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BACKGROUND: Gemcitabine and cisplatin has limited benefit as treatment for advanced biliary tract cancer (BTC). The addition of an anti-programmed death receptor (PD-1)/PD-ligand (L1) antibody to either systemic chemotherapy or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibody has shown benefit in multiple solid tumors. METHODS: In this phase 2 trial, patients 18 years or older with advanced BTC without prior systemic therapy and Eastern Cooperative Oncology Group Performance Status 0-1 were randomized across six academic centers. Patients in Arm A received nivolumab (360 mg) on day 1 along with gemcitabine and cisplatin on days 1 and 8 every 3 weeks for 6 months followed by nivolumab (240 mg) every 2 weeks. Patients in Arm B received nivolumab (240 mg) every 2 weeks and ipilimumab (1 mg/kg) every 6 weeks. RESULTS: Of 75 randomized patients, 68 received therapy (Arm A = 35, Arm B = 33); 51.5% women with a median age of 62.5 years. The observed primary outcome of 6-month progression-free survival (PFS) rates in the evaluable population was 59.4% in Arm A and 21.2% in Arm B. The median PFS and overall survival (OS) in Arm A were 6.6 and 10.6 months, and in Arm B 3.9 and 8.2 months, respectively, in patients who received any treatment. The most common treatment-related grade 3 or higher hematologic adverse event was neutropenia in 34.3% (Arm A) and nonhematologic adverse events were fatigue (8.6% Arm A) and elevated transaminases (9.1% Arm B). CONCLUSIONS: The addition of nivolumab to chemotherapy or ipilimumab did not improve 6-month PFS. Although median OS was less than 12 months in both arms, the high OS rate at 2 years in Arm A suggests benefit in a small cohort of patients.
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Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de los Conductos Biliares/etiología , Neoplasias del Sistema Biliar/tratamiento farmacológico , Cisplatino/efectos adversos , Desoxicitidina/análogos & derivados , Femenino , Humanos , Ipilimumab/efectos adversos , Masculino , Persona de Mediana Edad , Nivolumab/efectos adversos , GemcitabinaRESUMEN
BACKGROUND: KRAS variant alleles may have differential biological properties which impact prognosis and therapeutic options in pancreatic ductal adenocarcinomas (PDA). MATERIALS AND METHODS: We retrospectively identified patients with advanced PDA who received first-line therapy and underwent blood and/or tumor genomic sequencing at the University of Washington between 2013 and 2020. We examined the incidence of KRAS mutation variants with and without co-occurring PI3K or other genomic alterations and evaluated the association of these mutations with clinicopathological characteristics and survival using a Cox proportional hazards model. RESULTS: One hundred twenty-six patients had genomic sequencing data; KRAS mutations were identified in 111 PDA and included the following variants: G12D (43)/G12V (35)/G12R (23)/other (10). PI3K pathway mutations (26% vs. 8%) and homologous recombination DNA repair (HRR) defects (35% vs. 12.5%) were more common among KRAS G12R vs. non-G12R mutated cancers. Patients with KRAS G12R vs. non-G12R cancers had significantly longer overall survival (OS) (HR 0.55) and progression-free survival (PFS) (HR 0.58), adjusted for HRR pathway co-mutations among other covariates. Within the KRAS G12R group, co-occurring PI3K pathway mutations were associated with numerically shorter OS (HR 1.58), while no effect was observed on PFS. CONCLUSIONS: Patients with PDA harboring KRAS G12R vs. non-G12R mutations have longer survival, but this advantage was offset by co-occurring PI3K alterations. The KRAS/PI3K genomic profile could inform therapeutic vulnerabilities in patients with PDA.
