observation: 27%, p < 0.001 for both comparisons). There was no difference in rwPFS between the durvalumab and the observation cohorts. No significant difference in overall survival across the three cohorts was detected, likely due to the limited follow-up. Any-grade trAE occurred in 52% (2 [6.1%] grade ≥3) and 48% (10 [18%] grade ≥3) of patients treated with osimertinib and durvalumab, respectively. Of 45 patients who progressed on consolidation durvalumab, 37 (82%) subsequently received EGFR tyrosine kinase inhibitors. Of these, 14 (38%) patients developed trAEs including five patients with pneumonitis (14%; 2 [5.4%] grade ≥3) and five patients with diarrhea (14%; 1 [2.7%] grade ≥3). CONCLUSIONS: This study suggests that among patients with stage III unresectable NSCLC with a sensitizing EGFR mutation, consolidation osimertinib was associated with a significantly longer rwPFS compared to durvalumab or observation. No unanticipated safety signals were observed with consolidation osimertinib.
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Acrilamidas , Compostos de Anilina , Anticorpos Monoclonais , Carcinoma Pulmonar de Células não Pequenas , Quimiorradioterapia , Receptores ErbB , Neoplasias Pulmonares , Humanos , Estudos Retrospectivos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Masculino , Feminino , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Acrilamidas/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Pessoa de Meia-Idade , Idoso , Quimiorradioterapia/métodos , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Compostos de Anilina/uso terapêutico , Mutação , Quimioterapia de Consolidação/métodos , Indóis , PirimidinasRESUMO
LKB1/STK11 is a serine/threonine kinase that plays a major role in controlling cell metabolism, resulting in potential therapeutic vulnerabilities in LKB1-mutant cancers. Here, we identify the NAD + degrading ectoenzyme, CD38, as a new target in LKB1-mutant NSCLC. Metabolic profiling of genetically engineered mouse models (GEMMs) revealed that LKB1 mutant lung cancers have a striking increase in ADP-ribose, a breakdown product of the critical redox co-factor, NAD + . Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)-key downstream effectors of LKB1- induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer. SIGNIFICANCE: Loss-of-function mutations in the LKB1 tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.
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Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/genética , Inflamação/genética , Neoplasias Pulmonares/genética , Pulmão , Progressão da DoençaRESUMO
PURPOSE: Prostate gland segmentation is a critical step in prostate radiotherapy planning, where dose plans are typically formulated on CT. Pretreatment MRI is now beginning to be acquired at several medical centers. Delineation of the prostate on MRI is acknowledged as being significantly simpler to perform, compared to delineation on CT. In this work, the authors present a novel framework for building a linked statistical shape model (LSSM), a statistical shape model (SSM) that links the shape variation of a structure of interest (SOI) across multiple imaging modalities. This framework is particularly relevant in scenarios where accurate boundary delineations of the SOI on one of the modalities may not be readily available, or difficult to obtain, for training a SSM. In this work the authors apply the LSSM in the context of multimodal prostate segmentation for radiotherapy planning, where the prostate is concurrently segmented on MRI and CT. METHODS: The framework comprises a number of logically connected steps. The first step utilizes multimodal registration of MRI and CT to map 2D boundary delineations of the prostate from MRI onto corresponding CT images, for a set of training studies. Hence, the scheme obviates the need for expert delineations of the gland on CT for explicitly constructing a SSM for prostate segmentation on CT. The delineations of the prostate gland on MRI and CT allows for 3D reconstruction of the prostate shape which facilitates the building of the LSSM. In order to perform concurrent prostate MRI and CT segmentation using the LSSM, the authors employ a region-based level set approach where the authors deform the evolving prostate boundary to simultaneously fit to MRI and CT images in which voxels are classified to be either part of the prostate or outside the prostate. The classification is facilitated by using a combination of MRI-CT probabilistic spatial atlases and a random forest classifier, driven by gradient and Haar features. RESULTS: The authors acquire a total of 20 MRI-CT patient studies and use the leave-one-out strategy to train and evaluate four different LSSMs. First, a fusion-based LSSM (fLSSM) is built using expert ground truth delineations of the prostate on MRI alone, where the ground truth for the gland on CT is obtained via coregistration of the corresponding MRI and CT slices. The authors compare the fLSSM against another LSSM (xLSSM), where expert delineations of the gland on both MRI and CT are employed in the model building; xLSSM representing the idealized LSSM. The authors also compare the fLSSM against an exclusive CT-based SSM (ctSSM), built from expert delineations of the gland on CT alone. In addition, two LSSMs trained using trainee delineations (tLSSM) on CT are compared with the fLSSM. The results indicate that the xLSSM, tLSSMs, and the fLSSM perform equivalently, all of them out-performing the ctSSM. CONCLUSIONS: The fLSSM provides an accurate alternative to SSMs that require careful expert delineations of the SOI that may be difficult or laborious to obtain. Additionally, the fLSSM has the added benefit of providing concurrent segmentations of the SOI on multiple imaging modalities.
