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1.
Gastroenterology ; 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33524400

RESUMO

BACKGROUND AND AIMS: Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2. METHODS: We interrogated whole genome sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status. RESULTS: Biallelic tumor inactivation of gBRCA or PALB2 was evident in 43 of 49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumor classifiers suggested that 7% to 10% of PDACs that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetecthi cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D, and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared with BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC; however in advanced disease the GIS (P = .02), SBS3 (P = .03), and HRDetect score (P = .005) were predictive of platinum response and superior survival. PVs in gATM (n = 6) or gCHEK2 (n = 2) did not result in HRD-PDAC by any of the classifiers. In 4 patients, BRCA2 reversion mutations associated with platinum resistance. CONCLUSIONS: Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.

2.
Sci Rep ; 11(1): 787, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436995

RESUMO

To examine the ocular side effects of selected biological anti-cancer therapies and the ocular and systemic prognosis of patients receiving them. We retrospectively reviewed all medical records of patients who received biological anti-cancer treatment from 1/2012 to 12/2017 and who were treated at our ocular oncology service. The following data was retrieved: primary malignancy, metastasis, type of biological therapy, ocular side effects, ophthalmic treatment, non-ocular side effects, and ocular and systemic disease prognoses. Twenty-two patients received biological therapies and reported ocular side effects. Eighteen patients (81.8%) had bilateral ocular side effects, including uveitis (40.9%), dry eye (22.7%), and central serous retinopathy (22.7%). One patient (4.5%) had central retinal artery occlusion (CRAO), and one patient (4.5%) had branch retinal vein occlusion (BRVO). At the end of follow-up, 6 patients (27.27%) had resolution of the ocular disease, 13 patients (59.09%) had stable ocular disease, and 3 patients (13.64%) had progression of the ocular disease. Visual acuity improved significantly at the end of follow-up compared to initial values. Eighteen patients (81.8%) were alive at study closure. Biological therapies can cause a wide range of ocular side effects ranging from dry eye symptoms to severe pathologies that may cause ocular morbidity and vision loss, such as uveitis, CRAO and BRVO. All patients receiving biological treatments should be screened by ophthalmologists before treatment, re-screened every 4-6 months during treatment, and again at the end of treatment. Patients on biological treatment who have ocular complaints should be urgently referred to ocular consultation for early identification and early intervention.

3.
Br J Radiol ; 93(1115): 20200591, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32816525

RESUMO

OBJECTIVES: We aimed to analyze the association between the onsets of PE and of progressive disease (PD) in CT scans of oncological patients undergoing clinical trials. METHODS: We retrospectively searched our oncological clinical trials database (1/2012 - 6/2017). We retrieved patients who underwent protocol baseline and follow-up CT scans. RECIST 1.1 categories of response were calculated for each scan at interpretation. The entire dataset was searched for reports with incidental PE.For patients with incidental PE, we collected all the scans conducted up to and including the scan with PE. For each scan, we retrieved the recorded RECIST 1.1 category. We excluded patients with PE at baseline.The frequency of incidental PE in oncological clinical trial patients was calculated. For patients with incidental PE, we evaluated the association between PE and PD. RESULTS: During the study period, 1,070 patients underwent 3,818 CTs. The total number of follow-up months was 7,292 months. 18 patients developed incidental PE during follow-up. Thus, the frequency of incidental PE in oncological clinical trial patients was 3% per year of follow-up. Patients with incidental PE underwent 60 scans up to development of PE. Of 42 non-baseline scans, 6/6 (100%) PD showed PE, and 5/36 (13.9%) non-PD showed PE, making PE onset associated with PD onset (p < 0.001). CONCLUSION: In oncological clinical trials, the frequency of incidental PE is 3% per year of follow-up. The onset of incidental PE is linked to the onset of PD. ADVANCES IN KNOWLEDGE: Incidental PE is associated with the onset of disease progression. Radiologists interpret oncological scans should be aware of the association between PE and PD.


Assuntos
Progressão da Doença , Achados Incidentais , Neoplasias/diagnóstico por imagem , Embolia Pulmonar/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Bases de Dados Factuais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/epidemiologia , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/estatística & dados numéricos
4.
Biomed Rep ; 13(3): 17, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32765856

RESUMO

Innate immunity serves an important role in the healthy population, providing surveillance and protection against infections. Chemotherapy suppresses the body's immune system, including neutrophil and natural killer (NK) cell numbers and activity. This leads to an increased risk of infection which often requires the reduction or even discontinuation of the chemotherapeutic regimens. The botanical formula LCS102 was designed to stimulate the body's immune system. The effect of the formula on innate immunity was examined in human blood samples, as were its effect on the anti-cancer activity of chemotherapeutic agents on human cancer cells. Blood samples drawn from 20 volunteers (19 healthy subjects; 1 patient with breast cancer undergoing chemotherapy) and were exposed to LCS102. The effects on neutrophil and NK cell activity were tested using FACS. The anti-cancer effects of LCS102 were tested on T24, A549, MCF7, PANC-1 and U2OS human cancer cell lines, as were the effects of the formula on doxorubicin, Taxol, etoposide and cisplatin-treated cells using a sulforodamine B viability assay. LCS102 was shown to significantly increase the percentage of activated neutrophils and NK cells in the blood samples tested. The formula did not inhibit the cytotoxic effects of the chemotherapeutic agents, and in certain cases increased their anti-cancer activity. Further research is required to improve our understanding of the clinical value of LCS102; however, it may serve as an adjuvant during chemotherapy, to reduce the effects of chemotherapy on innate immunity.