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Neoplasias , Fosfatidilinositol 3-Quinasas , Humanos , Fosfatidilinositol 3-Quinasas/genética , Estudios Retrospectivos , Genómica , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Oncology research is increasingly incorporating molecular detection of circulating tumor DNA (ctDNA) as a tool for cancer surveillance and early detection. However, noninvasive monitoring of conditions with low tumor burden remains challenging, as the diagnostic sensitivity of most ctDNA assays is inversely correlated with total DNA concentration and ctDNA abundance. Here we present the Multiplex Enrichment using Droplet Pre-Amplification (MED-Amp) method, which combines single-molecule emulsification and short-round polymerase chain reaction (PCR) preamplification with digital droplet PCR detection of mutant DNA template. The MED-Amp assay increased mutant signal by over 50-fold with minimal distortion in allelic frequency. We demonstrate detection of as few as three mutant copies in wild-type DNA concentrations ranging from 5 to 50 ng. The MED-Amp assay successfully detected KRAS mutant ctDNA in 86% plasma samples obtained from patients with metastatic pancreatic ductal adenocarcinoma. This assay for high-sensitivity rare variant detection is appropriate for liquid biopsy samples or other limited clinical biospecimens.
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ADN Tumoral Circulante/sangre , Gotas Lipídicas/química , Proteínas Proto-Oncogénicas p21(ras)/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Colorantes Fluorescentes/química , Frecuencia de los Genes , Humanos , Límite de Detección , Biopsia Líquida , Masculino , Persona de Mediana Edad , Mutación , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Reacción en Cadena de la PolimerasaRESUMEN
Irinotecan (Camptosar©, CPT-11), a topoisomerase I inhibitor, is a commonly used cytotoxic chemotherapeutic in the treatment of multiple malignancies, particularly of gastrointestinal origin. Dysarthria secondary to irinotecan has been described as a rare side effect in a few case reports with limited data to recommend appropriate management. We describe herein a large single institution experience of patients with gastrointestinal malignancies who experienced dysarthria while being treated with irinotecan-based chemotherapy regimens (FOLFIRINOX or FOLFIRI+/-bevacizumab). Eighteen patients developed neurological manifestations during irinotecan infusion with the majority ( n = 17) developing dysarthria. Patients also experienced other known side effects including cholinergic effects (abdominal bloating, diarrhea, facial flushing, diaphoresis, and rhinorrhea), nausea, fatigue, perioral paresthesia and musculoskeletal discomfort. The dysarthria occurred as early as with the first infusion of irinotecan ( n = 9), but several patients did not develop symptoms until subsequent infusions (range, 1-6). Dose alterations of irinotecan did not obviously impact the reccurrence or severity of dysarthria. Management strategies included close observation, atropine, slower irinotecan infusion rate, and reassurance. Dysarthria resolved without consequence in all patients within hours of completion of the infusion. Oncologists and pharmacists should be aware of irinotecan-associated dysarthria as a rare, self-limited phenomenon with no long-term sequelae, and appropriately counsel patients and infusion nurses to avoid inadvertently withholding potentially beneficial therapy for patients with gastrointestinal malignancies.
