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1.
Cancer Immunol Immunother ; 68(9): 1493-1500, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31501955

RESUMO

Immunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), and RNA sequencing data from anti-PD1-treated patients at Sheba medical center. TNFSF4 mRNA is expressed in melanoma cell lines and melanoma samples, including those with low lymphocytic infiltrates, and is not associated with the ulceration status of the primary tumor. Low expression of TNFSF4 mRNA is associated with worse prognosis in all melanoma patients and in the cohorts of stage III and stage IIIc-IV patients. Low expression of TNFSF4 mRNAs is also associated with worse prognosis in the subgroup of patients with low lymphocytic infiltrates, suggesting that tumoral TNFSF4 is associated with outcome. TNFSF4 expression was not correlated with the expression of other known checkpoint mRNAs. Last, metastatic patients with TNFSF4 mRNA expression within the lowest quartile have significantly worse outcome on anti-PD1 treatment, and a significantly lower response rate to these agents. Our current work points to TNFSF4 expression in melanoma as a potential determinant of prognosis, and warrants further translational and clinical research.


Assuntos
Imunoterapia/métodos , Melanoma/metabolismo , Ligante OX40/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Ligante OX40/genética , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Análise de Sobrevida , Resultado do Tratamento
2.
Eur J Cancer ; 120: 122-131, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31518968

RESUMO

AIM: Immune-related toxicities of immune checkpoint inhibitors (CPIs) require prompt diagnosis and treatment. Atherosclerosis has an inflammatory component; we speculated this inflammation could be enhanced by CPIs. We aimed to evaluate the risk of acute vascular events (AVEs) on CPIs. METHODS: Patients treated by CPIs in Sheba Medical Center (Israel) between January 2015 and May 2018 were retrospectively identified from electronic medical records. AVEs were identified and verified by chart review. Age, sex, diabetes, hypertension, smoking, dyslipidemia, previous AVE, renal failure, cancer type and specific treatments were evaluated as potential risk factors. AVE rate on CPIs was compared with that on chemotherapy or on combined chemo-immunotherapy in patients with lung adenocarcinoma. Survival of patients with AVEs was compared with that of patients without AVEs. RESULTS: CPI was administered to 1215 patients. AVEs within six months after CPI initiation occurred in 2.6% (95% confidence interval [CI]: 1.8-3.6) of patients, more common than in later time periods. In lung adenocarcinoma, event rate was 5.2% (95% CI: 2.8-9.2). Lung adenocarcinoma, prior AVE, hypertension and dyslipidemia were correlated with AVEs. AVE rate in patients with non-small cell lung cancer adenocarcinoma was similar whether on chemotherapy or on CPI. Survival of patients with AVEs was worse than that of those without AVEs. CONCLUSION: The similarly increased rates of AVEs for patients on CPI, on chemotherapy or on both suggest that although CPI may not augment the risk of AVE over that of chemotherapy, it carries a similar and significant risk of such adverse event. Caution should be exercised for patients with risk factors for AVEs.

3.
Nucl Med Commun ; 40(9): 913-919, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31343612

RESUMO

OBJECTIVES: The purpose of this study was to evaluate the use of Gallium-68 prostatic-specific membrane antigen (PSMA) PET-computerized tomography (CT) in patients with prostate cancer undergoing imaging for initial staging, biochemical failure or the evaluation of metastatic disease. METHODS: This is a single institution retrospective study of 95 patients with prostate cancer who were referred for PSMA PET-CT scans. The National Comprehensive Cancer Network guidelines were used to generate treatment recommendations. Univariate and multivariate statistical analyses were performed to identify parameters associated with positive findings on a PET-CT PSMA scan. RESULTS: Mean age, Gleason score, and median prostate serum antigen (PSA) were: 72 years, 7.6 and 4 ng/ml, respectively. PSMA PET-CT was positive in 75.5% of the patients. A maximum standardized uptake value was 10.7 ± 8.8. PSMA avidity increased with rising PSA level: PSA ≤ 1 ng/ml: 5/15 patients (33%); PSA 1-5 ng/ml: 18/27 patients (67%), and PSA ≥ 5 ng/ml: 33/34 patients (97%). Following imaging in nine high-risk patients referred for staging, changes in treatment occurred in 6 (67%). Treatment recommendations changed in 27/35 (65%) patients referred due to biochemical failure; these included recurrences suitable for salvage therapy (n = 14), metastatic disease not suitable for salvage therapy (n = 10), and no lesion (n = 17). No changes in treatment occurred in any of the 35 patients referred to evaluate metastatic disease. DISCUSSION: PSMA PET-CT imaging may have a substantial impact on clinical management in prostate cancer patients at the time of initial staging or with biochemical failure; yet this modality does not appear useful in the management of patients with known metastatic disease.