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Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/radioterapia , Radioterapia Guiada por Imagem/métodos , Técnica de Subtração , Tomografia Computadorizada por Raios X/métodos , Algoritmos , Humanos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Modelos Biológicos , Modelos Estatísticos , Dosagem Radioterapêutica , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Tilsotolimod, an oligodeoxynucleotide TLR9 agonist, administered intratumorally, has been clinically evaluated. This compound has demonstrated the ability to induce changes within the tumor microenvironment, to convert noninflamed cold tumors into inflamed hot tumors, with the hope that these tumors will be more responsive to immune checkpoint blockade. See related article by Babiker et al., p. 5079.
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Neoplasias , Receptor Toll-Like 9 , Humanos , Apresentação de Antígeno , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Oligodesoxirribonucleotídeos/uso terapêutico , Adjuvantes ImunológicosRESUMO
Despite being the most frequently altered oncogenic protein in solid tumours, KRAS has historically been considered 'undruggable' owing to a lack of pharmacologically targetable pockets within the mutant isoforms. However, improvements in drug design have culminated in the development of inhibitors that are selective for mutant KRAS in its active or inactive state. Some of these inhibitors have proven efficacy in patients with KRASG12C-mutant cancers and have become practice changing. The excitement associated with these advances has been tempered by drug resistance, which limits the depth and/or duration of responses to these agents. Improvements in our understanding of RAS signalling in cancer cells and in the tumour microenvironment suggest the potential for several novel combination therapies, which are now being explored in clinical trials. Herein, we provide an overview of the RAS pathway and review the development and current status of therapeutic strategies for targeting oncogenic RAS, as well as their potential to improve outcomes in patients with RAS-mutant malignancies. We then discuss challenges presented by resistance mechanisms and strategies by which they could potentially be overcome.
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Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Transdução de Sinais/genética , Microambiente Tumoral/genéticaRESUMO
Many decades in the making, immunotherapy has demonstrated its ability to produce durable responses in several cancer types. In the last decade, immunotherapy has shown itself to be a viable therapeutic approach for non-small cell lung cancer (NSCLC). Several clinical trials have established the efficacy of immune checkpoint blockade (ICB), particularly in the form of anti-programmed death 1 (PD-1) antibodies, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies and anti-programmed death 1 ligand (PD-L1) antibodies. Many trials have shown progression free survival (PFS) and overall survival (OS) benefit with either ICB alone or in combination with chemotherapy when compared to chemotherapy alone. The identification of biomarkers to predict response to immunotherapy continues to be evaluated. The future of immunotherapy in lung cancer continues to hold promise with the development of combination therapies, cytokine modulating therapies and cellular therapies. Lastly, we expect that innovative advances in technology, such as artificial intelligence (AI) and machine learning, will begin to play a role in the future care of patients with lung cancer.
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4-1BB has been considered a promising target in cancer immunotherapy for decades. Nevertheless, early 4-1BB-targeted agents demonstrated significant liver immuno-toxicity. A new wave of 4-1BB-based therapy is being developed to circumvent hepatotoxicity with a bispecific molecule that directs 4-1BB agonism to the tumor microenvironment by targeting tumor-associated immune checkpoint molecule PD-L1. See related article by Peper-Gabriel et al., p. 3387.