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Disartria/inducido químicamente , Neoplasias Gastrointestinales/tratamiento farmacológico , Irinotecán/efectos adversos , Inhibidores de Topoisomerasa I/efectos adversos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Background Cabozantinib and gemcitabine improve tumor control in pancreatic ductal adenocarcinoma (PDAC) in preclinical models through c-Met inhibition. We sought to determine the maximum tolerated dose (MTD) of this combination in patients with advanced PDAC. Methods Patients with ≤1 prior treatment and adequate performance status were eligible. Cabozantinib was given orally once daily, beginning day (-)7 and continued with gemcitabine given intravenously on days 1, 8, and 15 every 28 days. Dose level was assigned using Time to Event Continual Reassessment Method (TITE-CRM). Primary endpoint was MTD, defined as the highest dose level at which ≤25 % of patients incurred a dose-limiting toxicity (DLT). Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS) and urinary biomarker assessment. Results Twelve patients were enrolled and treated with 10 patients evaluable for DLT. The probability of DLT was >25 % for all dose levels tested, and thus an MTD was not determined. DLTs included grade 3 ALT/AST elevations and thrombocytopenia. Three patients had partial responses, but each discontinued therapy due to toxicity. Median PFS and OS were 4.7 (95 % CI: 1.4-9.7) and 10.1 months (95 % CI: 3.6-20.6). Exploratory biomarker analysis showed correlation of c-Met and VEGF levels with response. Conclusions An MTD for the combination was not established. Cabozantinib and gemcitabine appear impractical for further development due to DLT at low doses and continuing toxicities with ongoing therapy. Acknowledging the small sample size, responses were seen suggesting further investigation of c-Met inhibition in PDAC may be warranted.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Anilidas/administración & dosificación , Biomarcadores de Tumor/metabolismo , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Pronóstico , Piridinas/administración & dosificación , Tasa de Supervivencia , GemcitabinaRESUMEN
PURPOSE: Familial pancreatic cancer kindreds contain at least two affected first-degree relatives. Comprehensive data are needed to assist clinical risk assessment and genetic testing. METHODS: Germ-line DNA samples from 727 unrelated probands with positive family history (521 met criteria for familial pancreatic cancer) were tested in compliance with the Clinical Laboratory Improvement Amendments for mutations in BRCA1 and BRCA2 (including analysis of deletions and rearrangements), PALB2, and CDKN2A. We compared prevalence of deleterious mutations between familial pancreatic cancer probands and nonfamilial pancreatic cancer probands (kindreds containing at least two affected biological relatives, but not first-degree relatives). We also examined the impact of family history on breast and ovarian cancers and melanoma. RESULTS: Prevalence of deleterious mutations (excluding variants of unknown significance) among familial pancreatic cancer probands was: BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; and CDKN2A, 2.5%. Four novel deleterious mutations were detected. Familial pancreatic cancer probands carry more mutations in the four genes (8.0%) than nonfamilial pancreatic cancer probands (3.5%) (odds ratio: 2.40; 95% confidence interval: 1.06-5.44; P = 0.03). The probability of testing positive for deleterious mutations in any of the four genes ranges up to 10.4%, depending on family history of cancers. BRCA2 and CDKN2A account for the majority of mutations in familial pancreatic cancer. CONCLUSION: Genetic testing of multiple relevant genes in probands with a positive family history is warranted, particularly for familial pancreatic cancer.
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Proteína BRCA2/genética , Carcinoma/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Mutación de Línea Germinal , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteína del Grupo de Complementación N de la Anemia de Fanconi , Femenino , Genes BRCA1 , Genes BRCA2 , Genes p16 , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis. METHODS: TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235. FINDINGS: From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]). INTERPRETATION: Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer. FUNDING: AstraZeneca.
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Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Sistema Biliar , Cisplatino , Desoxicitidina , Gemcitabina , Humanos , Cisplatino/administración & dosificación , Cisplatino/uso terapéutico , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/mortalidad , Neoplasias del Sistema Biliar/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Método Doble Ciego , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Adulto , Tasa de SupervivenciaRESUMEN
Pancreatic ductal adenocarcinoma (PDA) is highly aggressive and has few treatment options. To personalize therapy, it is critical to delineate molecular subtypes and understand inter- and intra-tumoral heterogeneity. Germline testing for hereditary genetic abnormalities is recommended for all patients with PDA and somatic molecular testing is recommended for all patients with locally advanced or metastatic disease. KRAS mutations are present in 90% of PDA, while 10% are KRAS wild type and are potentially targetable with epidermal growth factor receptor blockade. KRASG12C inhibitors have shown activity in G12C-mutated cancers, and novel G12D and pan-RAS inhibitors are in clinical trials. DNA damage repair abnormalities, germline or somatic, occur in 5-10% of patients and are likely to benefit from DNA damaging agents and maintenance therapy with poly-ADP ribose polymerase inhibitors. Fewer than 1% of PDA harbor microsatellite instability high status and are susceptible to immune checkpoint blockade. Albeit very rare, occurring in <1% of patients with KRAS wild-type PDAs, BRAF V600E mutations, RET and NTRK fusions are targetable with cancer agnostic Food and Drug Administration-approved therapies. Genetic, epigenetic, and tumor microenvironment targets continue to be identified at an unprecedented pace, enabling PDA patients to be matched to targeted and immune therapeutics, including antibody-drug conjugates, and genetically engineered chimeric antigen receptor or T-cell receptor - T-cell therapies. In this review, we highlight clinically relevant molecular alterations and focus on targeted strategies that can improve patient outcomes through precision medicine.
