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BACKGROUND: Report of a Phase 1 dose-escalation study of OBI-3424 monotherapy in patients with advanced solid tumors (NCT03592264). METHODS: A classic 3 + 3 design was used to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) of OBI-3424 administered intravenously, as a single agent, at doses of 1, 2, 4, 6, 8, or 12 mg/m2 (days 1 and 8 of a 21-day cycle, Schedule A) or 8, 10, 12, or 14 mg/m2 (day 1 of a 21-day cycle, Schedule B). RESULTS: Dose-limiting hematologic toxicities at 12 mg/m2 in Schedule A led to dose and schedule modifications (Schedule B). In Schedule B, maximum tolerated dose was not reached at the maximum dose tested (14 mg/m2). Grade ≥3 anemia was noted in 3/6 patients treated at 14 mg/m2; the RP2D was 12 mg/m2 (Schedule B). Grade ≥3 treatment-emergent adverse events were experienced by 19/39 (49%) and included anemia (41%) and thrombocytopenia (26%); three patients experienced serious treatment-emergent adverse events (grade ≥3 anemia and thrombocytopenia). One patient had a partial response and 21/33 (64%) had stable disease. CONCLUSIONS: The RP2D is 12 mg/m2 once every 3 weeks. OBI-3424 was well tolerated; dose-dependent, noncumulative thrombocytopenia and anemia were dose-limiting.
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Anemia , Antineoplásicos , Neoplasias Primarias Secundarias , Neoplasias , Trombocitopenia , Humanos , Anemia/inducido químicamente , Anemia/tratamiento farmacológico , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/farmacología , Relación Dosis-Respuesta a Droga , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Trombocitopenia/inducido químicamenteRESUMEN
Spiradenomas are rare skin adnexal tumors, usually benign, appearing in early adulthood. The etiology of this tumor is still debated. The tumor suppressor gene CYLD, responsible for the Brooke-Spiegler syndrome, causes spiradenomas, trichoepitheliomas, and cylindromas. With time, spiradenomas can degenerate into aggressive spiradenocarcinomas. With only 117 malignant cases reported, treatment recommendations are based on case reports and expert opinion. There is no standard of care beyond surgical resection for localized disease and no guidelines for management of metastatic disease. With the advent of immunotherapy and PD-1 inhibition, we present the first reported case of a metastatic spiradenocarcinoma managed with pembrolizumab.
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BACKGROUND: Some cancer patients who are diagnosed with thromboembolism may require dual treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and factor Xa inhibitors (low-molecular-weight heparin [LMWH] or direct oral anticoagulants [DOACs]). However, to the authors' knowledge, the safety of such combinations has not been well characterized. METHODS: Patients with advanced cancer who were treated with concurrent VEGFR TKIs and factor Xa inhibitors between 2010 and 2018 at The Ohio State University Comprehensive Cancer Center were included. Charts were reviewed retrospectively for clinically significant bleeding events occurring during concurrent treatment compared with those occurring during factor Xa inhibitor therapy alone, using each patient as their own control. The Fisher exact test was used to compare distribution of bleeding severities. The Cox proportional hazards model was used to compare bleeding risk between groups. RESULTS: Among 86 patients, there were 29 clinically significant bleeding events (including 8 major bleeding events) reported during concurrent treatment and 17 events (including 4 major bleeding events) reported during factor Xa inhibitor therapy alone over a median follow-up of 63 days. Concurrent treatment was associated with significantly higher risks of overall bleeding (hazard ratio, 2.45; 95% confidence interval, 1.28-4.69 [P = .007]) and first-onset bleeding (hazard ratio, 2.23; 95% confidence interval, 1.13-4.42 [P = .02]). Analysis of 6-month bleeding risk and the subgroups of patients treated with concurrent TKIs and LMWH versus LMWH alone demonstrated a similar trend. The sample size was inadequate for comparisons between treatment with concurrent TKIs and DOACs versus DOACs alone. CONCLUSIONS: Concurrent treatment with VEGFR TKIs and LMWH was found to be associated with a significantly increased risk of bleeding events when compared with LMWH therapy alone.
