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Neuroendocrine neoplasms are a diverse group of neoplasms that can occur in various areas throughout the body. Well-differentiated neuroendocrine tumors (NETs) most often arise in the gastrointestinal tract, termed gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Although GEP-NETs are still uncommon, their incidence and prevalence have been steadily increasing over the past decades. The primary treatment for GEP-NETs is surgery, which offers the best chance for a cure. However, because GEP-NETs are often slow-growing and do not cause symptoms until they have spread widely, curative surgery is not always an option. Significant advances have been made in systemic and locoregional treatment options in recent years, including peptide-receptor radionuclide therapy with α and ß emitters, somatostatin analogs, chemotherapy, and targeted molecular therapies.
Assuntos
Neoplasias Intestinais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Tumores Neuroendócrinos/terapia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/terapia , Neoplasias Gástricas/patologia , Neoplasias Intestinais/terapia , Neoplasias Intestinais/patologia , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Terapia de Alvo Molecular/métodosRESUMO
INTRODUCTION: Management of a clinical condition is patient centric. Interdisciplinary coordination plays an influential role in patient management. Pharmacology deals with the study of drugs. Clinical pharmacology deals with applied aspects of pharmacology in addition to clinical research. METHODOLOGY: We set up a survey to assess the perceptions of clinical pharmacologists (CPs) regarding their roles and about clinical pharmacology courses in India. The survey was administered via a Google questionnaire sent via LinkedIn, Email, or WhatsApp to 100 CP's working in India. RESULTS: Respondents to the questionnaire were working as CPs. They were either postgraduate in pharmacology (MD pharmacology (doctor of medicine in pharmacology) 60.2%) or had a super-specialization degree in clinical pharmacology (DM clinical pharmacology (doctorate in medicine in clinical pharmacology) (34.7%)) or other pharma postgraduates. They were working in pharmaceutical companies (41.8%), hospitals (26.5%), or academic institutions (30.6%). When the responses from the respondents were stratified by qualification or experience, they showed that most of the CPs felt that the CPs played a significant role in academia, pharmaceutical organizations, hospitals, and drug regulatory bodies. CONCLUSIONS: All the CPs opined that training during the postgraduation course was not sufficient to be qualified as CP. There was no consensus among the CPs on the benefit of existing certification courses in clinical research. However, they felt that the centres offering these courses should be accredited, and the curriculum should be uniform. Respondents opined that CPs' patient management role could be improved by collaborating with clinicians and organizing workshops and conferences.
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Farmacologia Clínica , Humanos , Currículo , Especialização , Inquéritos e Questionários , Indústria FarmacêuticaRESUMO
INTRODUCTION: Oxaliplatin is a platinum containing alkylating agent commonly used in the management of colorectal cancers. The most common dose-limiting toxicity of oxaliplatin is peripheral neuropathy, which can be severe enough to cause treatment discontinuation. We present a case of dysarthria and laryngopharyngeal dysesthesia (LPD) that developed during the first dose of oxaliplatin, which showed dose-dependent reduction in severity in subsequent cycles. CASE REPORT: A 52-year-old female patient with adenocarcinoma of rectum (pT4N2M0) was prescribed oxaliplatin (130â mg/m2) and capecitabine(2000mg/m2). She developed heaviness in the tongue, slurred speech, jaw pain, perioral paresthesia within 30â min after the end of 3â h infusion of oxaliplatin in the first cycle. The symptoms subsided without any sequelae in two days. However, in the subsequent cycles as the dose of the oxaliplatin was reduced, similar symptoms reappeared but were of reduced in severity. No dysesthesia symptoms were observed in the 4th cycle when the oxaliplatin was administered at 85â mg/m2. MANAGEMENT AND OUTCOME: As and when the patient developed symptoms - slurred speech, jaw pain during the first three cycles, she was managed with inj. Hydrocortisone (100â mg i.v.) and one ampoule of pheniramine (45â mg i.v.). DISCUSSION: Occurrence of laryngopharyngeal dysesthesia due to oxaliplatin does not warrant drug withdrawal, dose titration can be helpful, thereby preventing the drug withdrawal for the patient management.
