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1.
Immunotherapy ; 14(7): 505-510, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35380054

RESUMO

Immune checkpoint inhibitors (ICIs) are approved for the treatment of head and neck carcinoma. They have significantly improved survival in these patients but may cause immune-related adverse events (irAEs), some of which may be serious. The report presents a rare case of a neurologic adverse event associated with programmed death-1 inhibitor monotherapy. Neurologic irAEs (NirAEs) can occur in various and atypical forms, be potentially disabling and occur at various times during and after treatment. Prompt identification and drug withdrawal are essential to improve outcomes. A high dose of systemic corticosteroid has been recommended for the management of NirAEs, although optimal immunomodulatory treatment is still debated.


Current recommendations for head and neck squamous cell carcinoma treatments have been significantly modified after the introduction of immunotherapy. Indeed, immune checkpoint inhibitors (ICIs) are now recommended in localized and metastatic disease. Programmed death ligand-1 (PD-L1)-positive tumors can be treated with immunotherapy in the first and second lines regardless of PD-L1 expression. By increasing immune system activity, ICIs can have adverse effects. In most cases, these can be treated with the interruption of treatment and/or supportive therapy, which can include the administration of immunosuppressants. This report describes a case of suspected a neurologic adverse event characterized by trouble with balance and double vision in a person with head and neck cancer treated with nivolumab. This was adverse event was by pausing therapy and low-dose steroid treatment, leading to complete reduction of symptoms. Unfortunately, the laboratory and instrumental investigations could not determine an exact diagnosis or the area of neurological damage.


Assuntos
Antígeno B7-H1 , Inibidores de Checkpoint Imunológico , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunidade
2.
J Pers Med ; 12(3)2022 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-35330338

RESUMO

Gastrointestinal cancers represent more than 25% of all diagnosed cancers and more than 36% of cancer-related deaths worldwide [...].

3.
J Pers Med ; 12(3)2022 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-35330396

RESUMO

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and has the second highest mortality rate globally. Thanks to the advent of next-generation sequencing technologies, several novel candidate genes have been proposed for CRC susceptibility. Germline biallelic mutations in one or more of the 22 currently recognized Fanconi anemia (FA) genes have been associated with Fanconi anemia disease, while germline monoallelic mutations, somatic mutations, or the promoter hypermethylation of some FANC genes increases the risk of cancer development, including CRC. The FA pathway is a substantial part of the DNA damage response system that participates in the repair of DNA inter-strand crosslinks through homologous recombination (HR) and protects genome stability via replication fork stabilization, respectively. Recent studies revealed associations between FA gene/protein tumor expression levels (i.e., FANC genes) and CRC progression and drug resistance. Moreover, the FA pathway represents a potential target in the CRC treatment. In fact, FANC gene characteristics may contribute to chemosensitize tumor cells to DNA crosslinking agents such as oxaliplatin and cisplatin besides exploiting the synthetic lethal approach for selective targeting of tumor cells. Hence, this review summarizes the current knowledge on the function of the FA pathway in DNA repair and genomic integrity with a focus on the FANC genes as potential predisposition factors to CRC. We then introduce recent literature that highlights the importance of FANC genes in CRC as promising prognostic and predictive biomarkers for disease management and treatment. Finally, we represent a brief overview of the current knowledge around the FANC genes as synthetic lethal therapeutic targets for precision cancer medicine.