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Inhibidores del Factor Xa/efectos adversos , Hemorragia/inducido químicamente , Heparina de Bajo-Peso-Molecular/efectos adversos , Neoplasias/complicaciones , Inhibidores de Proteínas Quinasas/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Tromboembolia/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: Translation of basic discoveries to clinical care for patients with cancer is a difficult process greatly enabled by physician-trained researchers. Three categories of physicians, with responsibilities spanning from laboratory and preclinical research to direct patient care, are involved in the translational research continuum: physician-scientist (PS), clinician investigator (CI), and academic clinician (AC). METHODS: To define how protected time for research efforts is supported, the Association of American Cancer Institutes (AACI) conducted a survey of their member institutions, obtaining 56 responses documenting time spent in research and clinical activities across multiple cancer disciplines, and providing information about funding streams for the different categories of cancer physicians. RESULTS: Responses showed that PSs and ACs are minimally involved in clinical research activities; the driver or clinical research in academic cancer centers is the CI. A significant concern was a lack of stable funding streams for nonbillable clinical research activities, putting the sustainability of the CI in jeopardy. Limited funding was derived from hospital sources, with most support derived from cancer center sources. CONCLUSIONS: This study highlights the importance of the CI in translational cancer medicine and represents a call to action for institutions and research funding agencies to develop new programs targeted toward CI support to ensure continued progress against cancer.
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Neoplasias , Médicos , Investigadores , Investigación Biomédica Traslacional , Personal de Salud , Humanos , Neoplasias/terapia , Atención al PacienteRESUMEN
BACKGROUND: The microbiome has been shown to affect the response to Immune Checkpoint Inhibitors (ICIs) in a small number of cancers and in preclinical models. Here, we sought to broadly survey cancers to identify those in which the microbiome may play a prognostic role using retrospective analyses of patients with advanced cancer treated with ICIs. METHODS: We conducted a retrospective analysis of 690 patients who received ICI therapy for advanced cancer. We used a literature review to define a causal model for the relationship between medications, the microbiome, and ICI response to guide the abstraction of electronic health records. Medications with precedent for changes to the microbiome included antibiotics, corticosteroids, proton pump inhibitors, histamine receptor blockers, non-steroid anti-inflammatories and statins. We tested the effect of medication timing on overall survival (OS) and evaluated the robustness of medication effects in each cancer. Finally, we compared the size of the effect observed for different classes of antibiotics to taxa that have been correlated to ICI response using a literature review of culture-based antibiotic susceptibilities. RESULTS: Of the medications assessed, only antibiotics and corticosteroids significantly associated with shorter OS. The hazard ratios (HRs) for antibiotics and corticosteroids were highest near the start of ICI treatment but remained significant when given prior to ICI. Antibiotics and corticosteroids remained significantly associated with OS even when controlling for multiple factors such as Eastern Cooperative Oncology Group performance status, Charlson Comorbidity Index score, and stage. When grouping antibiotics by class, ß-lactams showed the strongest association with OS across all tested cancers. CONCLUSIONS: The timing and strength of the correlations with antibiotics and corticosteroids after controlling for confounding factors are consistent with the microbiome involvement with the response to ICIs across several cancers.
