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We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response. SIGNIFICANCE: WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-altered solid tumors despite compelling preclinical data indicating a synthetic lethal effect, which did not translate into robust tumor regression. Loss of the H3K36me3 trimethylation mark caused by SETD2-deficiency was confirmed in the majority of evaluable tumors. A subset of patients derived clinical benefit as manifested by minor tumor regressions and prolonged SD.
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Proteínas de Ciclo Celular , Histona-Lisina N-Metiltransferase , Proteínas Tirosina Quinases , Pirazóis , Humanos , Pessoa de Meia-Idade , Histona-Lisina N-Metiltransferase/genética , Masculino , Idoso , Feminino , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Pirimidinonas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/administração & dosagem , MutaçãoRESUMO
PURPOSE: Combining poly ADP-ribose polymerase (PARP) and topoisomerase I inhibitors has demonstrated synergistic effects in in vivo models. This phase I trial evaluated rucaparib and irinotecan in metastatic solid tumors with homologous recombination deficiency. METHODS: This study enrolled patients in three cohorts to determine the tolerability and preliminary efficacy of (1) rucaparib 400 mg PO twice a day (days 1-7, 15-21) and irinotecan 65 mg/m2 intravenously once every 2 weeks; (2) rucaparib 400 mg PO twice a day (D1-7, 15-21) and irinotecan 100 mg/m2 once every 2 weeks; and (3) rucaparib 400 mg per os twice a day (D1-7) and irinotecan 100 mg/m2 once every 3 weeks. RESULTS: Twenty patients were enrolled: 95% with previous platinum, 40% with previous irinotecan, and 20% with previous PARP inhibitor. The maximally tolerated was determined as rucaparib 400 mg twice a day days 1-7 and irinotecan 100 mg/m2 once every 3 weeks. Four dose-limiting toxicities (all grade 3-4 neutropenia) occurred during dose escalation with only neutropenia as other grade 3-4 toxicities (25%; grade 3 [n = 3], grade 4 [n = 2]). Treatment-related grade 1-2 adverse events included neutropenia (45%), diarrhea (45%), nausea (40%), and fatigue (30%). Of 17 patients with evaluable disease, six patients (35%) derived clinical benefit (n = 2 with PR, n = 4 with stable disease for over 6 months). Three patients remained on study >1 year: two with ATM mutations (small bowel carcinoma and pancreatic neuroendocrine tumor) and one patient with a PALB2 mutation (primary peritoneal cancer). CONCLUSION: Pulse dosing of rucaparib and once every 3 weeks irinotecan was well tolerated for up to 18 months with durable responses in BRCA-, PALB2-, and ATM-mutated cancers despite progression on previous platinum.
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Indóis , Irinotecano , Neoplasias , Humanos , Pessoa de Meia-Idade , Feminino , Masculino , Irinotecano/uso terapêutico , Irinotecano/administração & dosagem , Indóis/uso terapêutico , Indóis/administração & dosagem , Indóis/efeitos adversos , Idoso , Adulto , Neoplasias/tratamento farmacológico , Neoplasias/genética , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA2/genética , Proteína BRCA1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Recombinação Homóloga , Metástase NeoplásicaRESUMO
BACKGROUND: Ileal neuroendocrine tumors (i-NETs) are characterized by their multifocality and bulky mesenteric mass. Having shown that minimally invasive surgery (MIS) utilizing a hand-access port device has favorable short-term outcomes and achieves the goals of surgery for i-NETs, we sought to analyze long-term survival outcomes of MIS. METHODS: One hundred and sixty-eight patients who underwent resection of primary i-NETs at a single institution between January 2007 and February 2023 were retrospectively studied. Patients were categorized into the MIS or open surgery cohorts on an intention-to-treat basis. Open surgery was selected mainly based on the need for hepatectomy or bulky mesenteric mass resection. Overall survival was analyzed using log-rank tests with propensity score matching (PSM) and Cox proportional hazards regression. PSM was performed to reduce standardized mean differences of the variables to <0.2. RESULTS: Overall, 129 (77%) patients underwent MIS and 39 (23%) underwent open surgery. Twenty-seven MIS patients were converted to an open procedure. The median follow-up time was 49 months (interquartile range 23-87 months). In the PSM cohorts, overall survival did not differ significantly between the MIS and open surgery cohorts {median 99 months (95% confidence interval [CI] 91-not applicable [NA]) vs. 103 months (95% CI 86-NA), p = 0.77; hazard ratio 0.87 (95% CI 0.33-2.2), p = 0.77}. CONCLUSIONS: MIS is an alternative to open surgery for i-NETs, achieving similar short- and long-term oncological outcomes. Bulky mesenteric mass and a plan for concurrent liver resection are potential criteria for open surgery.