4.
Nat Med ; 25(5): 751-758, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31011205

RESUMO

Precision medicine focuses on DNA abnormalities, but not all tumors have tractable genomic alterations. The WINTHER trial ( NCT01856296 ) navigated patients to therapy on the basis of fresh biopsy-derived DNA sequencing (arm A; 236 gene panel) or RNA expression (arm B; comparing tumor to normal). The clinical management committee (investigators from five countries) recommended therapies, prioritizing genomic matches; physicians determined the therapy given. Matching scores were calculated post-hoc for each patient, according to drugs received: for DNA, the number of alterations matched divided by the total alteration number; for RNA, expression-matched drug ranks. Overall, 303 patients consented; 107 (35%; 69 in arm A and 38 in arm B) were evaluable for therapy. The median number of previous therapies was three. The most common diagnoses were colon, head and neck, and lung cancers. Among the 107 patients, the rate of stable disease ≥6 months and partial or complete response was 26.2% (arm A: 23.2%; arm B: 31.6% (P = 0.37)). The patient proportion with WINTHER versus previous therapy progression-free survival ratio of >1.5 was 22.4%, which did not meet the pre-specified primary end point. Fewer previous therapies, better performance status and higher matching score correlated with longer progression-free survival (all P < 0.05, multivariate). Our study shows that genomic and transcriptomic profiling are both useful for improving therapy recommendations and patient outcome, and expands personalized cancer treatment.


Assuntos
Neoplasias/genética , Neoplasias/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Terapia Combinada , Feminino , Perfilação da Expressão Gênica , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Medicina de Precisão , Intervalo Livre de Progressão , Análise de Sequência de DNA
5.
Artigo em Inglês | MEDLINE | ID: mdl-30523409

RESUMO

BACKGROUND AND PURPOSE: The botanical formula LCS101 has been shown in clinical research to reduce chemotherapy-induced toxicities. In pre-clinical research, the formula demonstrated selective anti-cancer effects, in part as a result of radical oxygen species (ROS) activity of the botanical components. The present study examined the interaction between LCS101 and radiation therapy on cancer cell lines. METHODS: Incremental doses of LCS101 were added to breast adenocarcinoma (MCF7), prostate (DU145), transitional cell bladder carcinoma (T24), pancreatic epithelioid carcinoma (PANC-1), and osteosarcoma (U20S) cell lines 4 h after single-dose irradiation (range 0.5-4 Gy). Cell viability was tested using sulforhodamine B (SRB) assay after 1 week, with ROS activity examined using 1 mM of the ROS scavenger sodium pyruvate (ROS scavenger), testing cell viability with an SRB assay. RESULTS: The addition of LCS101 to MCF7 (breast) and DU-145 (prostate) cancer cell lines resulted in a dose-dependent increase in the antiproliferative effects of radiation treatment. The addition of pyruvate inhibited radiation-induced cell death in all of the cell lines treated with LCS101. CONCLUSIONS: The addition of the botanical formula LCS101 to irradiated cancer cells results in an apparent additive effect, most likely through a ROS-mediated mechanism. These findings support the use of LCS101 by patients undergoing radiation therapy, for both its clinical as well as anti-cancer effects.