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Corticoesteroides/efectos adversos , Antibacterianos/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Bacterias/efectos de los fármacos , Disbiosis/mortalidad , Neoplasias/mortalidad , Disbiosis/inducido químicamente , Disbiosis/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Factores de TiempoRESUMEN
The chimeric DnaJ-PKAc enzymeresulting from an approximately 400-kb deletion of chromosome 19 is a primary contributor to the oncogenic transformation that occurs in fibrolamellar hepatocellular carcinoma, also called fibrolamellar carcinoma (FLC). This oncogenic deletion juxtaposes exon 1 of the DNAJB1 heat shock protein gene with exon 2 of the PRKACA gene encoding the protein kinase A catalytic subunit, resulting in DnaJ-PKAc fusion under the transcriptional control of the DNAJB1 promoter. The expression of DnaJ-PKAc is approximately 10 times that of wild-type (wt) PKAc catalytic subunits, causing elevated and dysregulated kinase activity that contributes to oncogenic transformation. In normal cells, PKAc activity is regulated by a group of endogenous proteins, termed protein kinase inhibitors (PKI) that competitively inhibit PKAc and assist with the nuclear export of the enzyme. Currently, it is scarcely known whether interactions with PKI are perturbed in DnaJ-PKAc. In this report, we survey existing data sets to assess the expression levels of the various PKI isoforms that exist in humans to identify those that are candidates to encounter DnaJ-PKAc in both normal liver and FLC tumors. We then compare inhibition profiles of wtPKAc and DnaJ-PKAc against PKI and demonstrate that extensive structural homology in the active site clefts of the two enzymes confers similar kinase activities and inhibition by full-length PKI and PKI-derived peptides.
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Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico , Proteínas del Choque Térmico HSP40 , Proteínas de Fusión Oncogénica , Péptidos/química , Inhibidores de Proteínas Quinasas/química , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/antagonistas & inhibidores , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/química , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/genética , Proteínas del Choque Térmico HSP40/antagonistas & inhibidores , Proteínas del Choque Térmico HSP40/química , Proteínas del Choque Térmico HSP40/genética , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/química , Proteínas de Fusión Oncogénica/genéticaRESUMEN
Autophagy has emerged as a mechanism critical to both tumorigenesis and development of resistance to multiple lines of anti-cancer therapy. Therefore, targeting autophagy and alternative cell death pathways has arisen as a viable strategy for refractory tumors. The anti-malarial 4-aminoquinoline compounds chloroquine and hydroxychloroquine are currently being considered for re-purposing as anti-cancer therapies intended to sensitize different tumors by targeting the lysosomal cell death pathway. Here, we describe a novel organometallic chloroquine derivative, cymanquine, that exhibits enhanced bioactivity compared to chloroquine in both normal, and reduced pH tumor microenvironments, thus overcoming a defined limitation of traditional 4-aminoquinolines. In vitro, cymanquine exhibits greater potency than CQ in a diverse panel of human cancer cell lines, including melanoma, in both normal pH and in reduced pH conditions that mimic the tumor microenvironment. Cymanquine treatment results in greater lysosomal accumulation than chloroquine and induces lysosomal dysfunction leading to autophagy blockade. Using a mouse model of vemurafenib-resistant melanoma, cymanquine slowed tumor growth greater than hydroxychloroquine, and when used in combination with vemurafenib, cymanquine partially restored sensitivity to vemurafenib. Overall, we show that cymanquine exhibits superior lysosomal accumulation and autophagy blockade than either chloroquine or hydroxychloroquine in vitro; and in addition to its high level of tolerability in mice, exhibits superior in vivo efficacy in a model of human melanoma.