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INTRODUCTION: Pancreatic cancer is the fourth leading cause of cancer-related death in the US with an increasing incidence in older adults (OA) over age 70. There are currently no treatment guidelines for OA with metastatic pancreatic cancer (mPCA) and selecting a chemotherapy regimen for these patients is subjective, based largely on chronologic age and performance status (PS). Geriatric screening tools provide a more objective and accurate evaluation of a patient's overall health but have not yet been validated in patient selection for mPCA treatment. This study aims to elucidate the optimal chemotherapy treatment of vulnerable OA with mPCA and understand the geriatric factors that affect outcomes in this population. METHODS/DESIGN: The GIANT (ECOG-ACRIN EA2186) study is multicenter, randomized phase II trial enrolling patients over age 70 with newly diagnosed mPCA. This study utilizes a screening geriatric assessment (GA) which characterizes patients as fit, vulnerable, or frail. Patients with mild abnormalities in functional status and/or cognition, moderate comorbidities, or over age 80 are considered vulnerable. Enrolled patients are randomized to one of two dose-reduced treatment regimens (gemcitabine/nab-paclitaxel every other week, or dose-reduced 5-fluoruracil (5FU)/ liposomal irinotecan (nal-IRI) every other week). GA and quality of life (QoL) evaluations are completed prior to treatment initiation and at each disease evaluation. Overall survival (OS) is the primary endpoint, with secondary endpoints including progression free survival (PFS) and objective response rate (ORR). Enrolled patients will be stratified by age (70-74 vs ≥75) and ECOG PS (0-1 vs 2). Additional endpoints of interest for OA include evaluation of risk factors identified through GA, QoL evaluation, and toxicities of interest for older adults. Correlative studies include assessment of pro-inflammatory biomarkers of aging in the blood (IL-6, CRP) and imaging evaluation of sarcopenia as predictors of treatment tolerance. DISCUSSION: The GIANT study is the first randomized, prospective national trial evaluating vulnerable OA with mPCA aimed at developing a tailored treatment approach for this patient population. This trial has the potential to establish a new way of objectively selecting vulnerable OA with mPCA for modified treatment and to establish a new standard of care in this growing patient population. TRIAL REGISTRATION: This trial is registered with ClinicalTrial.gov Identifier NCT04233866.