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Antígeno B7-H1 , Neoplasias , Humanos , Fatores Imunológicos , Imunoterapia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologiaRESUMO
Twenty to sixty percent of patients receiving immune checkpoint inhibitors (ICIs) experience high-grade immune-related adverse events (irAEs) which may prevent the continuation of treatment. Limited clinical evidence is available to guide treatment for these patients. Patients with stage IV or unresectable stage III melanoma at NYU Langone Health were reviewed from 1 January 2014 to 1 July 2019. Patients with first-line ICI systemic therapy, a high-grade irAE and a rechallenge with ICI therapy were included. Postrechallenge irAE recurrence, response rate, overall survival (OS) and progression-free survival (PFS) were evaluated. Postrechallenge irAEs recurred in 71.9% (n = 23/32) of patients at a median of 5.1 weeks from rechallenge, with 46.9% (15/32) recurring as high-grade events. Clinical response was achieved in 46.9% (15/32) of patients, including 40.6% (13/32) with a complete response and 6.3% (2/32) with partial response. Median OS from first ICI initiation was 85.4 weeks (45.7-140.7; 25th-75th percentile) and median PFS was 42.9 weeks (29.2-114.2; 25th-75th percentile). Patients with a shorter time to initial irAE and shorter time to postrechallenge irAE were at greater risk for disease progression [hazard ratio 7.80; 95% confidence interval (CI), 1.91-32.83; P = 0.004; hazard ratio 7.45, 95% CI, 1.57-35.35; P = 0.012). Those with greater duration to rechallenge (>10 weeks) were at lower risk for disease progression (hazard ratio 0.15, 0.03-0.68; P = 0.015). ICI rechallenge can be considered in patients with advanced melanoma, as the risk-benefit profile appears favorable. Treatment toxicity should be appropriately managed, as longer durations to rechallenge may lower the risk of disease progression.
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Inibidores de Checkpoint Imunológico/efeitos adversos , Melanoma/complicações , Melanoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de TumoresRESUMO
Immune checkpoint inhibitors (ICIs) are a class of medications targeting mostly the PD-1/PD-L1 and CTLA-4 immune pathways in the treatment of many cancers. Despite the encouraging success of ICIs, they are associated with immune-related adverse events as well as exacerbation of underlying autoimmune conditions. The treatment of these conditions often involves discontinuation of ICI in addition to the utilization of immunomodulatory agents. In this report, we discuss a case in which a patient with metastatic renal cell carcinoma experienced exacerbation of underlying paraneoplastic dermatomyositis after treatment with ICI. He was successfully continued on ICI with the use of intravenous immunoglobulin. The patient experienced adequate control of his myositis but also experienced deepening of his antitumor response.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Dermatomiosite/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Agentes de Imunomodulação/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: Treatment with epidermal growth factor receptor monoclonal antibodies extends life for patients with advanced colorectal cancers (CRCs) whose tumors exhibit wild-type KRAS, but KRAS testing may be underused. We studied the role of socioeconomic factors in the application of KRAS testing. MATERIALS AND METHODS: We identified subjects with stage IV colorectal adenocarcinoma diagnosed 2010-2015 in the Surveillance, Epidemiology, and End Results (SEER) database. We used multivariable logistic regression models to evaluate associations between clinical/demographic factors and the rate of KRAS testing. We used multivariable-adjusted Cox proportional hazards models to assess survival. RESULTS: We identified 37,676 patients with stage IV CRC, 31.1% of whom were tested for KRAS mutations, of those who had documented KRAS testing, 44% were KRAS mutant. Patients were more likely to be tested if they were younger (odds ratio [OR]=5.10 for age 20 to 29 vs. 80+, 95% confidence interval [CI]: 3.99-6.54, P<0.01), diagnosed more recently (OR=1.92 for 2015 vs. 2010, 95% CI: 1.77-2.08, P<0.01), or lived in an area of high median household income (OR=1.24 for median household income of >$69,311 vs. <$49,265, 95% CI: 1.14-1.35, P<0.01). Patients were less likely to be tested if they had Medicaid (OR=0.83, 95% CI: 0.77-0.88, P<0.01) or were unmarried (OR=0.78, 95% CI: 0.75-0.82, P<0.0001). The risk of death was decreased in patients who received KRAS testing (hazard ratio=0.77, 95% CI: 0.75-0.80, P<0.01). CONCLUSIONS: We found a low rate of KRAS testing in CRC patients with those living in low-income areas less likely to be tested, even after controlling for Medicaid insurance. Our study suggests that socioeconomic disparities persist despite Medicaid insurance.