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Proliferación Celular/efectos de los fármacos , Cloroquina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Melanoma/tratamiento farmacológico , Compuestos Organometálicos/farmacología , Animales , Antimaláricos/farmacología , Apoptosis/efectos de los fármacos , Femenino , Humanos , Melanoma/patología , Ratones , Ratones Desnudos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Screening mammography can detect early breast cancers and reduce subsequent cancer mortality. However, there is a lack of consensus as to when to discontinue screening. The absence of clear-cut guidelines on when not to screen means that many patients with advanced malignancies continue screening despite unclear benefit. METHODS: We performed a retrospective cohort study of female patients diagnosed with a non-breast malignancy to explore the incidence and effects of screening mammography. Female patients diagnosed with a non-breast malignancy stage II or higher between 2007 and 2012 were identified through the Vermont Cancer Registry and cross-referenced with mammography screening logs from January 1, 2007 to September 30, 2014. Additional data were collected through chart review, in May 2016. RESULTS: Twenty-six percent of women (398/1501) with a stage II or greater cancer (other than breast) diagnosed between 2007 and 2012 had a screening mammogram within the first 5 years of their diagnosis. Of these 398 women, 193 (48.5%) were alive without cancer, 132 (33.2%) had died, and 73 (18.3%) were alive with cancer at the time of chart review. Of those who died, 84 (63.6%) had a stage III or IV cancer. Eighteen (4.5%) had a breast biopsy following a screening mammogram suspicious for cancer, resulting in 13 (3.3%) benign diagnoses and 5 (1.3%) breast cancer diagnoses. No patient died of breast cancer. CONCLUSIONS: Except for highly curable cancers, female patients diagnosed with an advanced non-breast malignancy experienced mortality that outweighs a breast cancer mortality benefit from screening mammography as estimated from prior studies.
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Neoplasias de la Mama/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Primarias Secundarias/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Detección Precoz del Cáncer , Femenino , Humanos , Mamografía , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
The combination of personalized therapy with immunotherapy might lead to rapid complete remission in patients who are too sick to be eligible for clinical trials. We report 2 such extraordinary responders. A discussion on the use and purpose of clinical trials in this new era of very active anticancer drug discovery concludes that a paradigm shift is urgently needed.
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Ensayos Clínicos como Asunto/métodos , Neoplasias Hepáticas/terapia , Melanoma/terapia , Medicina de Precisión/métodos , Neoplasias Cutáneas/terapia , Carcinoma Anaplásico de Tiroides/terapia , Anciano , Femenino , Humanos , Neoplasias Hepáticas/secundario , Masculino , Melanoma/patología , Persona de Mediana Edad , Neoplasias Cutáneas/patologíaRESUMEN
Malignant mesothelioma (MM) is a relatively rare but devastating tumor that is increasing worldwide. Yet, because of difficulties in early diagnosis and resistance to conventional therapies, MM remains a challenge for pathologists and clinicians to treat. In recent years, much has been revealed regarding the mechanisms of interactions of pathogenic fibers with mesothelial cells, crucial signaling pathways, and genetic and epigenetic events that may occur during the pathogenesis of these unusual, pleiomorphic tumors. These observations support a scenario whereby mesothelial cells undergo a series of chronic injury, inflammation, and proliferation in the long latency period of MM development that may be perpetuated by durable fibers, the tumor microenvironment, and inflammatory stimuli. One culprit in sustained inflammation is the activated inflammasome, a component of macrophages or mesothelial cells that leads to production of chemotactic, growth-promoting, and angiogenic cytokines. This information has been vital to designing novel therapeutic approaches for patients with MM that focus on immunotherapy, targeting growth factor receptors and pathways, overcoming resistance to apoptosis, and modifying epigenetic changes.