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Gemcitabina , Neoplasias Pancreáticas , Humanos , Anciano , Anciano de 80 o más Años , Irinotecán , Fluorouracilo , Leucovorina , Calidad de Vida , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
OBJECTIVES: Pancreatic ductal adenocarcinoma (PDA) is the third most common cause of cancer death in the United States. Most patients who undergo resection develop recurrence. Standard treatment confers a median overall survival (OS) of 24 months. Exposure to alternate regimens may prevent chemoresistance. This study evaluated multiagent perioperative therapy for potentially resectable PDA patients to improve OS. METHODS: A single center, phase 2, trial of patients with resectable or borderline resectable PDA. Patients received neoadjuvant therapy with induction chemotherapy (gemcitabine, docetaxel, capecitabine) for 3 cycles, chemoradiation (intensity-modulated radiation therapy with capecitabine and oxaliplatin) followed by surgery, and 2 months of adjuvant gemcitabine and oxaliplatin and 2 months of gemcitabine. The primary endpoint was OS. The secondary endpoint was recurrence-free survival (RFS). RESULTS: Thirty-two eligible patients were enrolled. Twenty-two patients underwent surgical resection. After a median follow-up of 56.8 months, mOS was 31.6 months (95% confidence interval [CI], 14.2-58.1) for all patients, 58.1 months (95% CI, 31.6 to NR) for those who completed surgery. The mRFS was 31.3 months (95% CI, 12.5 to NR). CONCLUSIONS: Perioperative therapy with GTX, chemoradiotherapy, and adjuvant GemOx/Gem resulted in promising survival of 58 months for patients who underwent resection and may represent another treatment option for PDA.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patología , Capecitabina , Oxaliplatino , Adenocarcinoma/tratamiento farmacológico , Quimioradioterapia/métodos , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Terapia Neoadyuvante/efectos adversos , Terapia Neoadyuvante/métodos , Fluorouracilo , Neoplasias PancreáticasRESUMEN
PURPOSE: Devimistat (CPI-613) is a novel inhibitor of tumoral mitochondrial metabolism. We investigated the effect of devimistat in vitro and in a phase Ib clinical trial in patients with advanced biliary tract cancer (BTC). PATIENTS AND METHODS: Cell viability assays of devimistat ± gemcitabine and cisplatin (GC) were performed and the effect of devimistat on mitochondrial respiration via oxygen consumption rate (OCR) was evaluated. A phase Ib/II trial was initiated in patients with untreated advanced BTC. In phase Ib, devimistat was infused over 2 hours in combination with GC on days 1 and 8 every 21 days with a primary objective to determine the recommended phase II dose (RP2D). Secondary objectives included safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: In vitro, devimistat with GC had a synergistic effect on two cell lines. Devimistat significantly decreased OCR at higher doses and in arms with divided dosing. In the phase Ib trial, 20 patients received a median of nine cycles (range, 3-19). One DLT was observed, and the RP2D of devimistat was determined to be 2,000 mg/m2 in combination with GC. Most common grade 3 toxicities included neutropenia (n = 11, 55%), anemia (n = 4, 20%), and infection (n = 3, 15%). There were no grade 4 toxicities. After a median follow-up of 15.6 months, ORR was 45% and median PFS was 10 months (95% confidence interval, 7.1-14.9). Median OS is not yet estimable. CONCLUSIONS: Devimistat in combination with GC is well tolerated and has an acceptable safety profile in patients with untreated advanced BTC.
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Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Neutropenia , Humanos , Gemcitabina , Cisplatino , Supervivencia sin Enfermedad , Desoxicitidina , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/etiología , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neutropenia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Oxaliplatin is a key chemotherapeutic agent in the treatment of local and metastatic gastrointestinal (GI) malignancies. Dose density and treatment adherence can be limited by chemotherapy-induced peripheral neuropathy (CIPN). Early research suggests CIPN incidence and severity may be mitigated by acupuncture, but rigorous data in GI oncology patients is limited. Here, we describe the protocol of a randomized, waitlist-controlled pilot study testing the use of preemptive of acupuncture plus acupressure to decrease CIPN and chemotherapy-related toxicities. METHODS: Patients with a GI malignancy (n = 56) with planned 5-fluorouracil (5-FU) and oxaliplatin IV (FOLFOX, FOLFIRINOX) every 2 weeks are being recruited. Additional concurrent anti-neoplastic agents may be used. Enrolled patients are randomized 1:1 to a 3-month intervention of Arm A: acupuncture with acupressure and standard-of-care treatment, or Arm B: standard-of-care alone. In Arm A, on days 1 and 3 of each chemotherapy cycle a standardized acupuncture protocol is administered and patients are taught self-acupressure to perform daily between chemotherapy treatments. Patients in both arms are given standard-of-care oral and peripheral (hands/feet) ice chip cryotherapy during oxaliplatin administration. CIPN and other symptoms are assessed at baseline, 6 weeks, and 3 months from registration. The primary endpoint is CIPN severity at 3 months (EORTC-CIPN 20). Additional endpoints evaluate CIPN incidence (CTCAE, Neuropen, tuning fork); incidence of pain, fatigue, nausea, oral dysesthesia, and anxiety; and feasibility (recruitment, retention, adherence, acceptability). If warranted, trial results will inform the design of a multi-center trial to expand testing of the intervention to a larger patient cohort.