4.
Updates Surg ; 74(2): 637-647, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35217982

RESUMO

Patients with ulcerative colitis (UC) are at risk of developing a colorectal cancer. The aim of this study was to examine our experience in the treatment of ulcerative Colitis Cancer (CC), the role of the ileal pouch-anal anastomosis (IPAA), and the clinical outcome of the operated patients. Data from 417 patients operated on for ulcerative colitis were reviewed. Fifty-two (12%) were found to have carcinoma of the colon (n = 43) or the rectum (n = 9). The indication to surgery, the histopathological type, the cancer stage, the type of surgery, the oncologic outcome, and the functional result of IPAA were examined. The majority of the patients had a mucinous or signet-ring carcinoma. An advanced stage (III or IV) was present in 28% of the patients. Early (stage I or II) CC was found in all except one patient submitted to surgery for high-grade dysplasia, low-grade dysplasia, or refractory colitis. Thirty-nine (75%) of the 52 patients underwent IPAA, 10 patients were treated with a total abdominal proctocolectomy with terminal ileostomy. IPAA was possible in 6/9 rectal CC. Cumulative survival rate 5 and 10 years after surgery was 61% and 53%, respectively. The survival rate was significantly lower for mucinous or signet-ring carcinomas than for other adenocarcinoma. No significant differences of the functional results and quality of life were observed between IPAA patients aged less than or more than 65 years. Failure of the pouch occurred in 5 of 39 (12.8%) patients for cancer of the pouch (2 pts) or for tumoral recurrence at the pelvic or peritoneal level. Early surgery must be considered every time dysplasia is discovered in patients affected by UC. The advanced tumoral stage and the mucous or signet-ring hystotype influence negatively the response to therapy and the survival after surgery. IPAA can be proposed in the majority of the patients with a functional result similar to that of UC patients not affected by CC. Failures of IPAA for peritoneal recurrence or metachronous cancer of the pouch can be observed when CC is advanced, moucinous, localized in the distal rectum, or is associated with primary sclerosing cholangitis.


Assuntos
Carcinoma , Colite Ulcerativa , Proctocolectomia Restauradora , Neoplasias Retais , Anastomose Cirúrgica/efeitos adversos , Carcinoma/cirurgia , Colite Ulcerativa/complicações , Colite Ulcerativa/cirurgia , Humanos , Proctocolectomia Restauradora/efeitos adversos , Qualidade de Vida , Neoplasias Retais/cirurgia , Resultado do Tratamento
5.
Medicine (Baltimore) ; 101(2): e28249, 2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35029172

RESUMO

RATIONALE: Lung cancer is the most common cause of cancer-related deaths worldwide. Approximately 50% of patients is metastatic at diagnosis and the most common metastatic sites are bone, lungs, brain, adrenal glands, liver, and extra thoracic lymph nodes. The occurrence of gastrointestinal metastasis from lung carcinoma is rare and seems more commonly related to small cell lung cancer compared to non-small cell lung cancer (NSCLC). PATIENT INFORMATION AND DIAGNOSIS: A 78-year-old man with completely surgically resected NSCLC and no initial evidence of distant metastases developed colon and gastric metastases 7 months after diagnosis, confirmed by serial radiological examinations and endoscopic biopsies. INTERVENTIONS: The patient was subjected to total gastrectomy with D2 lymph node dissection plus partial colectomy for intraoperative detection of a transverse colon neoformation. Subsequent instrumental imaging showed bilateral lung tumor recurrence, treated with gemcitabine monotherapy for 8 months as first line chemotherapy for lung adenocarcinoma. RESULTS: The patient presented complete response to therapy and was disease-free for 4 years. LESSONS: Colonic and gastric metastasis are very infrequent in NSCLC. The resection of gastrointestinal metastasis may provide benefits in terms of both symptom control and survival in patients properly selected.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias do Colo , Neoplasias Pulmonares , Neoplasias Gástricas , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias do Colo/secundário , Neoplasias do Colo/cirurgia , Gastrectomia , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Excisão de Linfonodo , Masculino , Neoplasias Gástricas/secundário , Neoplasias Gástricas/cirurgia
6.
Pharmacol Ther ; 231: 107973, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34453999