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Mesotelioma/patología , Mesotelioma/terapia , Amianto/efectos adversos , Epigénesis Genética , Humanos , Inmunoterapia , Inflamación/patología , Mesotelioma/diagnóstico , Mesotelioma/genética , Modelos BiológicosRESUMEN
PURPOSE: The 21st Century Cures Act mandates the immediate release of clinical information (IRCI) to patients. Immediate sharing of sensitive test results to patients with cancer might have serious unintended consequences for patients and providers. METHODS: A 22-question REDCap survey was designed by the Association of American Cancer Institutes Physician Clinical Leadership Initiative Steering Committee to explore oncology providers' opinions on IRCI policy implementation. It was administered twice in 2021 with a 3-month interval. A third survey with a single question seeking providers' opinions about their adaptation to the IRCI mandate was administered 1 year later to those who had responded to the earlier surveys. The data were analyzed using descriptive statistics such as chi-squared or Fisher's exact tests for categorical variables. The survey was sent to all Association of American Cancer Institutes cancer center members. In the first or second administration, 167 practitioners answered the survey; 31 responded to the third survey. RESULTS: Three quarters of the providers did not favor the new requirement for IRCI and 62% encountered questions from patients about results being sent to them without provider interpretation. Only half of the hospitals had a plan in place to deal with the new IRCI requirements. A third survey, for longitudinal follow-up, indicated a more favorable trend toward adoption of IRCI. CONCLUSION: IRCI for patients with cancer was perceived negatively by academic oncology providers after its implementation. It was viewed to be associated with higher levels of patient anxiety and complaints about the care delivered. Providers preferred to discuss test results with patients before release.
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Neoplasias , Pacientes , Humanos , Estados Unidos , Encuestas y Cuestionarios , Neoplasias/terapia , Oncología Médica , Atención a la SaludRESUMEN
PURPOSE: SYNB1891 is a live, modified strain of the probiotic Escherichia coli Nissle 1917 (EcN) engineered to produce cyclic dinucleotides under hypoxia, leading to STimulator of INterferon Genes (STING) activation in phagocytic antigen-presenting cells in tumors and activating complementary innate immune pathways. PATIENTS AND METHODS: This first-in-human study (NCT04167137) enrolled participants with refractory advanced cancers to receive repeat intratumoral injections of SYNB1891 either alone or in combination with atezolizumab, with the primary objective of evaluating the safety and tolerability of both regimens. RESULTS: Twenty-four participants received monotherapy across six cohorts, and 8 participants received combination therapy in two cohorts. Five cytokine release syndrome events occurred with monotherapy, including one that met the criteria for dose-limiting toxicity at the highest dose; no other SYNB1891-related serious adverse events occurred, and no SYNB1891-related infections were observed. SYNB1891 was not detected in the blood at 6 or 24 hours after the first intratumoral dose or in tumor tissue 7 days following the first dose. Treatment with SYNB1891 resulted in activation of the STING pathway and target engagement as assessed by upregulation of IFN-stimulated genes, chemokines/cytokines, and T-cell response genes in core biopsies obtained predose and 7 days following the third weekly dose. In addition, a dose-related increase in serum cytokines was observed, as well as stable disease in 4 participants refractory to prior PD-1/L1 antibodies. CONCLUSIONS: Repeat intratumoral injection of SYNB1891 as monotherapy and in combination with atezolizumab was safe and well tolerated, and evidence of STING pathway target engagement was observed.
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Escherichia coli , Neoplasias , Humanos , Escherichia coli/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Anticuerpos Monoclonales Humanizados , Factores Inmunológicos/uso terapéutico , Citocinas/uso terapéuticoRESUMEN
PURPOSE: Treatment options are limited in patients with metastatic neuroendocrine neoplasms (NEN). We present the results for a phase II trial of combination nivolumab and temozolomide in patients with advanced NEN along with results of immune changes in peripheral blood. PATIENTS AND METHODS: NCT03728361 is a nonrandomized, phase II study of nivolumab and temozolomide in patients with NEN. The primary endpoint was response rate using RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Immune profiling was performed by mass cytometry to evaluate the effect on peripheral blood immune cell subsets. RESULTS: Among all 28 patients with NEN, the confirmed response rate was 9/28 [32.1%, 95% confidence interval (CI): 15.9-52.4]. Of 11 patients with lung NEN, the response rate was 64% (n = 7); there was a significant difference in responses by primary tumor location (lung vs. others, P = 0.020). The median PFS was 8.8 months (95% CI: 3.9-11.1 months), and median OS was 32.3 months (95% CI: 20.7-not reached months). Exploratory blood immune cell profiling revealed an increase in circulating CD8+ T cells (27.9% ± 13.4% vs. 31.7% ± 14.6%, P = 0.03) and a decrease in CD4+ T cells (59.6% ± 13.1% vs. 56.5% ± 13.0%, P = 0.001) after 2 weeks of treatment. LAG-3-expressing total T cells were lower in patients experiencing a partial response (0.18% ± 0.24% vs. 0.83% ± 0.55%, P = 0.028). Myeloid-derived suppressor cell levels increased during the study and did not correlate with response. CONCLUSIONS: Combination nivolumab and temozolomide demonstrated promising activity in NEN. See related commentary by Velez and Garon, p. 691.