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Neoplasias do Íleo , Procedimentos Cirúrgicos Minimamente Invasivos , Tumores Neuroendócrinos , Humanos , Masculino , Feminino , Tumores Neuroendócrinos/cirurgia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/mortalidade , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Seguimentos , Neoplasias do Íleo/cirurgia , Neoplasias do Íleo/mortalidade , Neoplasias do Íleo/patologia , Procedimentos Cirúrgicos Minimamente Invasivos/mortalidade , Idoso , Prognóstico , Hepatectomia/mortalidade , Hepatectomia/métodos , AdultoRESUMO
Posttreatment imaging of γ-emissions after peptide receptor radionuclide therapy (PRRT) can be used to perform quantitative dosimetry as well as assessment response using qualitative measures. We aimed to assess the impact of qualitative posttreatment imaging on the management of patients undergoing PRRT. Methods: In this retrospective study, we evaluated 100 patients with advanced well-differentiated neuroendocrine tumors undergoing PRRT, who had posttreatment SPECT/CT imaging at 24 h. First, we evaluated the qualitative assessment of response at each cycle. Then using a chart review, we determined the impact on management from the posttreatment imaging. The changes in management were categorized as major or minor, and the cycles at which these changes occurred were noted. Additionally, tumor grade was also evaluated. Results: Of the 100 sequential patients reviewed, most (80% after cycle 2, 79% after cycle 3, and 73% after cycle 4) showed qualitatively stable disease during PRRT. Management changes were observed in 27% (n = 27) of patients; 78% of those (n = 21) were major, and 30% (n = 9) were minor. Most treatment changes occurred after cycle 2 (33% major, 67% minor) and cycle 3 (62% major, 33% minor). Higher tumor grade correlated with increased rate of changes in management (P = 0.006). Conclusion: In this retrospective study, qualitative analysis of posttreatment SPECT/CT imaging informed changes in management in 27% of patients. Patients with higher-grade tumors had a higher rate of change in management, and most of the management changes occurred after cycles 2 and 3. Incorporating posttreatment imaging into standard PRRT workflows could potentially enhance patient management.
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Tumores Neuroendócrinos , Octreotida , Humanos , Octreotida/uso terapêutico , Estudos Retrospectivos , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/radioterapia , Tumores Neuroendócrinos/patologia , Radioisótopos , Receptores de PeptídeosRESUMO
INTRODUCTION: The primary objective of this study was to determine whether workplace culture in academic oncology differed by gender, during the COVID-19 pandemic. MATERIALS AND METHODS: We used the Culture Conducive to Women's Academic Success (CCWAS), a validated survey tool, to investigate the academic climate at an NCI-designated Cancer Center. We adapted the CCWAS to be applicable to people of all genders. The full membership of the Cancer Center was surveyed (total faculty = 429). The questions in each of 4 CCWAS domains (equal access to opportunities, work-life balance, freedom from gender bias, and leadership support) were scored using a 5-point Likert scale. Median score and interquartile ranges for each domain were calculated. RESULTS: A total of 168 respondents (men = 58, women = 106, n = 4 not disclosed) submitted survey responses. The response rate was 39% overall and 70% among women faculty. We found significant differences in perceptions of workplace culture by gender, both in responses to individual questions and in the overall score in the following domains: equal access to opportunities, work-life balance, and leader support, and in the total score for the CCWAS. CONCLUSIONS: Our survey is the first of its kind completed during the COVID-19 pandemic at an NCI-designated Cancer Center, in which myriad factors contributed to burnout and workplace challenges. These results point to specific issues that detract from the success of women pursuing careers in academic oncology. Identifying these issues can be used to design and implement solutions to improve workforce culture, mitigate gender bias, and retain faculty.