5.
Cancers (Basel) ; 12(5)2020 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-32357427

RESUMO

Lutetium-177-PSMA ([177Lu]-PSMA-617), a radiolabeled small molecule, binds with high affinity to prostate-specific membrane antigen (PSMA), enabling targeted radiation therapy to metastatic prostate lesions. Our objective was to retrospectively analyze the activity of [177Lu]-PSMA-617 given off-trial to men with metastatic castration resistant prostate cancer (mCRPC) and identify clinical factors associated with PSA response. Electronic medical records of all men treated with [177Lu]-PSMA-617 were reviewed and analyzed. Overall survival was calculated using the Kaplan-Meier method. The association between potential variables and PSA response was analyzed by univariate analysis, using either logistic regression or χ2/Fisher's exact test. Multivariable analysis was carried out using logistic regression on all categorical variables with a P-value of <0.1 on univariate analysis. Variables found to be statistically significant were then used to define a categorical score. A total of 52 patients received at least one cycle of [177Lu]-PSMA-617. Clinical benefit was observed in 28 patients (52%). PSA decline ≥20% and ≥50% was observed in 26 (50%) and 18 patients (35%), respectively. Achievement of any PSA decline at first measurement was significantly associated with survival. There was a negative association between the number of previous chemotherapy lines and PSA decline above 20%. Univariate analysis followed by multivariable analysis showed that older age and higher hemoglobin were significantly associated with a PSA decline >20%. A score combining these two parameters was significantly associated with PSA response. In summary, [177Lu]-PSMA-617 is active in the 'real-life' setting of heavily pretreated men with mCRPC.

6.
Oncologist ; 25(9): 787-792, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32430954

RESUMO

BACKGROUND: Prostate cancer is a common malignancy of the elderly, and with the aging of the population, the need is growing for therapies suitable for this age group. Lutetium-177-prostate-specific membrane antigen (Lu-PSMA), a radiolabeled small molecule, binds with high affinity to prostate-specific membrane antigen, enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer (mCRPC). In a recent single-arm phase II trial and a subsequent expansion cohort, a prostate-specific antigen (PSA) decline of ≥50% was observed in approximately 60% of patients receiving Lu-PSMA. Taking into account the specific challenges and potential toxicities of Lu-PSMA administration in elderly men, we sought to retrospectively analyze the safety and activity of Lu-PSMA in men aged older than 75 years with mCRPC. PATIENTS AND METHODS: The electronic medical records of 24 patients aged older than 75 years treated with Lu-PSMA "off-trial" were reviewed, and clinical data were extracted. Clinical endpoints were toxicity and activity, defined as a PSA decline ≥50%. Descriptive statistics were performed using Excel. RESULTS: The median age at treatment start was 81.7 years (range 75.1-91.9). The median number of previous treatment lines was four. The number of treatment cycles ranged from one to four; the mean administered radioactivity was 6 GBq per cycle. Treatment was generally tolerable; side effects included fatigue (n = 8, 33%), anemia (n = 7, 29%), thrombocytopenia (n = 5, 21%), and anorexia/nausea (n = 3, 13%). Clinical benefit was observed in 12 of 22 patients (54%); PSA decline above 50% was observed in 11 patients (48%) and was associated with significantly longer overall survival. CONCLUSION: Our results indicate that Lu-PSMA is safe and active in elderly patients with mCRPC. IMPLICATIONS FOR PRACTICE: Lutetium-177-prostate-specific membrane antigen (Lu-PSMA), a radiolabeled small molecule, binds with high affinity to prostate-specific membrane antigen, enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer (mCRPC). The recently published single-arm phase II trial with Lu-PSMA, describing its safety and activity, did not include patients aged older than 75 years. In this study, Lu-PSMA activity was retrospectively analyzed in patients aged older than 75 years and results indicate that treatment was tolerable and similarly active in this age group, with no new emerging safety signals. Despite the small cohort size, this analysis suggests that Lu-PSMA can serve as an advanced palliative treatment line in mCRPC in elderly patients.