Assuntos
Antineoplásicos , Neoplasias Colorretais , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Desoxicitidina , Disartria , Feminino , Fluoruracila , Humanos , Pessoa de Meia-Idade , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina/efeitos adversos , Dor/tratamento farmacológico , Parestesia/induzido quimicamente , Parestesia/tratamento farmacológico , FalaRESUMO
BACKGROUND: Adrenocortical carcinoma (ACC) commonly metastasizes to the lungs, and pulmonary metastasectomy (PM) is utilized due to limited systemic options. METHODS: All ACC patients with initially only lung metastases (LM) from a single institution constituted this observational case series. Kaplan-Meier and Cox proportional hazard analyses evaluated the association with potential prognostic factors and outcomes. Overall survival (OS) was calculated from the date of the PM or, in those patients who did not undergo surgery, from the development of LM. RESULTS: A total of 75 ACC patients over a 45-year period met the criteria; 52 underwent PM, and 23 did not. The patients undergoing PM had a median OS of 3.1 years (95% CI: 2.4, 4.7 years) with the 5- and 10-year OS being 35.5% and 32.8%, respectively. The total resected LM did not impact the OS nor the DFS. The patients who developed LM after 11 months from the initial ACC resection had an improved OS (4.2 years; 95% CI: 3.2, NR; p = 0.0096) compared to those developing metastases earlier (2.4 years; 95% CI: 1.6, 2.8). Patients who underwent PM within 11 months of adrenalectomy demonstrated a reduced OS (2.2 years; 95% CI: 1.0, 2.7) compared to those after 11 months (3.6 years, 95% CI: 2.6, NR; p = 0.0045). PM may provide benefit to those patients with LM at presentation (HR: 0.5; p = 0.2827), with the time to first PM as a time-varying covariate. CONCLUSIONS: PM appears to have a role in ACC patients. The number of nodules should not be an exclusion factor. Patients developing LM within a year of primary tumor resection may benefit from waiting before further surgeries, which may provide additional insight into who may benefit from PM.
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Immunotherapeutic targeting of cell surface proteins is an increasingly effective cancer therapy. However, given the limited number of current targets, the identification of new surface proteins, particularly those with biological importance, is critical. Here, we uncover delta-like non-canonical Notch ligand 1 (DLK1) as a cell surface protein with limited normal tissue expression and high expression in multiple refractory adult metastatic cancers including small cell lung cancer (SCLC) and adrenocortical carcinoma (ACC), a rare cancer with few effective therapies. In ACC, ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC), shows potent in vitro activity among established cell lines and a new cohort of patient-derived organoids as well as robust in vivo anti-tumor responses in cell line-derived and patient-derived xenografts. However, ADCT-701 efficacy is overall limited in ACC due to high expression and activity of the drug efflux protein ABCB1 (MDR1, P-glycoprotein). In contrast, ADCT-701 is extremely potent and induces complete responses in DLK1+ ACC and SCLC in vivo models with low or no ABCB1 expression. Genetic deletion of DLK1 in ACC dramatically downregulates ABCB1 and increases ADC payload and chemotherapy sensitivity through NOTCH1-mediated adrenocortical de-differentiation. Single cell RNA-seq of ACC metastatic tumors reveals significantly decreased adrenocortical differentiation in DLK low or negative cells compared to DLK1 positive cells. This works identifies DLK1 as a novel immunotherapeutic target that regulates tumor cell plasticity and chemoresistance in ACC. Our data support targeting DLK1 with an ADC in ACC and neuroendocrine neoplasms in an active first-in-human phase I clinical trial (NCT06041516).