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Sucesso Acadêmico , COVID-19 , Neoplasias , Humanos , Feminino , Masculino , Sexismo , Pandemias , Docentes de Medicina , COVID-19/epidemiologia , Neoplasias/epidemiologiaRESUMO
Lung neuroendocrine tumors (NETs) have few known predictors of survival. We investigated associations of sociodemographic, clinicopathologic, and treatment factors with overall survival (OS) and lung cancer-specific survival (LCSS) for incident lung NET cases (typical or atypical histology) in the California Cancer Registry (CCR) from 1992 to 2019. OS was estimated with the Kaplan-Meier method and compared by sociodemographic and disease factors univariately with the log-rank test. We used sequential Cox proportional hazards regression for multivariable OS analysis. LCSS was estimated using Fine-Gray competing risks regression. There were 6038 lung NET diagnoses (5569 typical, 469 atypical carcinoid); most were women (70%) and non-Hispanic White (73%). In our multivariable model, sociodemographic factors were independently associated with OS, with better survival for women (hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.57-0.68, P < 0.001), married (HR 0.76, 95% CI 0.70-0.84, P < 0.001), and residents of high socioeconomic status (SES) neighborhoods (HRQ5vsQ1 0.73, 95% CI 0.62-0.85, P < 0.001). Compared to cases with private insurance, OS was worse for cases with Medicare (HR 1.24, 95% CI 1.10-1.40, P < 0.001) or Medicaid/other public insurance (HR 1.45, 95% CI 1.24-1.68, P < 0.001). In our univariate model, non-Hispanic Black Californians had worse OS than other racial/ethnic groups, but differences attenuated after adjusting for stage at diagnosis. In our LCSS models, we found similar associations between sex and marital status on survival, but no differences in outcomes by SES or insurance. By race/ethnicity, American Indian cases had worse LCSS. In summary, beyond disease-related and treatment variables, sociodemographic factors were independently associated with survival in lung NETs.
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Carcinoma Neuroendócrino , Neoplasias Pulmonares , Tumores Neuroendócrinos , Idoso , Humanos , Feminino , Estados Unidos , Masculino , Tumores Neuroendócrinos/epidemiologia , Fatores Sociodemográficos , Medicare , Neoplasias Pulmonares/patologia , California/epidemiologia , PulmãoRESUMO
PURPOSE: To develop recommendations for systemic therapy for well-differentiated grade 1 (G1) to grade 3 (G3) metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS: ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS: Eight randomized controlled trials met the inclusion criteria for the systematic review. RECOMMENDATIONS: Somatostatin analogs (SSAs) are recommended as first-line systemic therapy for most patients with G1-grade 2 (G2) metastatic well-differentiated GI-NETs. Observation is an option for patients with low-volume or slow-growing disease without symptoms. After progression on SSAs, peptide receptor radionuclide therapy (PRRT) is recommended as systematic therapy for patients with somatostatin receptor (SSTR)-positive tumors. Everolimus is an alternative second-line therapy, particularly in nonfunctioning NETs and patients with SSTR-negative tumors. SSAs are standard first-line therapy for SSTR-positive pancreatic (pan)NETs. Rarely, observation may be appropriate for asymptomatic patients until progression. Second-line systemic options for panNETs include PRRT (for SSTR-positive tumors), cytotoxic chemotherapy, everolimus, or sunitinib. For SSTR-negative tumors, first-line therapy options are chemotherapy, everolimus, or sunitinib. There are insufficient data to recommend particular sequencing of therapies. Patients with G1-G2 high-volume disease, relatively high Ki-67 index, and/or symptoms related to tumor growth may benefit from early cytotoxic chemotherapy. For G3 GEP-NETs, systemic options for G1-G2 may be considered, although cytotoxic chemotherapy is likely the most effective option for patients with tumor-related symptoms, and SSAs are relatively ineffective. Qualifying statements are provided to assist with treatment choice. Multidisciplinary team management is recommended, along with shared decision making with patients, incorporating their values and preferences, potential benefits and harms, and other characteristics and circumstances, such as comorbidities, performance status, geographic location, and access to care.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.