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Neoplasias Pulmonares , Tumores Neuroendocrinos , Humanos , Nivolumab/uso terapéutico , Temozolomida/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Supervivencia sin ProgresiónRESUMEN
PURPOSE: CMB305 is a heterologous prime-boost vaccination regimen created to prime NY-ESO-1-specific CD8 T-cell populations and then activate the immune response with a potent TLR-4 agonist. This open-label randomized phase II trial was designed to investigate the efficacy and safety of adding the CMB305 regimen to atezolizumab (anti-programmed death ligand-1 therapy) in comparison with atezolizumab alone in patients with synovial sarcoma or myxoid liposarcoma. PATIENTS AND METHODS: Patients with locally advanced, relapsed, or metastatic synovial sarcoma or myxoid liposarcoma (any grade) were randomly assigned to receive CMB305 with atezolizumab (experimental arm) or atezolizumab alone (control arm). The primary end points were progression-free survival (PFS) and overall survival (OS) analyzed using the Kaplan-Meier method. Safety and immune responses were assessed. RESULTS: A total of 89 patients were enrolled; 55.1% had received ≥ 2 prior lines of chemotherapy. Median PFS was 2.6 months and 1.6 months in the combination and control arms, respectively (hazard ratio, 0.9; 95% CI, 0.6 to 1.3). Median OS was 18 months in both treatment arms. Patients treated with combination therapy had a significantly higher rate of treatment-induced NY-ESO-1-specific T cells (P = .01) and NY-ESO-1-specific antibody responses (P < .0001). In a post hoc analysis of all dosed patients, OS was longer (36 months) in the subset who developed anti-NY-ESO-1 T-cell immune response (hazard ratio, 0.3; P = .02). CONCLUSION: Although the combination of CMB305 and atezolizumab did not result in significant increases in PFS or OS compared with atezolizumab alone, some patients demonstrated evidence of an anti-NY-ESO-1 immune response and appeared to fare better by imaging than those without such an immune response. Combining prime-boost vaccines such as CMB305 with anti-programmed death ligand-1 therapies merits further evaluation in other clinical contexts.
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Liposarcoma Mixoide , Sarcoma Sinovial , Sarcoma , Neoplasias de los Tejidos Blandos , Adyuvantes Inmunológicos , Adulto , Anticuerpos Monoclonales Humanizados , Antígenos de Neoplasias , Humanos , Sarcoma/tratamiento farmacológicoRESUMEN
The role of clinical researchers is vital to cancer progress. The teaching, research, and leadership roles that academic oncologists hold need to be accounted for and appropriately compensated. National metrics are currently inexistent, but are necessary to move the oncology research field forward. Clinical research and routine clinical care must be harmoniously integrated without competing. This article reviews the national landscape of clinical cancer research and proposes a call for action.