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Adenocarcinoma/genética , Neoplasias Colorretais/genética , Técnicas de Diagnóstico Molecular/estatística & dados numéricos , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma/patologia , Adulto , Idoso , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Mau Uso de Serviços de Saúde/estatística & dados numéricos , Humanos , Renda , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Medicina de Precisão , Programa de SEER , Fatores SocioeconômicosRESUMO
OBJECTIVES: Small studies suggest that a new entity of high-grade (HG) (G3, by Ki-67 or mitotic index) well-differentiated (histologically) gastrointestinal neuroendocrine tumors (NETs) exists, but prognosis and characteristics are unknown. We further characterized demographics and prognosis of patients with colorectal G3 NETs. MATERIALS AND METHODS: We used the Surveillance Epidemiology and End Results (SEER) database to study colorectal NETs diagnosed from 2000 to 2015. We evaluated demographic, clinical, and tumor characteristics. We compared overall survival (OS) for G1-2 NET, G3 NET, and NEC (neuroendocrine carcinoma). We used logistic regression to detect grade associations and Cox proportional hazards models to examine predictors of survival. RESULTS: We identified 5894 cases with colorectal NET (5780 [98.1%] G1-2 and 114 [1.9%] G3); the cohort was 66% white, 47% male, and had a median age of 54. Patients with G3 NET were likely to be older (odds ratio [OR]: 2.23; 95% confidence interval [CI]: 1.19-4.19 for 60 to 69 vs. <50), unmarried (OR: 1.56; 95% CI: 1.02-2.38), and less likely to be diagnosed after 2010 (OR: 0.09; 95% CI: 0.06-0.15). OS for G3 NET (median, 36 mo; 95% CI: 13-92) fell between OS for NEC (median, 7 mo; 95% CI: 6-8), and G1-2 NET (median not reached, >120 mo). Among G1-3 NETs, black patients (hazard ratio [HR]: 1.30; 95% CI: 1.03-1.62), older patients (HR: 3.63; 95% CI: 2.63-5.01 for age 60 to 69 vs. <50), unmarried patients (HR: 1.40; 95% CI: 1.17-1.68), and those with HG features (HR: 3.97; 95% CI: 3.15-4.99) had worse survival. CONCLUSIONS: We defined a subset of G3 NETs that are HG and well differentiated, more common in older, unmarried patients, with a prognosis between that of NEC and G1-2 NETs. Our analysis adds the first national registry study in support of a new classification of nonpancreatic HG and well-differentiated NETs.
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Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Modelos Logísticos , Masculino , Estado Civil , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Programa de SEER , Estados Unidos/epidemiologiaRESUMO
Peritoneal carcinomatosis (PC) can occur as an advanced consequence of multiple primary malignancies. Surgical resection, radiation or systemic interventions alone have proven inadequate for this aggressive cancer presentation, since PC still has a poor survival profile. Photodynamic therapy (PDT), in which photosensitive drugs are exposed to light to generate cytotoxic reactive oxygen species, may be an ideal treatment for PC because of its ability to deliver treatment to a depth appropriate for peritoneal surface tumors. Additionally, epidermal growth factor receptor (EGFR) signaling plays a variety of roles in cancer progression and survival as well as PDT-mediated cytotoxicity, so EGFR inhibitors may be valuable in enhancing the therapeutic index of intraperitoneal PDT. This study examines escalating doses of benzoporphyrin derivative (BPD)-mediated intraperitoneal PDT combined with the EGFR-inhibitor cetuximab in a canine model. In the presence or absence of small bowel resection (SBR) and cetuximab, we observed a tolerable safety and toxicity profile related to the light dose received. Additionally, our findings that BPD levels are higher in the small bowel compared with other anatomical regions, and that the risk of anastomotic failure decreases at lower light doses will help to inform the design of similar PC treatments in humans.
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Antineoplásicos/administração & dosagem , Cetuximab/administração & dosagem , Modelos Animais de Doenças , Neoplasias Peritoneais/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , Animais , Antineoplásicos/farmacologia , Cetuximab/farmacologia , Cães , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , MasculinoRESUMO
Cancer cells are known to have distinct metabolic characteristics compared with normal cells, given the catabolic and anabolic demands of increased cell growth and proliferation. This altered metabolism in cancer cells imbues differential dependencies, and substantial effort has been invested in developing therapeutic strategies to exploit these potential vulnerabilities. Parallel to these efforts has been a growing appreciation for the presence of notable intratumoral metabolic heterogeneity. Although many novel agents are showing some promising results in targeting specific metabolic processes, the challenge moving forward will be to develop combination strategies to address the aforementioned metabolic heterogeneity and its interplay with both epigenetic and immune factors in the tumor microenvironment. In this review, we discuss recent developments in targeting tumor catabolism, lipid biosynthesis, glycolysis, and the citric acid cycle as well as efforts to combine these approaches with immunotherapy.