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Neoplasias Intestinais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Guias de Prática Clínica como Assunto , Neoplasias Gástricas , Humanos , Everolimo/uso terapêutico , Neoplasias Intestinais/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Somatostatina , Neoplasias Gástricas/tratamento farmacológico , SunitinibeRESUMO
Adrenocortical cancer is an aggressive endocrine malignancy with an incidence of 0.72 to 1.02 per million people/year, and a very poor prognosis with a five-year survival rate of 22%. As an orphan disease, clinical data are scarce, meaning that drug development and mechanistic research depend especially on preclinical models. While a single human ACC cell line was available for the last three decades, over the last five years, many new in vitro and in vivo preclinical models have been generated. Herein, we review both in vitro (cell lines, spheroids, and organoids) and in vivo (xenograft and genetically engineered mouse) models. Striking leaps have been made in terms of the preclinical models of ACC, and there are now several modern models available publicly and in repositories for research in this area.
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High-grade neuroendocrine neoplasms are a rare disease entity and account for approximately 10% of all neuroendocrine neoplasms. Because of their rarity, there is an overall lack of prospectively collected data available to advise practitioners as to how best to manage these patients. As a result, best practices are largely based on expert opinion. Recently, a distinction was made between well-differentiated high-grade (G3) neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas, and with this, pathologic details, appropriate imaging practices and treatment have become more complex. In an effort to provide practitioners with the best guidance for the management of patients with high-grade neuroendocrine neoplasms of the gastrointestinal tract, pancreas, and gynecologic system, the North American Neuroendocrine Tumor Society convened a panel of experts to develop a set of recommendations and a treatment algorithm that may be used by practitioners for the care of these patients. Here, we provide consensus recommendations from the panel on pathology, imaging practices, management of localized disease, management of metastatic disease and surveillance and draw key distinctions as to the approach that should be utilized in patients with well-differentiated G3 neuroendocrine tumors vs poorly differentiated neuroendocrine carcinomas.
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Carcinoma Neuroendócrino , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Feminino , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/terapia , Tumores Neuroendócrinos/patologia , Consenso , Gradação de Tumores , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/terapia , Carcinoma Neuroendócrino/patologia , América do Norte , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patologiaRESUMO
BACKGROUND: To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarker-unselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation. METHODS: Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy. PRIMARY ENDPOINT: objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated. RESULTS: Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2-33.9%), median PFS 1.8 months (95% CI, 1.7-21.4), median OS 7.8 months (95% CI, 3.1-not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0-22.8%), median PFS 2.0 months (95% CI, 1.9-3.4), median OS 4.8 months (95% CI, 4.1-8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours. DISCUSSION: Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03136055.