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Benchmarking , Docentes Médicos , Humanos , Liderazgo , Oncología Médica , InvestigadoresRESUMEN
A new job is always a difficult step to take in one's career. Negotiating the optimal contract is paramount. The contract should be a reasonable agreement that satisfies both parties: the enterprise and the prospective candidate. Some contract clauses are usually non-negotiable because these items are required for the job. Examples include board certification, insurance for liabilities, faculty standing for a specific position, and so forth. Other clauses are negotiable and should be negotiated, including salary, resources to perform the job, work hours, and so on. This article details what to expect in a contract, how to think about it, and how to act on it. Possible careers for an oncologist are reviewed and include academia, private practice, and industry at the largest sense. Recommendations are to be certain that the choice of career feels comfortable, to read and fully understand the contract, to obtain a few contracts from different job offers to draw comparisons, to ask questions until all items are clarified, and to not be shy in asking what is not reflected in the contract but would assuage the unknown of assuming the duties and deliverables of a new job.
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Contratos , HumanosRESUMEN
INTRODUCTION: Avelumab, an antiprogrammed death ligand-1 antibody, is approved as a monotherapy for treatment of metastatic Merkel cell carcinoma and advanced urothelial carcinoma, and in combination with axitinib for advanced renal cell carcinoma. We report the efficacy and safety of first-line avelumab in advanced non-small cell lung cancer (NSCLC). METHODS: In a phase I expansion cohort of the JAVELIN Solid Tumor trial, patients with treatment-naive, metastatic, or recurrent NSCLC received 10 mg/kg avelumab intravenously every 2 weeks. Endpoints included best overall response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 156 patients were enrolled and treated. Median duration of follow-up was 18.6 months (range, 15 to 23 months). The objective response rate was 19.9% (95% CI, 13.9 to 27.0), including complete response in 3 (1.9%) and partial response in 28 (17.9%). Median DOR was 12.0 months (95% CI, 6.9 to not estimable). Median PFS was 4.0 months (95% CI, 2.7 to 5.4) and the 6-month PFS rate was 38.5% (95% CI, 30.7 to 46.3). Median OS was 14.1 months (95% CI, 11.3 to 16.9) and the 12-month OS rate was 56.6% (95% CI, 48.2 to 64.1). Treatment-related adverse events (TRAEs) occurred in 107 patients (68.6%), including grade ≥3 TRAEs in 19 (12.2%). Immune-related adverse events and infusion-related reactions occurred in 31 (19.9%) and 40 patients (25.6%), respectively. No treatment-related deaths occurred. CONCLUSION: Avelumab showed antitumor activity with a tolerable safety profile as a first-line treatment in patients with advanced NSCLC. These data support further investigation of avelumab in the phase III JAVELIN Lung 100 study. TRIAL REGISTRATION DETAILS: ClinicalTrials.gov NCT01772004; registered January 21, 2013.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos Inmunológicos/farmacología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: Receptors for estrogen (ER) and progesterone (PR) are prognostic indicators for a variety of endocrine tumors including breast and endometrial. This study was conducted to determine if ER and PR expression patterns are predictive of outcome in patients with epithelial ovarian cancer (EOC) or ovarian low malignant potential (LMP) tumors. METHODS: ER and PR protein levels were assessed by immunohistochemistry in 45 LMP and 89 EOC samples. Patterns of ER/PR expression (individually and combinations of ER-/PR-, ER+/PR-, ER-/PR+, and ER+/PR+) were correlated with standard prognostic factors of overall survival (OS) in this patient population. RESULTS: For patients with EOC, the 5-year OS per ER-/PR+, ER+/PR-, ER+/PR+, and ER-/PR- expression was 83%, 79%, 61%, and 48%, respectively, and these differences were statistically significant. In multivariate analyses, ER/PR expression patterns were found to be independent predictors of OS, as were the classical prognostic factors of grade, stage, debulking, and chemotherapy response to treatment. In patients with mucinous LMP tumors, ER and PR were absent. Because no LMP patients died of disease during the studied period, no correlation analysis with OS could be performed. CONCLUSIONS: Patterns of ER/PR expression provide prognostic information in EOC. Additional studies evaluating hormonal inhibition may help personalize the therapy of patients with ovarian cancer.