6.
Am J Clin Oncol ; 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30451730

RESUMO

PURPOSE/OBJECTIVES: The main purpose of this study was to report treatment outcomes of definitive image-guided accelerated hypofractionated radiation therapy for elderly patients with muscle-invasive bladder cancer unsuitable for surgery or trimodality therapy. MATERIALS AND METHODS: Patients with confirmed muscle-invasive or high-risk T1 transitional cell carcinoma of the bladder, stage T1-T4aN0M0, who underwent transurethral resection of bladder tumor were irradiated with 45 Gy in 15 fractions. Comorbidity was assessed by Charlson Comorbidity Index. Cystoscopy, cytology, and computerised tomography imaging were used to evaluate treatment outcomes. RESULTS: Seventeen patients with a median age of 87 (range, 81 to 95) years and age-adjusted Charlson Comorbidity Index ≥3 were included. Transurethral resection of bladder tumor was incomplete in 65%. Radiation technique evolved from 3-dimensional conformal radiotherapy (3D CRT, 47%) to volumetric modulated arc therapy (VMAT, 53%). Ninety-four percent completed radiotherapy, with a median time of 20 days. The median follow-up was 65.3 months. Complete local response at 3-month cystoscopy was 69%. Six patients developed a local recurrence (35%), and 2 patients developed distant metastases (11.7%). Overall survival at 1 year was 47% and 23% at 2 years. Cancer-specific survival at 1 and 2 years were 85% and 63%, respectively. Acute grade 3 gastrointestinal or genitourinary toxicities were 6% and 24%, respectively. No grade 4 toxicity was documented. Diarrhea of any grade occurred in 35% of patients treated with 3D CRT, but in none of the patients treated with VMAT (P=0.002). CONCLUSIONS: Accelerated hypofractionated radiotherapy alone provides good local control in elderly patients unfit for chemoradiotherapy. Contemporary radiation techniques such as VMAT were associated with reduced bowel toxicity compared with 3D CRT.

7.
Integr Cancer Ther ; 17(4): 1020-1026, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30303021

RESUMO

BACKGROUND AND PURPOSE: LCS101 is a botanical formula extracted from 14 botanical components. While conventional oncology focuses on targeted medicine, research on LCS101 adopts a multi-targeted approach, examining its preclinical (in vitro, in vivo, and ex vivo) and clinical (randomized controlled trial, pragmatic) effects. This includes examining the formula's impact on the immune system, selective anticancer effects, and improved chemotherapy-related symptoms and quality of life. Effects on the Immune System: In murine splenic cell cultures, LCS101 significantly increased T-cell proliferation and macrophage tumor necrosis factor-α production. Blood samples from healthy volunteers exposed to LCS101 showed a dose-dependent increase in natural killer cell activity; and a randomized controlled trial showed significantly lower rates of leucopenia/neutropenia and anemia in patients with breast cancer undergoing chemotherapy. Selective Anticancer Effects: In vitro LCS101 demonstrated selective growth inhibition (on XTT viability assay) in human breast and prostate cancer cell lines, without any harmful effects on normal human epithelial cells. The anticancer effects were attributed to reactive oxygen species activity. Cytotoxic effects of doxorubicin and 5-fluorouracil on breast cancer cell lines were significantly increased following exposure to LCS101, with a protective effect in normal cells. Symptom Relief and Quality of Life: Clinical research shows that patients taking LCS101 during chemotherapy are less likely to report symptoms such as fatigue, pain, nausea and vomiting. CONCLUSION: LCS101 exhibits multi-targeted effects, with significant implications for cancer care. Further research is needed to better understand the impact of these findings.

8.
Cancer Discov ; 8(7): 812-821, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29848605

RESUMO

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients (N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted.Significance: BJG398 is active in patients with alterations in FGFR3, resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. Cancer Discov; 8(7); 812-21. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781.