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Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic options for ACC. An extensive drug screen was conducted to identify compounds with potential activity against ACC cell lines. We further investigated the mechanism of action of the identified compound, TAK-243, its synergistic effects with current ACC therapeutics, and its efficacy in ACC models including patient-derived organoids and mouse xenografts. TAK-243, a clinical ubiquitin-activating enzyme (UAE) inhibitor, showed potent activity in ACC cell lines. TAK-243 inhibited protein ubiquitination in ACC cells, leading to the accumulation of free ubiquitin, activation of the unfolded protein response, and induction of apoptosis. TAK-243 was found to be effluxed out of cells by MDR1, a drug efflux pump, and did not require Schlafen 11 (SLFN11) expression for its activity. Combination of TAK-243 with current ACC therapies (e.g., mitotane, etoposide, cisplatin) produced synergistic or additive effects. In addition, TAK-243 was highly synergistic with BCL2 inhibitors (Navitoclax and Venetoclax) in preclinical ACC models including patient-derived organoids. The tumor suppressive effects of TAK-243 and its synergistic effects with Venetoclax were further confirmed in a mouse xenograft model. These findings provide preclinical evidence to support the initiation of a clinical trial of TAK-243 in patients with advanced-stage ACC. TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors. SIGNIFICANCE: ACC is a rare endocrine cancer with poor prognosis and limited therapeutic options. We report that TAK-243 is active alone and in combination with currently used therapies and with BCL2 and mTOR inhibitors in ACC preclinical models. Our results suggest implementation of TAK-243 in clinical trials for patients with advanced and metastatic ACC.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Antineoplásicos , Compostos Bicíclicos Heterocíclicos com Pontes , Pirazóis , Pirimidinas , Sulfetos , Sulfonamidas , Humanos , Animais , Camundongos , Carcinoma Adrenocortical/tratamento farmacológico , Mitotano , Xenoenxertos , Enzimas Ativadoras de Ubiquitina/uso terapêutico , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Organoides , Proteínas Proto-Oncogênicas c-bcl-2/uso terapêutico , Proteínas Nucleares/uso terapêuticoRESUMO
Gastroenteropancreatic neuroendocrine neoplasms (NENs) are a heterogenous group of tumors that are incurable when metastatic, regardless of grade. The aim of this article is to understand tumor heterogeneity and grade progression as possible contributors to drug resistance in gastroentropancreatic neuroendocrine tumors (GEP-NETs). Heterogeneity has been observed in the genetic, pathological, and imaging features of these tumors at baseline. Diagnostic challenges related to tumor sampling and the potential for changes in grade over time further confound our ability to optimize therapy for patients. A better understanding of NEN biology and tumor heterogeneity at baseline and over time could lead to the development of new therapeutic avenues.
RESUMO
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal gland with an unfavorable prognosis. It is rare in the pediatric population, with an incidence of 0.2-0.3 patients per million in patients under 20 years old. It is primarily associated with Li-Fraumeni and Beckwith-Wiedemann tumor predisposition syndromes in children. The incidence of pediatric ACC is 10-15fold higher in southern Brazil due to a higher prevalence of TP53 mutation associated with Li-Fraumeni syndrome in that population. Current treatment protocols are derived from adult ACC and consist of surgery and/or chemotherapy with etoposide, doxorubicin, and cisplatin (EDP) with mitotane. Limited research has been reported on other treatment modalities for pediatric ACC, including mitotane, pembrolizumab, cabozantinib, and chimeric antigen receptor autologous cell (CAR-T) therapy.