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Carcinoma Neuroendócrino , Tumores Neuroendócrinos , Humanos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Tumores Neuroendócrinos/tratamento farmacológico , Intervalo Livre de ProgressãoRESUMO
Refined risk stratification for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has the potential to improve comparisons of study populations across clinical trials and facilitate drug development. Tumor growth rate (TGR) is a radiological metric with demonstrated prognostic value in well differentiated grade 1 and 2 (G1-2) GEP-NETs, but little is known about TGR in G3 NETs. In this retrospective study of 48 patients with advanced G1-3 GEP-NET, we calculated baseline TGR (TGR0 ) from radiological images of metastases acquired prior to first-line therapy and evaluated its association with disease characteristics and outcomes. The median pretreatment Ki67 proliferation index for G1-3 tumors combined was 5% (range = 0.1%-52%) and median TGR0 was 4.8%/month (m) (range = 0%-45.9%/m). TGR0 correlated with pretreatment Ki67 across G1-3 pooled and within G3 GEP-NET. Patients with higher TGR0 (>11.7%/m) tumors, which were primarily G3 pancreatic NETs, exhibited decreased time to first therapy (median, 2.2 vs. 5.3 months; p = .03) and shorter overall survival (median, 4.1 years vs. not reached; p = .003). Independent of therapies given, higher TGR0 GEP-NETs experienced a greater incidence of Ki67 increase (100 vs. 50%; p = .02) and greater magnitude of Ki67 change (median, 14.0 vs. 0.1%; p = .04) upon serial biopsy. Importantly, TGR0 , but not grade, predicted for future Ki67 increase in this series. Given the heterogeneity of well differentiated GEP-NETs, future clinical trials may benefit from stratification for TGR0 , particularly in G1-2 tumors, in which TGR0 does not correlate with Ki67. TGR0 has the potential to noninvasively identify patients with previously undiagnosed grade progression and those in whom more or less frequent monitoring may be appropriate. Additional research is needed to determine the prognostic and predictive value of TGR0 in larger and more homogeneously treated cohorts, and to ascertain if post-treatment TGR has value in previously treated patients starting a new line of therapy.
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Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Tumores Neuroendócrinos/patologia , Antígeno Ki-67 , Estudos RetrospectivosRESUMO
Since its approval in 2018 by the US Food and Drug Administration, peptide receptor radionuclide therapy (PRRT) has become a mainstay in the treatment of neuroendocrine tumors. Lutetium-177-DOTATATE, the only approved agent, is indicated for the treatment of gastroenteropancreatic-neuroendocrine tumors. Although patient selection appears straightforward with somatostatin receptor-positron emission tomography, there is considerable complexity when deciding which patients to treat and when to start PRRT. Herein, we review the many factors that affect patient selection, focusing on the optimal patients to treat. Although significant effort has been expended to determine which patients benefit the most from PRRT, a validated predictive biomarker remains elusive. Although PRRT has been used for more than 2 decades in Europe and standards of care exist for safe treatment, there remain numerous questions regarding when PRRT should be used relative to other treatments. It is important to remember that multidisciplinary discussions are essential. Currently, there are a number of ongoing studies looking to assess the efficacy of PRRT compared with other treatment options and to optimize treatment through combination therapy, different dosing strategies, or use of different radionuclides and radioligands.
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Neoplasias Intestinais , Tumores Neuroendócrinos , Compostos Organometálicos , Humanos , Neoplasias Intestinais/radioterapia , Tumores Neuroendócrinos/radioterapia , Octreotida/uso terapêutico , Compostos Organometálicos/uso terapêutico , Tomografia por Emissão de Pósitrons , Radioisótopos/uso terapêutico , Cintilografia , Receptores de PeptídeosRESUMO
Circulating tumor cell (CTC) clusters are present in cancer patients with severe metastasis, resulting in poor clinical outcomes. However, CTC clusters have not been studied as extensively as single CTCs, and the clinical utility of CTC clusters remains largely unknown. In this study, we aim sought to explore the feasibility of NanoVelcro Chips to simultaneously detect both single CTCs and CTC clusters with negligible perturbation to their intrinsic properties in neuroendocrine tumors (NETs). We discovered frequent CTC clusters in patients with advanced NETs and examined their potential roles, together with single NET CTCs, as novel biomarkers of patient response following peptide receptor radionuclide therapy (PRRT). We observed dynamic changes in both total NET CTCs and NET CTC cluster counts in NET patients undergoing PRRT which correlated with clinical outcome. These preliminary findings suggest that CTC clusters, along with single CTCs, offer a potential non-invasive option to monitor the treatment response in NET patients undergoing PRRT.