RESUMO

Cancer treatment has been deeply changed by immunotherapy, achieving unprecedented improvement in overall and progression-free survival in several advanced and metastatic cancers. Currently, immune checkpoint inhibitor (ICI) antibodies against cytotoxic T-lymphocyte antigen (CTLA-4) and programmed death/ligand 1 (PD-1/PD-L1) are being tested and approved for different tumors, ranging from melanoma to lung carcinoma. However, only a subgroup of patients can reach treatment benefits and long-term responses, and reliable biomarkers that can accurately predict clinical responses to immunotherapy are still unidentified. In the last decade, accumulating evidence seems to suggest the gut microbiota as one of the modulators that can alter the efficacy and toxicity of immunotherapy drugs (as well as chemotherapeutics), mainly acting through the local and systemic immune system. Herein, we reviewed the highly dynamic and complex microbiome-immune system interface, its bidirectional relationship with cancer immunotherapies, and explored the future possibilities and risks in manipulating the gut microbiome.


Assuntos
Antineoplásicos , Microbioma Gastrointestinal , Neoplasias Pulmonares , Melanoma , Antineoplásicos/farmacologia , Antígeno CTLA-4/uso terapêutico , Humanos , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico
7.
Pharmacol Ther ; 229: 107924, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34175369

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma representing approximately one third of all non-Hodgkin lymphomas and about 40% of patients do not benefit of the standard first-line immune-chemotherapeutic treatment (i.e., R-CHOP - rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) that is administered as upfront therapy to substantially all patients independently from the stage of disease and other prognostic parameters. The administration of other pharmacological treatments is in fact limited to selected patients, unfitting for R-CHOP. Although clinical prognostic scores, i.e. International Prognostic Index (IPI), and molecular classifiers based on the cell of origin are available, at present no biomarkers predictive of R-CHOP response has been identified and validated. Constitutional polymorphisms of genes involved in the mechanism of action of drugs included in R-CHOP have been suggested by many authors to play a role in the efficacy and in some case in the toxicity of this treatment. Thus, it is conceivable that in the future, after proper validation, some polymorphisms can be used as pharmacogenetic biomarkers of therapeutic outcome in this disease setting. This review discusses the status of the art on molecular biomarkers predictive of DLBCL prognosis and deals with the relevant issue of the variability in response to DLBCL drug treatment. Overall, this review focuses on single nucleotide polymorphisms (SNPs) that, based on a candidate gene approach or on a genome-wide association study (GWAS) analysis, have been suggested to play a role in response to R-CHOP. In particular, SNPs discovered by a candidate gene approach are related to genes involved in drug transport (i.e., ATP-binding cassette transporters), drug metabolism, drug detoxification enzymes, oxidative stress, apoptosis, DNA repair, immunity and angiogenesis. Data from a GWAS analysis performed in DLBCL patients treated with R-CHOP, identified two SNPs associated with clinical outcomes related to genes involved in pivotal cellular processes and in transcriptional regulation and cell cycle progression, respectively. Ongoing prospective pharmacogenetic clinical trials, including a GWAS study we performed, have also been discussed.


Assuntos
Linfoma Difuso de Grandes Células B , Farmacogenética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Estudo de Associação Genômica Ampla , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Prednisona/uso terapêutico , Prognóstico , Estudos Prospectivos , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/uso terapêutico
8.
Cancers (Basel) ; 13(24)2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34944846

RESUMO

Colorectal cancer (CRC) is the third and second cancer for incidence and mortality worldwide, respectively, and is becoming prevalent in developing countries. Most CRCs derive from polyps, especially adenomatous polyps, which can gradually transform into CRC. The family of Matrix Metalloproteinases (MMPs) plays a critical role in the initiation and progression of CRC. Prominent MMPs, including MMP-1, MMP-2, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, MMP-14, and MMP-21, have been detected in CRC patients, and the expression of most of them correlates with a poor prognosis. Moreover, many studies have explored the inhibition of MMPs and targeted therapy for CRC, but there is not enough information about the role of MMPs in polyp malignancy. In this review, we discuss the role of MMPs in colorectal cancer and its pathogenesis.