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Acupresión , Terapia por Acupuntura , Antineoplásicos , Neoplasias Gastrointestinales , Neoplasias Pancreáticas , Enfermedades del Sistema Nervioso Periférico , Humanos , Oxaliplatino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estudios de Factibilidad , Antineoplásicos/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/prevención & control , Terapia por Acupuntura/efectos adversos , Terapia por Acupuntura/métodos , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/etiología , Crioterapia , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
INTRODUCTION: Immune checkpoint inhibitors (ICI) have not yielded significant efficacy in pancreatic ductal adenocarcinoma (PDA), despite the role of the innate and adaptive immune systems on progression and survival. However, recently identified pathways have identified new targets and generated promising clinical investigations into promoting an effective immune-mediated antitumor response in PDA. AREAS COVERED: We review biological mechanisms associated with immunotherapy resistance and outline strategies for therapeutic combinations with established and novel therapies in PDA. EXPERT OPINION: Pancreatic cancers rarely benefit from treatment with ICI due to an immunosuppressive tumor microenvironment (TME). New understandings of factors associated with the suppressive TME include low- and poor-quality neoantigens, constrained effector T cells infiltration, and the presence of a dense, suppressive myeloid cell population. These findings have been translated into new clinical investigations evaluating novel therapies in combination with ICI and/or standard systemic chemotherapy and radiotherapy. The epithelial, immune, and stromal compartments are intricately related in PDA, and the framework for successful targeting of this disease requires a comprehensive and personalized approach.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Inmunoterapia , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with few effective treatment options. Our knowledge of molecular alterations in PDAC has significantly grown and helped identify new therapeutic targets. The success of immune checkpoint inhibition in mismatch repair deficient tumors, PARP inhibitors for tumors with DNA repair defects, and targeting hyaluronan with PEGPH20 in patients with high expressing (hyaluronan-high) tumors are examples of promising biomarker-driven therapies. We review the major biological mechanisms in PDAC and discuss current and future directions for molecularly targeted therapies in this disease.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Carcinoma Ductal Pancreático/tratamiento farmacológico , Ácido Hialurónico/antagonistas & inhibidores , Terapia Molecular Dirigida/métodos , Neoplasias Pancreáticas/tratamiento farmacológico , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Humanos , Ácido Hialurónico/metabolismo , Terapia Molecular Dirigida/tendencias , Neoplasias Pancreáticas/metabolismo , Análisis de Supervivencia , Microambiente Tumoral/efectos de los fármacosRESUMEN
PURPOSE: The inclusion of metformin in the treatment arms of cancer clinical trials is based on improved survival that has been demonstrated in retrospective epidemiologic studies; however, unintended biases may exist when analysis is performed by using a conventional Cox proportional hazards regression model with dichotomous ever/never categorization. We examined the impact of metformin exposure definitions, analytical methods, and patient selection on the estimated effect size of metformin exposure on survival in a large cohort of patients with pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Of newly diagnosed patients with PDAC with diabetes, 980 were retrospectively included, and exposure to metformin documented. Median survival was assessed by using Kaplan-Meier and log-rank methods. Hazard ratios (HR) and 95% CIs were computed to compare time-varying covariate analysis with conventional Cox proportional hazards regression analysis. RESULTS: Median survival of metformin users versus nonusers was 9.9 versus 8.9 months, respectively. By the time-varying covariate analysis, metformin use was not statistically significantly associated with improved survival (HR, 0.93; 95% CI, 0.81 to1.07; P = .28). There was no evidence of benefit in the subset of patients who were naïve to metformin at the time of PDAC diagnosis (most representative of patients enrolled in clinical trials; HR, 1.01; 95% CI, 0.80 to 1.30; P = .89); however, when the analysis was performed by using the conventional Cox model, an artificial survival benefit of metformin was detected (HR, 0.88; 95% CI, 0.77 to 1.01; P = .08), which suggested biased results from the conventional Cox analysis. CONCLUSION: Our findings did not suggest the benefit of metformin use after patients are diagnosed with PDAC. We highlight the importance of patient selection and appropriate statistical analytical methods when studying medication exposure and cancer survival.