9.
Int J Cancer ; 143(1): 179-183, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29396858

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. BRCA-associated PDAC comprises a clinically relevant subtype. A portion of these patients are highly susceptible to DNA damaging therapeutics, however, responses are heterogeneous and clinical resistance evolves. We have developed unique patient-derived xenograft (PDX) models from metastatic lesions of germline BRCA-mutated patients obtained at distinct time points; before treatment and at progression. Thus, closely mimicking clinical scenarios, to further investigate treatment naïve and resistant patients. DNA was isolated from six BRCA-mutated PDXs and classified by whole-genome sequencing to stable-genome or homologous recombination deficient (HRD)-genome. The sensitivity to DNA-damaging agents was evaluated in vivo in three BRCA-associated PDAC PDXs models: (1) HRD-genome naïve to treatments; (2) stable-genome naïve to treatment; (3) HRD-genome resistant to treatment. Correlation between disease course at tissue acquisition and response to PARP inhibitor (PARPi)/platinum was demonstrated in PDXs in vivo. Only the HRD-genome PDX, naïve to treatment, was sensitive to PARP inhibitor/cisplatin treatments. Our results demonstrate heterogeneous responses to DNA damaging agents/PARPi in BRCA-associated PDX thus reflecting the wide clinical spectrum. An HRD-genome PDX generated from a naïve to treatment biopsy was sensitive to platinum/PARPi whereas no benefit was observed in treating a HRD-genome PDXs generated from a patient that had acquired resistance nor stable-genome PDXs.

10.
Hum Mutat ; 39(5): 593-620, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29446198

RESUMO

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

11.
Integr Cancer Ther ; 17(2): 486-492, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29094627

RESUMO

BACKGROUND: Homeopathy has the potential to reduce symptoms related to cancer treatment. The present study examined the feasibility of a homeopathic consultation and treatment program, provided as part of an integrative oncology service. METHODS: The electronic medical files of patients undergoing a homeopathic consultation in an integrative oncology service clinic were examined retrospectively. Adherence to the homeopathic treatment regimen and perceived response to the treatment were evaluated. RESULTS: The files of 124 patient (34 males, 90 females) were examined, of which two-thirds reported acquiring and self-administering the homeopathic remedy as prescribed, and nearly three-quarters reporting a beneficial effect. Adherence to the homeopathic treatment regimen was greatest among patients attending a second visit, as opposed to having only telephone/e-mail follow-up ( P < .005). An association was found between a perceived beneficial effect of treatment with attending a follow-up visit ( P = .04), female gender ( P = .02), younger age ( P = .048), diagnosis of breast cancer ( P = .014), and current radiation treatment (vs chemotherapy; P = .003). Patients reporting chemotherapy-induced peripheral neuropathy were also more likely to report a beneficial effect ( P = .004), as were female patients reporting hot flashes ( P = .005) and those referred by an oncologist ( P = .046). No adverse effects were attributed to the homeopathic treatment. CONCLUSIONS: Homeopathy can be successfully incorporated within a supportive care integrative oncology service. In addition to demographic and cancer-related characteristics, as well as symptoms, patients attending a second visit (vs only telephone/e-mail follow-up) were more likely to adhere to and perceive a beneficial effect from the homeopathic regimen.

12.
World J Surg Oncol ; 15(1): 193, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29096642

RESUMO

BACKGROUND: Positive surgical margins (PSM) are recognized as an adverse prognostic sign and are often associated with higher rates of local and systemic disease recurrence. The data regarding the oncological outcome for PSM following radical nephrectomy (RN) is limited. We examined the predictive factors for PSM and its influence on survival and site of recurrence in patients treated with RN for renal cell carcinoma (RCC). METHODS: Clinical, pathologic and follow-up data on 714 patients undergoing RN for kidney cancer were analyzed. Secondary analysis included 44 patients with metastatic RCC upon diagnosis who underwent cytoreductive nephrectomy (CRN). Univariate and multivariable logistic regression models were fit to determine clinicopathologic features associated with PSM. A Cox proportional-hazards regression model was used to test the independent effects of clinical and pathologic variables on survival. RESULTS: PSM was documented in 17 cases (2.4%). PSM were associated with tumour size, advanced pathologic stage (pT3 vs. ≤ pT2) and presence of necrosis. On multivariate analysis, cancer-specific survival (CSS) was associated with tumour stage, size, presence of necrosis and PSM. PSM was also associated with local recurrence but not distant metastasis or overall survival (OS). CSS and OS were comparable between the PSM and metastatic RCC groups, but significantly lower than the negative margin group. CONCLUSIONS: The prevalence of PSM following RN is rare. Pathological data, including advanced stage (> pT2), tumour necrosis and tumour size, are associated with the presence of PSM. PSM is associated with tumour recurrence and CSS. Patients with PSM are a potential group for adjuvant therapy or for more careful and thorough follow-up following surgery.