9.
Expert Rev Clin Pharmacol ; 14(11): 1353-1365, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34289756

RESUMO

INTRODUCTION: : The evolving therapeutic landscape of advanced hepatocellular carcinoma (HCC) includes the increasing implementation of target-therapy and immunotherapy. Lenvatinib, a multi-target tyrosine kinase inhibitor (TKI), is an emerging first-line therapy for hepatocellular carcinoma. Its approval has changed the scenario of first-line therapies for advanced HCC, where just sorafenib proved clinical efficacy for over a decade. AREAS COVERED: : The current evidence on the role of lenvatinib for patients with advanced HCC is reviewed in this article. Particularly, therapeutic mechanisms and clinical efficacy of lenvatinib are summarized and the management of adverse events is discussed. In addition, future perspectives on the emerging role of combine therapy for HCC are highlighted. EXPERT OPINION: In the first line, lenvatinib was found to be non-inferior to sorafenib for overall survival, with significantly better progression-free survival and objective response rate. Immune checkpoint inhibitors (ICIs) are now part of HCC treatment, and recently the combination of atezolizumab plus bevacizumab has become the recommended standard of care first-line therapy for selected patients. The antitumor and immunomodulatory activities that lenvatinib shows in preclinical studies, and the positive outcomes achieved using a combination of lenvatinib plus ICIs, open new perspectives for advanced HCC treatment.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagem , Carcinoma Hepatocelular/patologia , Humanos , Imunoterapia/métodos , Neoplasias Hepáticas/patologia , Terapia de Alvo Molecular , Compostos de Fenilureia/farmacologia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Sorafenibe/administração & dosagem , Taxa de Sobrevida
10.
Pharmaceutics ; 13(5)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063389

RESUMO

Auranofin (AF) and its iodido analog, i.e., Au(PEt3) I (AFI), were reported to exhibit very promising anticancer properties both in vitro and in vivo. However, both these gold compounds have a scarce aqueous solubility that hampers their pharmaceutical use. Here, we explore whether encapsulation of these metallodrugs inside hydroxypropyl-beta-cyclodextrin (HPß-CD) may lead to an improved biopharmaceutical profile for the resulting adducts. Phase solubility studies, performed at 25 °C in an aqueous buffer, revealed, in both cases, the formation of a 1:1 drug to cyclodextrin complex; a far greater apparent stability constant (K1:1) was measured for AFI compared to AF (331 M-1 versus ca. 30 M-1). NMR studies conducted on the AFI/HPß-CD system confirmed the formation of a stable 1:1 adduct. Then, binary systems of AF and AFI with HPß-CD were prepared by colyophilization and characterized by DSC and PXRD. The results revealed the occurrence of drug complexation and/or amorphization for the AFI/HPß-CD binary system. Afterwards, the antiproliferative properties of the two cyclodextrin adducts and of the corresponding free drugs were comparatively evaluated in vitro in three representative ovarian cancer cell lines, i.e., A2780, SKOV3, and IGROV-1. The results, in all cases, point out that CD complexation of the two gold drugs does not substantially affect their biological activity. The implications of these findings are discussed in the frame of the current knowledge of AF and its analogs.

11.
Front Oncol ; 11: 632256, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34094913

RESUMO

In the last few years the advent of targeted therapies against oncogenic drivers significantly improved the survival of non small cell lung cancer (NSCLC) patients with a favourable toxicity profile. Therefore, genetic testing, including at least EGFR mutations and ALK/ROS1 rearrangements, should be performed in all NSCLC patients (in particular with adenocarcinoma) who received a diagnosis of advanced disease. This review focuses on novel druggable oncogenic drivers, such as MET exon 14 mutations/MET amplification, RET fusions, BRAF V600E mutations, KRAS G12C mutations, NTRK rearrangements, and HER2 alterations.