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Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Síndrome de Li-Fraumeni , Adulto , Humanos , Criança , Adulto Jovem , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/terapia , Carcinoma Adrenocortical/genética , Mitotano/uso terapêutico , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/terapia , Neoplasias do Córtex Suprarrenal/patologia , Síndrome de Li-Fraumeni/genéticaRESUMO
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors that arise from chromaffin cells. PHEOs arise from the adrenal medulla, whereas PGLs arise from the neural crest localized outside the adrenal gland. Approximately 40% of all cases of PPGLs (pheochromocytomas/paragangliomas) are associated with germline mutations and 30-40% display somatic driver mutations. The mutations associated with PPGLs can be classified into three groups. The pseudohypoxic group or cluster I includes the following genes: SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, IDH1/2, MHD2, EGLN1/2 and HIF2/EPAS; the kinase group or cluster II includes RET, NF1, TMEM127, MAX and HRAS; and the Wnt signaling group or cluster III includes CSDE1 and MAML3. Underlying mutations can help understand the clinical presentation, overall prognosis and surveillance follow-up. Here we are discussing the new genetic insights of PPGLs.
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Epigenetic regulation of gene expression is essential in many biological processes, and its deregulation contributes to pathology including tumor formation. We used an image-based cell assay that measures the induction of a silenced GFP-estrogen receptor reporter to identify novel classes of small molecules involved in the regulation of gene expression. Using this Locus Derepression assay, we queried 283,122 compounds by quantitative high-throughput screening evaluating compounds at multiple concentrations. After confirmation and independent validation, the Locus Derepression assay identified 19 small molecules as new actives that induce the GFP message over 2-fold. Viability assays demonstrated that 17 of these actives have anti-proliferative activity, and two of them show selectivity for cancer versus patient-matched normal cells and cause unique changes in gene expression patterns in cancer cells by altering histone marks. Hence, these compounds represent chemical tools for understanding the molecular mechanisms of epigenetic control of transcription and for modulating cell growth pathways.
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Antineoplásicos/farmacologia , Transcrição Gênica/efeitos dos fármacos , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
The pharmacological inhibition of general transcriptional regulators has the potential to block growth through targeting multiple tumorigenic signalling pathways simultaneously. Here, using an innovative cell-based screen, we identify a structurally unique small molecule (named JIB-04) that specifically inhibits the activity of the Jumonji family of histone demethylases in vitro, in cancer cells, and in tumours in vivo. Unlike known inhibitors, JIB-04 is not a competitive inhibitor of α-ketoglutarate. In cancer, but not in patient-matched normal cells, JIB-04 alters a subset of transcriptional pathways and blocks viability. In mice, JIB-04 reduces tumour burden and prolongs survival. Importantly, we find that patients with breast tumours that overexpress Jumonji demethylases have significantly lower survival. Thus, JIB-04, a novel inhibitor of Jumonji demethylases in vitro and in vivo, constitutes a unique potential therapeutic and research tool against cancer, and validates the use of unbiased cellular screens to discover chemical modulators with disease relevance.
Assuntos
Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Hidrazonas/farmacologia , Hidrazonas/uso terapêutico , Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Aminopiridinas/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Histonas/metabolismo , Humanos , Hidrazonas/química , Concentração Inibidora 50 , Isomerismo , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Lisina/metabolismo , Metilação/efeitos dos fármacos , Camundongos , Neoplasias/genética , Bibliotecas de Moléculas Pequenas/química , Análise de Sobrevida , Transcrição Gênica/efeitos dos fármacosRESUMO
Studies involving two methods for measuring a continuous response are regularly conducted in health sciences to evaluate agreement of a method with itself and agreement between methods. Notwithstanding their wide usage, the design of such studies, in particular, the sample size determination, has not been addressed in the literature when the goal is the simultaneous evaluation of intra- and inter-method agreement. We fill this need by developing a simulation-based Bayesian methodology for determining sample sizes in a hierarchical model framework. Unlike a frequentist approach, it takes into account uncertainty in parameter estimates. This methodology can be used with any scalar measure of agreement available in the literature. We demonstrate this for four currently used measures. The proposed method is applied to an ongoing proteomics project, where we use pilot data to determine the number of individuals and the number of replications needed to evaluate the agreement between two methods for measuring protein ratios. We also apply our method to determine the sample size for an experiment involving measurement of blood pressure.