Assuntos
Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Margens de Excisão , Recidiva Local de Neoplasia/epidemiologia , Nefrectomia/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Nefrectomia/métodos , Prognóstico , Estudos Retrospectivos
13.
Artigo em Inglês | MEDLINE | ID: mdl-28706506

RESUMO

The insulin-like growth factor-1 receptor (IGF1R) emerged in recent years as a promising therapeutic target in oncology. Identification of potential biomarkers capable of predicting response to IGF1R-targeted therapy is of cardinal importance. Tumor suppressor BRCA1 has important roles in multiple pathways, including gene transcription, DNA damage repair, and control of apoptosis. Early studies have identified the IGF1R gene as a downstream target for inhibitory regulation by wild-type, but not mutant, BRCA1. The aim of the present study was to evaluate the hypothesis that the mutational status of BRCA1 may influence the ability of IGF1R-directed therapies to efficiently inhibit the IGF1R axis. Using breast cancer-derived cell lines expressing a wild-type or a mutant BRCA1, we demonstrate that the capacity of MK-0646, a monoclonal antibody antagonist to the human IGF1R, to inhibit insulin-like growth factor-1-stimulated IGF1R and downstream mediators' phosphorylation was impaired in mutant BRCA1-expressing cell lines. In addition, the antibody was able to reduce proliferation of wild-type BRCA1-expressing cells but had a reduced inhibitory effect in mutant BRCA1-expressing cells. In summary, our data indicate that the mutational status of BRCA1 must be taken into account when selecting patients for IGF1R targeting protocols.

14.
J Cancer Res Clin Oncol ; 143(11): 2267-2273, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28667389

RESUMO

PURPOSE: To identify the unmonitored use of herbal medicine by female patients with breast cancer, examining the impact of an integrative physician (IP) consultation on this practice. METHODS: The files of 269 female patients with breast cancer following an IP consultation were surveyed retrospectively for use of herbal medicine for cancer-related goals. Expectations from the IP consultation and adherence to the IP-guided treatments were examined as well. RESULTS: Among the cohort, 111 (41.3%) reported using herbal medicine for cancer-related goals, unmonitored by their oncology healthcare professional. Factors predicting herbal medicine use were the adoption of dietary changes (odds ratio = 13.6, p < 0.001, CI 7.16-26.0) and the expectation that the IP consultation and treatments would address cancer-related goals (odds ratio = 3.29, p = 0.001, CI 1.64-6.6). Patients with metastatic disease were more likely to be using herbal medicine than non-users (34.5 vs. 22.8%; p = 0.088), as were those who had consulted with a complementary/alternative medicine practitioner (54.9 vs. 20.8%; p = 0.005). The IP advised 17 patients (15.3%) to stop taking specific herbal products due to safety-related concerns; and 10 patients to take dietary supplements for relief of specific symptoms. Herbal medicine users were less likely than non-users to adhere to the IP-recommended treatment program (34.7 vs. 48.3%; p = 0.037). CONCLUSIONS: Unmonitored use of herbal medicine by patients with breast cancer is more frequent among those adopting dietary changes for cancer-related goals. Integrative physicians provide evidence-based guidance on the safe and effective use of herbal products, and reframe patient expectations from cancer-related goals to reducing symptoms and improving quality of life.