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Neoplasias Ováricas/metabolismo , Receptores de Estrógenos/biosíntesis , Receptores de Progesterona/biosíntesis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Células Epiteliales/patología , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Adulto JovenRESUMEN
OBJECTIVES: GPR30 is a 7-transmembrane G protein-coupled estrogen receptor that functions alongside traditional estrogen receptors to regulate cellular responses to estrogen. Recent studies suggest that GPR30 expression is linked to lower survival rates in endometrial and breast cancer. This study was conducted to evaluate GPR30 expression in ovarian tumors. METHODS: GPR30 expression was analyzed using immunohistochemistry and archival specimens from 45 patients with ovarian tumors of low malignant potential (LMP) and 89 patients with epithelial ovarian cancer (EOC). Expression, defined as above or below the median (intensity times the percentage of positive epithelial cells) was correlated with predictors of adverse outcome and survival. RESULTS: GPR30 expression above the median was observed more frequently in EOC than in LMP tumors (48.3% vs. 20%, p=0.002), and in EOC was associated with lower 5-year survival rates (44.2% vs. 82.6%, Log-rank p<0.001). Tumor grade and FIGO stage, the other significant predictors of survival, were used to stratify cases into "high risk" and "low risk" groups. The 5-year survival rate for "low risk" EOC (all grade 1 and Stage I/II, grade 2) was 100%. In "high risk" EOC (all grade 3 and Stage III/IV, grade 2), the difference in 5-year survival by GPR 30 expression was significant (33.3% vs. 72.4%, p=0.001). CONCLUSIONS: The novel estrogen-responsive receptor GPR30 is preferentially expressed in "high risk" EOC and is associated with lower survival rates. Further investigation of GPR30 as a potential target for therapeutic intervention in high risk EOC is warranted.
Asunto(s)
Biomarcadores de Tumor/biosíntesis , Neoplasias Ováricas/metabolismo , Receptores Acoplados a Proteínas G/biosíntesis , Células Epiteliales/patología , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Pronóstico , Receptores de Estrógenos , Tasa de SupervivenciaRESUMEN
BACKGROUND: The neutrophil to lymphocyte ratio (NLR) is known to be prognostic for patients with advanced cancers treated with immune checkpoint inhibitors (ICI), but has generally been evaluated as a single threshold value at baseline. We evaluated NLR at baseline and within first month during treatment in patients who received ICI for advanced cancer to evaluate the prognostic value of baseline and of changes from baseline to on-treatment NLR. METHODS: A retrospective review of patients with advanced cancer treated with ICI from 2011 to 2017 at the Ohio State University was performed. NLR was calculated at the initiation of ICI and repeated at median of 21 days. Overall survival (OS) was calculated from the initiation of ICI to date of death or censored at last follow-up. Significance of Cox proportional hazards models were evaluated by log-rank test. Calculations were performed using the survival and survminer packages in R, and SPSS. RESULTS: 509 patients were identified and included in the analysis. Patients with baseline and on-treatment NLR < 5 had significantly longer OS (P < 0.001). The change in NLR overtime was a predictor of OS and was observed to be non-linear in nature. This property remained statistically significant with P < 0.05 after adjusting for age, body mass index, sex, cancer type, performance status, and days to repeat NLR measurement. Patients with a moderate decrease in NLR from baseline had the longest OS of 27.8 months (95% CI 21.8-33.8). Patients with significant NLR decrease had OS of 11.4 months (95% CI 6.1-16.7). Patients with a significant increase in NLR had the shortest OS of 5.0 months (95% CI 0.9-9.1). CONCLUSIONS: We confirmed the prognostic value of NLR in patients with advanced cancer treated with ICIs. We found that change in NLR over time is a non-linear predictor of patient outcomes. Patients who had moderate decrease in NLR during treatment with ICI were found to have the longest survival, whereas a significant decrease or increase in NLR was associated with shorter survival. To our knowledge, this is the first study to demonstrate a non-linear change in NLR over time that correlates with survival.