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Adenocarcinoma/mortalidad , Carcinoma Ductal Pancreático/mortalidad , Metformina/uso terapéutico , Neoplasias Pancreáticas/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios RetrospectivosAsunto(s)
Biomarcadores de Tumor/genética , Carcinoma Ductal Pancreático/cirugía , Daño del ADN , Mutación , Pancreatectomía , Neoplasias Pancreáticas/cirugía , Reparación del ADN por Recombinación , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Humanos , Pancreatectomía/efectos adversos , Pancreatectomía/mortalidad , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare, clinically heterogeneous disease due to heritable mutations that lead to misfolding of a precursor protein and multisystem disease. This study sought to define the clinical characteristics, distribution of mutations and phenotypic presentation of patients presenting to our center with hereditary ATTR amyloidosis. METHODS: With institutional review board approval, the study retrospectively identified patients who had hereditary ATTR amyloidosis and presented to Mayo Clinic in Rochester, Minnesota, from 1 January 1970, to 29 January 2013. RESULTS: Of the 266 patients with the diagnosis of hereditary ATTR amyloidosis, a pathogenic mutation was identified in 206; the most common mutation was Thr60Ala (68 patients [25%]). Median age at diagnosis was 63.3 years; median survival after diagnosis was 56.8 months (10th-90th percentile, 16.0-297.9). On multivariate analysis, age at diagnosis (risk ratio, 15.65; p < 0.0001), Thr60Ala mutation (risk ratio, 1.52; p = 0.04), Val122Ile mutation (risk ratio, 2.83; p = 0.003), peripheral neuropathy (risk ratio, 1.69; p = 0.013) and weight loss (risk ratio, 1.81; p = 0.002) were risk factors for death. CONCLUSION: Our data characterize the features of hereditary ATTR amyloidosis in a large cohort, demonstrate the heterogeneity among mutations and support the need to better characterize the clinical progression of individual mutations.
Asunto(s)
Neuropatías Amiloides Familiares/genética , Prealbúmina/genética , Anciano , Amiloidosis Familiar/genética , Cardiomiopatías/genética , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Mutación/genéticaRESUMEN
Cholesterol embolization syndrome (CES) is a complication sometimes occurring after invasive endovascular procedures. CES is characterized by release of cholesterol crystals and particles from atheromatous plaques, which can occlude distal vessels and induce an inflammatory response, resulting in end-organ damage. We report the case of a 66-year-old man who presented with an acute ST-elevation myocardial infarction. An intra-aortic balloon pump was placed due to hemodynamic instability following percutaneous coronary intervention. Ten weeks after discharge, he presented with signs and symptoms of CES (e.g., livedo reticularis, acrocyanosis, acute renal failure), and a new left ventricular apical thrombus. Withdrawal of anticoagulation is often recommended in the setting of CES, on the presumption that anticoagulants favor plaque hemorrhage and subsequent cholesterol micro-embolization. Because of the potential disastrous consequences of an embolus, the patient was anticoagulated with warfarin concurrently with corticosteroids to suppress the inflammatory response to cholesterol crystals. His renal function continued to improve and was discharged without the need for dialysis. This case illustrates that anticoagulation therapy in CES is feasible and appears to be safe in patients with a coexisting urgent indication for anticoagulation.