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Técnicas Biossensoriais , Células Neoplásicas Circulantes , Tumores Neuroendócrinos , Biomarcadores Tumorais , Humanos , Metástase Neoplásica , Células Neoplásicas Circulantes/patologiaRESUMO
The PI3K pathway may be a potential mechanism to overcome cisplatin resistance. We conducted a phase Ib trial of alpelisib and cisplatin for patients with solid tumor malignancies with planned dose expansion in HPV-associated tumors. The primary objective was to determine the MTD and recommended phase II dose. Two different weekly doses of cisplatin (30 and 35 mg/m2) were evaluated with escalating doses of alpelisib, administered daily during a 21-day treatment cycle. Twenty-three patients were enrolled: 91% received >3 prior regimens with median of 4 (range 1-10), and 78% progressed on prior platinum. The MTD was alpelisib 250 mg daily with weekly cisplatin 30 mg/m2. There were 3 DLTs: all grade 4 hyperglycemia. Frequent treatment-related adverse events of any grade included fatigue (52%), diarrhea (39%), nausea (38%), hyperglycemia (30%), anemia (22%), and nephropathy (17%). Hyperglycemia was linked to baseline hemoglobin A1C, but not body mass index. Twelve patients discontinued treatment for toxicity (n = 9 during cycle 1) and 11 discontinued for progression. Of 14 evaluable patients who received at least one treatment cycle, 4 (29%) patients demonstrated partial response, and 7 had stable disease for a disease control rate of 79%. The median PFS measured 4.3 months (95% CI, 1.6-4.5). No difference in PFS was observed between PIK3CA-mutated and wild-type tumors. While the combination of alpelisib and cisplatin demonstrated preliminary evidence of activity despite platinum resistance, toxicities hindered prolonged treatment. Prospective studies are planned using carboplatin and alpelisib to improve toxicity and tolerability. Significance: The PI3K inhibitor alpelisib has limited activity alone, but there is interest in combinations in platinum-resistant tumors. In this phase Ib study of alpelisib with cisplatin, the objective response rate measured 29% but adverse events limited dose intensity. These promising results provide rationale for studying combinations with better tolerated platinum agents.
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Cisplatino , Neoplasias , Humanos , Cisplatino/efeitos adversos , Fosfatidilinositol 3-Quinases/metabolismo , Estudos Prospectivos , Neoplasias/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 QuinaseRESUMO
BACKGROUND: /Objectives: Although the presence of lymph node metastasis (LNM) defines malignant potential, preoperative prediction of LNM has not been established for non-functional pancreatic neuroendocrine neoplasm (NF-PNEN). We sought to develop a prediction system using only preoperatively available factors that would stratify the risk of LNM for NF-PNEN. METHODS: We retrospectively reviewed patients who underwent R0/1 resection of NF-PNEN at Kyoto University (2007-2019) and the University of California, San Francisco (2010-2019). Risk stratification of LNM was developed using preoperative factors by the logistic regression analysis. Long-term outcomes were compared across the risk groups. RESULTS: A total of 131 patients were included in this study. Lymph nodes were pathologically examined in 116 patients, 23 (20%) of whom had LNM. Radiological tumor size [1.5-3.5 cm (odds ratio: 13.5, 95% confidence interval: 1.77-398) and >3.5 cm (72.4, 9.06-2257) against ≤1.5 cm], <50% cystic component (8.46 × 10^6, 1.68 × 10^106-), and dilatation of main pancreatic duct ≥5 mm (31.2, 3.94-702) were independently associated with LNM. When patients were classified as the low-risk (43 patients), intermediate-risk (44 patients), and high-risk groups (29 patients), proportions of LNM differed significantly across the groups (0%, 14%, and 59%, respectively). Recurrence-free survival (RFS) of the low- and intermediate-risk groups were significantly better than that of the high-risk group (5-year RFS rates of 92.2%, 85.4%, and 47.1%, respectively). CONCLUSIONS: The prediction system using preoperative radiological factors stratifies the risk of LNM for NF-PNEN. This stratification helps to predict malignant potential and determine the surgical procedure and necessity of regional lymphadenectomy.