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Metabolismo Energético , Redes e Vias Metabólicas , Neoplasias/metabolismo , Neoplasias/terapia , Gerenciamento Clínico , Humanos , Terapia de Alvo Molecular , Neoplasias/etiologia , Neoplasias/patologiaRESUMO
BACKGROUND/AIM: National guidelines offer little guidance on the use of PSA progression (PSA increase as defined below) as a clinical endpoint in metastatic castration-resistant prostate cancer (mCRPC). The aim of the study was to examine treatment patterns/outcomes with abiraterone (abi)/enzalutamide (enza) throughout PSA progression and near the end of life (EOL). PATIENTS AND METHODS: Cases of mCRPC treated with abi or enza from the New York Veterans Affairs (VA) from 6/2011-8/2017 were reviewed. Regression analyses were conducted to identify factors associated with continuation of abi/enza treatment up to the EOL, and survival. RESULTS: Of 184 patients, 72 received abi alone, 28 received enza alone, and 84 received both. Treatment was changed for PSA progression alone in 39.1% (abi) and 25.7% (enza) of patients. A total of 37 patients (20%) received abi/enza within 1 month before death, 30% of whom were receiving hospice services. Older patients and black patients were less likely to receive abi/enza up to the EOL. CONCLUSION: Abi/enza are frequently discontinued for PSA progression alone and continued at EOL. The clinical benefit of these practices warrants additional study.
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Androstenos/administração & dosagem , Feniltioidantoína/análogos & derivados , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Benzamidas , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Nitrilas , Feniltioidantoína/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Assistência Terminal , Resultado do TratamentoRESUMO
OBJECTIVE: Vascular abnormalities and expression of proangiogenic factors have been repeatedly reported in inflammatory bowel disease (IBD). Thrombospondin 1 (TSP-1) is a protein well known for its antiangiogenic and anti-inflammatory properties. Using the dextran sulfate sodium (DSS) model, the role of TSP-1 in IBD has been investigated in vivo. METHODS: TSP-1-deficient mice (TSP-1-/-) and WT mice were treated with DSS for 7 days. Disease activity indices, myeloperoxidase activity (MPO) and histology were analyzed. Microvascular density (MVD) was quantified using immunohistochemistry (IMH) with CD31 antibody. TGF-beta(1), basic FGF, VEGF, TNF-alpha and MMPs protein levels were evaluated by IMH and enzyme-linked immunoabsorbent assay (ELISA). Mice were treated with ABT-510 (Abbott Laboratories), an antiangiogenic TSP peptide, using miniosmotic pumps for 7 days. RESULTS: TSP-1(-/-) mice had a worse clinical outcome and exhibited severe signs of rectal bleeding compared to the WT controls. The TSP-1-/- mice showed a higher level of crypt damage and deeper lesions. The grade of inflammation and the levels of MPO activity were also significantly higher in colons of TSP-1-/- mice. TSP-1-/- mice displayed higher MVD in focal areas of the colon after only 3 days of DSS treatment. Furthermore, clinical severity of the colitis and angiogenesis was significantly diminished when mice was treated with ABT-510. CONCLUSIONS: These findings directly link TSP-1 as a protective factor in IBD and suggest antiangiogenesis treatment, including compounds such as ABT-510 as an adjuvant therapy for IBD.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Colite/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Trombospondina 1/metabolismo , Animais , Colite/metabolismo , Colite/patologia , Colo/irrigação sanguínea , Colo/patologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Inativação Gênica , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Bombas de Infusão , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microcirculação , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Trombospondina 1/genéticaRESUMO
OBJECTIVES/HYPOTHESIS: Presentation of a case of esophageal perforation caused by ingestion of a foreign body that was difficult to visualize endoscopically, and systematic review of the current literature with a focus on available diagnostic modalities and missed diagnoses. DATA SOURCES: MEDLINE (1946-2014). REVIEW METHODS: We conducted a systematic review of MEDLINE for cases and studies of esophageal perforation due to foreign bodies. RESULTS: A systematic review of esophageal perforations caused by foreign bodies revealed 40 studies that included 168 patients. Neck/chest pain, odynophagia, and dysphagia were the most common presenting symptoms--each occurring in the majority of patients. Where reported, diagnostic sensitivity of lateral neck X-rays was 56%, and computed tomography (CT) scan was 100%. Nine of 168 cases specifically mentioned a missed diagnosis. Very few studies reported a failure to visualize the foreign object at the time of primary rigid or flexible esophagoscopy. No studies reported nonvisualization of the foreign body at the time of open surgery. CONCLUSION: Esophageal perforations due to foreign bodies are rare but carry potentially devastating complications. Delays in diagnosis are common, and no standard diagnostic algorithm exists. Lateral neck X-rays are an easy but insensitive screening test. Laryngoscopy is an excellent screening test but not always diagnostic. CT is a more sensitive diagnostic method, which can also help guide management based on the detection of complications. Although seldom described, if an object is not visualized at the time of endoscopic or surgical intervention, follow-up CT may be useful in determining the persistence of effects of the perforation or the foreign body.