7.
Oncotarget ; 11(17): 1515-1530, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32391121

RESUMO

Clinical, epidemiological and experimental data identified the insulin-like growth factor-1 receptor (IGF1R) as a candidate therapeutic target in oncology. While this paradigm is based on well-established biological facts, including the potent anti-apoptotic and cell survival capabilities of the receptor, most Phase III clinical trials designed to target the IGF1R led to disappointing results. The present study was aimed at evaluating the hypothesis that combined treatment composed of selective IGF1R inhibitor along with classical chemotherapy might be more effective than individual monotherapies in breast cancer treatment. Analyses included comprehensive measurements of the synergism achieved by various combination regimens using the CompuSyn software. In addition, proteomic analyses were conducted to identify the proteins involved in the synergistic killing effect at a global level. Data presented here demonstrates that co-treatment of IGF1R inhibitor along with chemotherapeutic drugs markedly improves the therapeutic efficiency in breast cancer cells. Of clinical relevance, our analyses indicate that high IGF1R baseline expression may serve as a predictive biomarker for IGF1R targeted therapy. In addition, we identified a ten-genes signature with potential predictive value. In conclusion, the use of a series of bioinformatics tools shed light on some of the biological pathways that might be responsible for synergysm in cancer therapy.

8.
Transl Oncol ; 13(2): 193-200, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31869744

RESUMO

Immune checkpoint inhibitors have revolutionized cancer therapy, but not all cancers respond to the currently available drugs, and even within cancers considered responsive to such modality, response rates range between 15 and 40%, depending on the cancer type, the line of treatment, and yet unknown clinical/molecular factors. Coordinated expression of checkpoint proteins was shown to occur on T cells, probably allowing fine-tuning of the signal transmitted to the cell. We performed a bioinformatic analysis of the expression of putative checkpoint mRNAs at the cancer side of the immunological synapse from the bladder cancer tumorgenome atlas (TCGA) database. Fifteen mRNAs, corresponding to both coinhibitory and costimulatory checkpoints, were shown to be expressed above a designated threshold. Of these, seven mRNAs were found to be coexpressed: CD277, PD-1L, CD48, CD86, galectin-9, TNFRSF14 (HVEM), and CD40. The expression of 2 of these mRNAs-BTN3A1 (CD277) and TNFRSF14 (HVEM)-was positively correlated with overall survival in the TCGA database. All these seven mRNA share putative binding sites of a few transcription factors (TFs). Of these, the expression of the TF BACH-2 was positively correlated with the expression of checkpoint mRNAs from the network. This suggests a joint transcriptional regulation on the expression of checkpoint mRNAs at the bladder tumor side of the immunological synapse.

9.
NPJ Breast Cancer ; 5: 38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31700994

RESUMO

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

10.
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
11.
Eur J Cancer ; 120: 122-131, 2019 10.
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.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Imunoterapia/efeitos adversos , Imunoterapia/mortalidade , Neoplasias/tratamento farmacológico , Doenças Vasculares/induzido quimicamente , Doença Aguda , Idoso , Feminino , Seguimentos , Humanos , Masculino , Neoplasias/imunologia , Neoplasias/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Doenças Vasculares/patologia
12.
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.


Assuntos
Glicoproteínas de Membrana , Compostos Organometálicos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/diagnóstico por imagem , Idoso , Humanos , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Estudos Retrospectivos
13.
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
14.
J Cancer Res Clin Oncol ; 145(3): 609-613, 2019 Mar.
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.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Humanos , Espécies Reativas de Oxigênio/efeitos da radiação , Raios X
15.
Am J Clin Oncol ; 42(2): 179-183, 2019 02.
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.


Assuntos
Carcinoma de Células de Transição/radioterapia , Recidiva Local de Neoplasia/radioterapia , Hipofracionamento da Dose de Radiação , Radioterapia Conformacional/métodos , Radioterapia de Intensidade Modulada/métodos , Neoplasias da Bexiga Urinária/radioterapia , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/patologia , Feminino , Seguimentos , Humanos , Masculino , Recidiva Local de Neoplasia/patologia , Taxa de Sobrevida , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia
16.
Integr Cancer Ther ; 17(4): 1020-1026, 2018 12.
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.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Células HCT116 , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Células MCF-7 , Masculino , Camundongos , Neoplasias da Próstata/metabolismo , Qualidade de Vida , Células RAW 264.7 , Ensaios Clínicos Controlados Aleatórios como Assunto , Espécies Reativas de Oxigênio/metabolismo
17.
Cancer Discov ; 8(7): 812-821, 2018 07.
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.


Assuntos
Mutação , Compostos de Fenilureia/uso terapêutico , Pirimidinas/uso terapêutico , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Neoplasias Urológicas/tratamento farmacológico , Administração Oral , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Resultado do Tratamento , Neoplasias Urológicas/metabolismo
18.
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.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Compostos de Platina/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Animais , Carcinoma Ductal Pancreático/genética , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Instabilidade Genômica , Recombinação Homóloga , Humanos , Camundongos , Mutação , Metástase Neoplásica , Transplante de Neoplasias , Neoplasias Pancreáticas/genética , Compostos de Platina/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Prognóstico , Sequenciamento Completo do Genoma
19.
Hum Mutat ; 39(5): 593-620, 2018 05.
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.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Internacionalidade , Mutação/genética , Bases de Dados Genéticas , Família , Geografia , Humanos
20.
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.


Assuntos
Neoplasias/terapia , Feminino , Homeopatia/métodos , Humanos , Oncologia Integrativa/métodos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Qualidade de Vida , Estudos Retrospectivos , Inquéritos e Questionários
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