Assuntos
Neoplasias da Mama/terapia , Terapias Complementares/estatística & dados numéricos , Medicina Herbária/métodos , Cooperação do Paciente , Qualidade de Vida , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Médicos , Fitoterapia , Prognóstico , Estudos Retrospectivos
15.
Eur J Cancer ; 83: 229-236, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28755607

RESUMO

BACKGROUND: Cabozantinib (XL184), an orally bioavailable inhibitor of vascular endothelial growth factor receptor 2 and MET, was assessed in a cohort of ovarian carcinoma patients as part of a phase 2 randomised discontinuation trial (RDT) with cohorts from nine different tumour types. PATIENTS AND METHODS: Patients received 100-mg cabozantinib daily. Those with stable disease (SD) per Response Evaluation Criteria in Solid Tumors at week 12 were randomised to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) after random assignment. RESULTS: Seventy patients with ovarian carcinoma, 50% of whom were platinum refractory/resistant, were enrolled in this RDT. Median PFS from day 1 was 5.5 months for all patients. The ORR at week 12 was 21%; one patient achieved a complete response (CR), and 14 patients (20%) achieved a confirmed partial response (PR). The overall disease control rate (CR + PR + SD) at week 12 was 50%. Throughout the study, 70% of the patients with ≥1 postbaseline scan had tumour regression, and randomisation was discontinued early. For patients with SD randomised to cabozantinib, PFS was 5.9 months after randomisation. The most common grade 3/4 adverse events were diarrhoea (14%), palmar-plantar erythrodysesthesia syndrome (6%), asthenia (6%), hypertension (6%) and neutropenia (6%). Dose reductions were required in 37% of the patients during the first 12 weeks. CONCLUSION: Cabozantinib demonstrates clinical activity, with acceptable toxicities, in patients with ovarian carcinoma based on ORR and regression of tumour target lesions. REGISTRATION: This trial is registered at ClinicalTrial.gov (NCT00940225).


Assuntos
Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Análise de Sobrevida
16.
Oncotarget ; 8(25): 40778-40790, 2017 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-28489577

RESUMO

Pancreatic ductal adenocarcinoma has limited treatment options. There is an urgent need for developing appropriate pre-clinical models recapitulating metastatic disease, the most common clinical scenario at presentation. Ascites accumulation occurs in up to 20-30% of patients with pancreatic cancer; this milieu represents a highly cellular research resource of metastatic peritoneal spread. In this study, we utilized pancreatic ascites/pleural effusion cancer cells to establish patient derived xenografts.Ascites/pleural effusion-patient derived xenografts were established from twelve independent cases. Xenografts were serially passed in nude mice and tissue bio-specimen banking has been established. Histopathology of emergent tumors demonstrates poorly to moderately differentiated, glandular and mucin producing tumors, mirroring morphology of primary pancreatic cancer tumors. Whole genome sequencing of six patient derived xenografts samples demonstrates common mutations and structural variations similar to those reported in primary pancreatic cancer. Xenograft tumors were dissociated to single-cells and in-vitro drug sensitivity screen assays demonstrated chemo-resistance, correlating with patient clinical scenarios, thus serving as a platform for clinically relevant translational research.Therefore, establishment of this novel ascites/pleural effusion patient derived xenograft model, with extensive histopathology and genomic characterization, opens an opportunity for the study of advanced aggressive pancreatic cancer. Characterization of metastatic disease and mechanisms of resistance to therapeutics may lead to the development of novel drug combinations.


Assuntos
Ascite/patologia , Carcinoma Ductal Pancreático/patologia , Animais , Ascite/etiologia , Ascite/genética , Carcinoma Ductal Pancreático/genética , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , Transfecção , Sequenciamento Completo do Genoma/métodos
17.
Isr Med Assoc J ; 19(1): 19-24, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28457109