12.
Endocrine ; 74(1): 172-179, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34036513

RESUMO

PURPOSE: Immune checkpoint inhibitors have opened a new scenario in the treatment of cancer. These agents can elicit adverse events, which may affect different systems and organs, including the endocrine system. The aims of this study were to evaluate the impact of the anti-PD-1 molecules nivolumab and pembrolizumab on endocrine toxicity and on patient outcome. METHODS: A retrospective and multicentre study was designed, which involved a total of 251 patients affected by different tumors (mostly non-small cell lung cancer, 68.92% and melanoma, 24.30%) and treated with the PD-1 inhibitors nivolumab (61.35%) or pembrolizumab (38.65%) for up to 60 months. Clinical and biochemical data were recorded until July 31, 2020. RESULTS: Endocrine toxicity occurred in 70 out of 251 patients (27.89%). It was mostly related to thyroid dysfunction and in 75% of cases occurred within 6 months from the beginning of therapy. A previous endocrine morbidity and female gender were predictors of endocrine toxicity. There was no association between endocrine dysfunction and patient outcome. However, when all toxicities (i.e., endocrine and non endocrine) were considered, a significant association with progression-free survival and overall survival was found. CONCLUSIONS: Thyroid alterations are frequently observed in cancer patients treated with anti PD-1 drugs, particularly in women and in the presence of a previous endocrinopathy. We suggest that regular thyroid assessment should be performed in these patients, especially in the first months of therapy. Finally, the onset of side effects, related to anti PD-1 agents, appears to be associated with a better outcome.


Assuntos
Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Estudos Retrospectivos , Glândula Tireoide
13.
Future Oncol ; 17(20): 2573-2579, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33858202

RESUMO

ALTERTASTE is a prospective study to evaluate changes in taste/flavor perception and food preferences in patients treated with adjuvant or neoadjuvant chemotherapy for breast or colorectal cancer. The study adopts a longitudinal approach. Taste and odor responsiveness, food preferences and habits, emotions elicited by foods, and quality of life will be measured at six-time points: before chemotherapy (T0), after two cycles (T1, after around 1 month), after four cycles (T2, after around 2 months), after six cycles (T3, after around 4 months), at the end of chemotherapy (T4, after around 6 months) and 3 months after the conclusion of the therapy (T5). In addition, patients will be characterized for oral responsiveness and their psychological traits and attitudes toward food. The ALTERTASTE trial is expected to improve the understanding of the impact of chemotherapy on taste and smell and the repercussions of these alterations on food behaviors. Furthermore, the trial aims to develop an easy and reliable procedure to test smell, taste and food behavior alterations to allow a routine measure with patients. Clinical trial registration: NCT04495387 (ClinicalTrials.gov).


Lay abstract Malnutrition (under- or over-nutrition) is highly prevalent in cancer patients receiving chemotherapy and is an important predictor of morbidity, mortality, treatment response and toxicity. Alterations in taste and smell are frequently reported as side effects of chemotherapy and may contribute strongly to malnutrition through an impact on eating behaviors and to a worse quality of life. ALTERTASTE is a prospective longitudinal study to evaluate changes in taste/flavor perception and food preferences in patients treated with chemotherapy for breast, colon or rectal cancer. Taste and odor responsiveness, food preferences and habits, emotions elicited by foods, and quality of life will be measured at six-time points: before chemotherapy (T0), after two cycles (T1, after around 1 month), after four cycles (T2, after around 2 months), after six cycles (T3, after around 4 months), at the end of chemotherapy (T4, after around 6 months) and 3 months after the conclusion of the therapy (T5). In addition, patients will be characterized for oral responsiveness and psychological traits and attitudes toward food. The ALTERTASTE trial is expected to improve the understanding of the impact of chemotherapy on taste and smell and the repercussions of these alterations on food behaviors.