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Excisão de Linfonodo , Linfonodos/patologia , Metástase Linfática/patologia , Neoplasias Pancreáticas/patologia , Idoso , California , Feminino , Humanos , Japão , Linfonodos/cirurgia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Pancreáticas/cirurgia , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de RiscoRESUMO
OBJECTIVE: To illustrate the applications of various imaging tools including conventional MDCT, MRI including DWI, CT & MRI radiomics, FDG & DOTATATE PET-CT for diagnosis, staging, grading, prognostication, treatment planning and assessing treatment response in cases of pancreatic neuroendocrine neoplasms (PNENs). BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) are very diverse clinically & biologically. Their treatment and prognosis depend on staging and primary site, as well as histological grading, the importance of which is also reflected in the recently updated WHO classification of GEP NENs. Grade 3 poorly differentiated neuroendocrine carcinomas (NECs) are aggressive & nearly always advanced at diagnosis with poor prognosis; whereas Grades-1 and 2 well-differentiated neuroendocrine tumors (NETs) can be quite indolent. Grade 3 well-differentiated NETs represent a new category of neoplasm with an intermediate prognosis. Importantly, the evidence suggest grade heterogeneity can occur within a given tumor and even grade progression can occur over time. Emerging evidence suggests that several non-invasive qualitative and quantitative imaging features on CT, dual-energy CT (DECT), MRI, PET and somatostatin receptor imaging with new tracers, as well as texture analysis, may be useful to grade, prognosticate, and accurately stage primary NENs. Imaging features may also help to inform choice of treatment and follow these neoplasms post-treatment. CONCLUSION: GEP NENs treatment and prognosis depend on the stage as well as histological grade of the tumor. Traditional ways of imaging evaluation for diagnosis and staging does not yet yield sufficient information to replace operative and histological evaluation. Recognition of important qualitative imaging features together with quantitative features and advanced imaging tools including functional imaging with DWI MRI, DOTATATE PET/CT, texture analysis with radiomics and radiogenomic features appear promising for more accurate staging, tumor risk stratification, guiding management and assessing treatment response.
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Neoplasias Intestinais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Radioisótopos de Gálio , Humanos , Neoplasias Intestinais/patologia , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Cintilografia , Compostos Radiofarmacêuticos , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Grade 3 gastroenteropancreatic neuroendocrine neoplasms (G3 GEPNENs) are often aggressive, and the optimal treatment is unclear for this subgroup of neuroendocrine neoplasms (NENs). Temozolomide (TEM)-based regimens have been increasingly used to treat grade 1-2 NENs, but their efficacy in G3 NENs remains undetermined. We aimed to assess the clinical efficacy of TEM-containing regimens in advanced grade 3 GEPNENs. MATERIALS AND METHODS: A multicenter retrospective review (2008-2018) of patients with metastatic/unresectable G3 GEPNENs who received a TEM-containing regimen was undertaken within a North American partnership to pool data. The primary endpoint was time to treatment failure (TTF). Radiologic response was extracted from local reports. RESULTS: One hundred and thirty patients in six high-volume NEN centers were included (median age 55, 64% male, 18% functional, 67% pancreatic NEN). Forty-nine percent were well-differentiated, 35% poorly differentiated, and 15% unknown based on local pathology reports. The regimen used was capecitabine and temozolomide (CAPTEM) in 92% and TEM alone in 8%. Radiological response by local assessment was seen in 36% of patients. Median TTF was 3.6 months and median overall survival (OS) 19.2 months. Six percent of patients required discontinuation of therapy due to adverse events. TTF was longer in first-line treatment (7.8 months vs. 2.9 months; hazard ratio, 1.62; 95% confidence interval, 1.11-2.36; p = .015) and in patients with pancreatic NENs (panNENs) compared with gastrointestinal NENs (5.8 months vs 1.8 months; p = .04). The overall response rate was higher in the first-line setting (51% vs 29%; p = .02) and in panNEN (41% vs 23%; p = .04). CONCLUSION: This is the largest TEM treatment series in G3 NEN, involving collaboration of several major North American NEN centers as a partnership. Thirty-six percent of patients showed some degree of radiographic response, and treatment was generally well tolerated, although the median duration of response was short. Response rates and time to treatment failure were superior in the first-line setting. CAPTEM should be considered a viable treatment option in this setting. Further randomized trials are warranted. IMPLICATIONS FOR PRACTICE: Neuroendocrine neoplasms (NENs) are heterogeneous, and optimal treatment for aggressive grade 3 (G3) NENs remains undetermined. The capecitabine and temozolomide (CAPTEM) regimen has been used in low-grade pancreas NENs but there are few data for its safety and efficacy in the G3 setting. This article reports on the efficacy of temozolomide-containing regimens, particularly CAPTEM, in management of G3 NENs. The good tolerance and response rate show that CAPTEM should be considered a viable regimen in treatment of G3 NENs pending confirmatory prospective studies.