RESUMO

BACKGROUND: Radiotherapy to the prostate bed is used to eradicate residual microscopic disease following radical prostatectomy for prostate cancer. Recommendations are based on historical series. OBJECTIVES: To determine outcomes and toxicity of contemporary salvage radiation therapy (SRT) to the prostate bed. METHODS: We reviewed a prospective ethics committee-approved database of 229 patients referred for SRT. Median pre-radiation prostate-specific antigen (PSA) was 0.5 ng/ml and median follow-up was 50.4 months (range 13.7-128). Treatment was planned and delivered using modern three-dimensional radiation techniques. Mean bioequivalent dose was 71 Gy (range 64-83 Gy). Progression was defined as two consecutive increases in PSA level > 0.2 ng/ml, metastases on follow-up imaging, commencement of anti-androgen treatment for any reason, or death from prostate cancer. Kaplan-Meier survival estimates and multivariate analysis was performed using STATA. RESULTS: Five year progression-free survival was 68% (95%CI 59.8-74.8%), and stratified by PSA was 87%, 70% and 47% for PSA < 0.3, 0.3-0.7, and > 0.7 ng/ml (P < 0.001). Metastasis-free survival was 92.5%, prostate cancer-specific survival 96.4%, and overall survival 94.9%. Low pre-radiation PSA value was the most important predictor of progression-free survival (HR 2.76, P < 0.001). Daily image guidance was associated with reduced risk of gastrointestinal and genitourinary toxicity (P < 0.005). CONCLUSIONS: Contemporary SRT is associated with favorable outcomes. Early initiation of SRT at PSA < 0.3 ng/ml improves progression-free survival. Daily image guidance with online correction is associated with a decreased incidence of late toxicity.


Assuntos
Antígeno Prostático Específico/sangue , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/terapia , Radioterapia Adjuvante , Terapia de Salvação , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Estudos Prospectivos , Prostatectomia , Neoplasias da Próstata/sangue , Dosagem Radioterapêutica
18.
Oncol Lett ; 13(4): 2642-2648, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28454445

RESUMO

Numerous botanicals have been shown to exhibit in vitro and in vivo anticancer activity, some of which is the result of the induction of reactive oxygen species (ROS) in cancer cells with a high ROS content. The present study compared sensitivities to a series of botanicals among cancer cell lines, using an XTT viability test, in order to create a specific cancer-herb profile. Of the 27 botanicals screened, 10 exhibited a cytotoxic effect, 7 of which were ROS-mediated. The sensitivity profiles of the ROS-inducing botanicals in 10 cancer cell lines were similar, unlike 3 cytotoxic ROS-independent botanicals that displayed divergent botanical-specific profiles. The correlation between sensitivity profiles of ROS-inducing botanicals suggests a common mechanism of action, in contrast to the varied mechanism of ROS-independent botanicals. This implies that the investigation of the anticancer activity of botanicals should start with the examination of ROS-mediated activity. Further investigation of ROS sensitivity among various tumor types is required in order to guide research into developing evidence-based guidelines in the use of botanicals for cancer treatment.

19.
Lancet Oncol ; 18(2): 212-220, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28081914

RESUMO

BACKGROUND: PD-1 and its ligands are expressed in urothelial cancer, and findings have shown that inhibition of the PD-1 pathway has clinical benefit. We aimed to assess the safety and activity of an anti-PD-1 antibody pembrolizumab in patients with locally advanced or metastatic urothelial cancer. METHODS: This study was part of the non-randomised, multi-cohort, open-label, phase 1b KEYNOTE-012 basket trial. We enrolled patients aged 18 years and older with a histologically or cytologically confirmed diagnosis of locally advanced or metastatic urothelial cancer, including cancers of the renal pelvis, ureter, bladder, or urethra, from eight hospitals in the USA and Israel. Patients were required to have at least 1% PD-L1 expression detected on the tumour cells or in tumour stroma, as determined by immunohistochemistry. Patients were given 10 mg/kg intravenous pembrolizumab every 2 weeks until disease progression, unacceptable toxic effects, or the end of the study (ie, 24 months of treatment). Primary endpoints were safety and overall response (defined by Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1), as assessed by a masked, independent central review. Safety was assessed in patients who received one or more doses of pembrolizumab (all-patients-as-treated population); activity was assessed in patients who received pembrolizumab, had measurable disease at baseline, and had one or more post-baseline scans, or discontinued because of progressive disease or treatment-related adverse events (full analysis set). This study is registered with ClinicalTrials.gov, number NCT01848834, and is no longer enrolling patients; follow-up is ongoing. FINDINGS: Between May 14, 2013, and Dec 10, 2013, 115 patients were tissue pre-screened as part of a two-part consent process. 61 (53%) patients were PD-L1 positive, of whom 33 were enrolled in this study. All enrolled patients received at least one dose of pembrolizumab and were included in the safety analyses. 27 patients comprised the full analysis set and were deemed assessable for activity. Six patients were not assessable: three discontinued study drug because of a non-treatment-related adverse event before the first post-baseline scan, two withdrew before the first post-baseline scan, and one had no measurable disease at baseline. The most common treatment-related adverse events were fatigue (six [18%] of 33 patients) and peripheral oedema (4 [12%]). Five (15%) patients had 11 grade 3 treatment-related adverse events; no single event occurred in more than one patient. Three (9%) patients experienced five serious treatment-related adverse events. After median follow-up of 13 months (range 1-26, IQR 5-23), an overall response was achieved in seven (26% [95% CI 11-46]) of 27 assessable patients, with three (11% [2-29]) complete and four (15% [4-34]) partial responses. Of the four deaths that occurred during the study (cardiac arrest, pneumonia, sepsis, and subarachnoid haemorrhage), none were deemed treatment related. INTERPRETATION: Pembrolizumab showed anti-tumour activity and acceptable safety in patients with advanced urothelial cancer, supporting ongoing phase 2 and 3 studies of pembrolizumab in this population. FUNDING: Merck & Co., Inc.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Urológicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Segurança , Taxa de Sobrevida , Neoplasias Urológicas/patologia
20.
Radiat Oncol ; 12(1): 5, 2017 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-28061904

RESUMO

OBJECTIVE: To evaluate outcomes in prostate cancer patients classified as high-risk (HR) or very high-risk (VHR) who were treated with conformal radiation therapy (CRT) and androgen deprivation therapy (ADT). METHODS: Between 11/2001 and 3/2012, 203 patients with HR disease received CRT to the prostate (78-82 Gy) and pelvic lymph nodes (46-50 Gy) with ADT (6 m-2 years). Median follow-up was 50 months (12 m-142 m). Biochemical failure was defined according to Phoenix definition. Imaging studies were used to identify local, regional or metastatic failure. Four different VHR/HR groupings were formed using the 2014 and revised 2015 NCCN guidelines. Differences were examined using Kaplan Meier (KM) estimates with log rank test and uni- and multivariate Cox regression analysis (MVA). RESULTS: Failure occurred in 30/203 patients (15%). Median time to failure was 30 m (4 m-76 m). KM estimate of 4 year biochemical disease free survival (b-DFS) for the entire cohort was 87% (95%CI: 82-92%). Four year KM survival estimates for b-DFS, PCSS and OS were comparable for each NCCN subgroup. On univariate analysis, the NCCN subgroups were not predictive of b-DFS at 4 years, however, DMFS was worse for both VHR subgroups (p = .03and .01) respectively. Cox univariate analysis was also significant for: PSA ≥40 ng/ml p = 0.001; clinical stages T2c p = .004, T3b p = .02 and > 4 cores with Gleason score 8-10 p < .03. On MVA, only PSA ≥ 40 ng/ml was predictive for b-DFS or MFS at 4 years (HR: 3.75 and 3.25, p < 0.005). CONCLUSION: Patients with HR and VHR disease treated with CRT and ADT had good outcomes. Stratification into HR and VHR sub-groups provided no predictive value. Only PSA ≥40 ng/ml predicted poor outcomes on MVA. Distant failure was dominant and local recurrence rare, suggesting that improved systemic treatment rather than intensification of local therapy is needed. Patients with high-risk prostate cancer are most often treated with conformal dose escalated radiation therapy with androgen deprivation. Stratification into high versus very high-risk subgroups using 2014 or revised 2015 National Comprehensive Cancer Network (NCCN) criteria did not impact treatment outcomes. Only Prostate Serum Antigen (PSA) ≥40 ng/ml was predictive of poor prognosis. Distant failure was dominant and local recurrence uncommon which challenges the notion that intensification of local therapy will further improve outcomes in patients with high-risk disease.


Assuntos
Neoplasias da Próstata/classificação , Neoplasias da Próstata/terapia , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/uso terapêutico , Quimiorradioterapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Neoplasias da Próstata/mortalidade , Radioterapia Conformacional , Risco , Resultado do Tratamento
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