Assuntos
Neoplasias , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Temozolomida/uso terapêuticoRESUMO
BACKGROUND: Neuroendocrine neoplasms (NENs) comprise a rare and heterogenous group of cancers, for which the role of radiation therapy continues to evolve. The purpose of this study is to analyze oncologic outcomes after the use of high-dose radiation in management of NENs at a tertiary hospital. MATERIALS AND METHODS: We performed a retrospective review of patients who received high-dose radiation with intent to cure or provide durable local control (defined as biologically effective dose (BED) ≥40, α/ß = 10) for a localized or metastatic NEN from 2006 to 2019. Evaluation of disease status after radiation was performed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria when possible. Patients were grouped by differentiation (well-differentiated (WD) or poorly-differentiated (PD)) and stage (localized/locally advanced disease (L) or metastatic (M)) in analysis of probabilities of progression after radiation. RESULTS: 45 patients completed a radiation course with BED ≥40 for a NEN (median BED 72). With a median follow-up of 24 months after radiation, the 2-year actuarial rates of local relapse-free survival, new metastasis-free survival, progression-free survival, and overall survival after radiation were 98%, 45%, 41%, and 69%, respectively. 25 patients (56%) developed new metastases after completion of radiation, including 33% (n = 3) of patients with WD-L disease, 44% (n = 8) of WD-M, 77% (n = 10) of PD-L, and 80% (n = 4) of PD-M, with progressively shorter median times to progression (26, 9, 8, and 3 months, respectively; p = 0.093). Of the 25 patients evaluable by RECIST, 68% (n = 17) achieved either a complete or partial best response in the irradiated lesion. CONCLUSIONS: These data suggest that focal, high-dose radiation has a role in the management of selected patients with NENs. Local failure is rare in patients with both well-differentiated and poorly-differentiated disease, although the predominant pattern of failure remains development of new metastases.
Assuntos
Recidiva Local de Neoplasia/radioterapia , Tumores Neuroendócrinos/radioterapia , Adulto , Idoso , Relação Dose-Resposta à Radiação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: Current National Comprehensive Cancer Network guidelines for gastroenteropancreatic neuroendocrine tumors (GEPNETs) recommend complete (R0) surgical resection of the primary tumor and metastases, if feasible. However, large multicenter studies of recurrence patterns of GEPNETs after resection have not been performed. METHODS: Patients 18 years or older who presented to 7 participating National Comprehensive Cancer Network institutions between 2004 and 2008 with a new diagnosis of a small bowel, pancreas, or colon/rectum neuroendocrine tumor (NET) and underwent R0 resection of the primary tumor, and synchronous metastases, if present, were included in this analysis. Descriptive statistics and Kaplan-Meier estimates were used to calculate recurrence rates and time-associated end points, respectively. RESULTS: Of 294 patients with GEPNETs, 50% were male, 88% were White, and 99% had Eastern Cooperative Oncology Group performance status 0 to 1. The median age was 55 years (range, 20-90). The median follow-up time from R0 resection was 62.1 months. Recurrence rates were 18% in small bowel NETs (n = 110), 26% in pancreatic NETs (n = 141), and 10% in colon/rectum NETs (n = 50). The frequency of surveillance imaging was highly variable. CONCLUSIONS: R0 resection was associated with variable risk of recurrence across subtypes. Further research to inform refinement of guidelines for the appropriate duration of surveillance after R0 resection is needed.