Assuntos
Antineoplásicos/administração & dosagem , Preferências Alimentares/efeitos dos fármacos , Desnutrição/prevenção & controle , Neoplasias/tratamento farmacológico , Qualidade de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Preferências Alimentares/psicologia , Humanos , Estudos Longitudinais , Masculino , Desnutrição/etiologia , Desnutrição/psicologia , Pessoa de Meia-Idade , Neoplasias/complicações , Estudos Observacionais como Assunto , Estudos Prospectivos , Olfato/efeitos dos fármacos , Paladar/efeitos dos fármacos , Resultado do Tratamento , Adulto Jovem
14.
J Pers Med ; 11(2)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33672900

RESUMO

This study aimed at building a prognostic signature based on a candidate gene panel whose expression may be associated with lymph node metastasis (LNM), thus potentially able to predict colorectal cancer (CRC) progression and patient survival. The mRNA expression levels of 20 candidate genes were evaluated by RT-qPCR in cancer and normal mucosa formalin-fixed paraffin-embedded (FFPE) tissues of CRC patients. Receiver operating characteristic curves were used to evaluate the prognosis performance of our model by calculating the area under the curve (AUC) values corresponding to stage and metastasis. A total of 100 FFPE primary tumor tissues from stage I-IV CRC patients were collected and analyzed. Among the 20 candidate genes we studied, only the expression levels of VANGL1 significantly varied between patients with and without LNMs (p = 0.02). Additionally, the AUC value of the 20-gene panel was found to have the highest predictive performance (i.e., AUC = 79.84%) for LNMs compared with that of two subpanels including 5 and 10 genes. According to our results, VANGL1 gene expression levels are able to estimate LNMs in different stages of CRC. After a proper validation in a wider case series, the evaluation of VANGL1 gene expression and that of the 20-gene panel signature could help in the future in the prediction of CRC progression.

15.
Crit Rev Oncol Hematol ; 160: 103307, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33753249

RESUMO

The interest in maintenance therapy for patients with advanced cancers has been rapidly growing. Maintenance therapy is a useful strategy that may strengthen results of induction therapy thus extending survival and preserving the quality of life (QoL) with less toxicity. Maintenance also represents a suitable setting to investigate novel agents. The value of maintenance therapy after first-line chemotherapy has been well established in several solid tumours, such as colorectal, lung, breast, and ovarian cancer in which it is largely adopted. To date, there is no established role for maintenance therapy following first-line chemotherapy for advanced gastric cancer (GC). This review summarizes the current knowledge regarding maintenance strategies in advanced GC exploring cytotoxic agents, biologic agents and immunotherapy. We also critically review new issues to optimize randomized clinical trials for maintenance therapies and suggest clinical consideration to guide a personalized approach in daily clinical practice for this setting.


Assuntos
Antineoplásicos , Neoplasias Gástricas , Antineoplásicos/uso terapêutico , Humanos , Imunoterapia , Quimioterapia de Manutenção , Qualidade de Vida , Neoplasias Gástricas/tratamento farmacológico
16.
Gastric Cancer ; 24(4): 765-779, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33742317

RESUMO

Gastric cancer is one of the most common malignancy worldwide. In unresectable or metastatic disease, the prognosis is poor and in generally less than a year. HER2 expression remains an important biomarker to lead the addition of trastuzumab to first-line systemic chemotherapy in unresectable or metastatic gastroesophageal adenocarcinoma. To date, a major issue is represented by resistance to trastuzumab developed during treatment, considering the not improved outcomes in this molecular subtype of gastroesophageal adenocarcinoma to other HER2 target strategies. In this review, we summarize the available data on the mechanisms underlying primary and secondary resistance to HER2-targeted therapy and current challenges in the treatment of HER2-positive advanced gastric cancer refractory to trastuzumab. Furthermore, we describe the prognostic value of new non-invasive screening methods, under development novel agents (e.g., HER2 antibody-drug conjugates and bispecific antibodies) and strategies with antitumor activity in early studies.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/genética , Trastuzumab/uso terapêutico , Biomarcadores Tumorais/genética , Humanos , Prognóstico , Neoplasias Gástricas/tratamento farmacológico
17.
Am J Clin Oncol ; 44(3): 121-125, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33617179

RESUMO

OBJECTIVES: The aim of our study was to collect data about of the outcome of metastatic renal cell carcinoma patients who progressed after immune checkpoint inhibitors in order to enhance data about efficacy and safety of treatment beyond immune-oncology (IO). MATERIALS AND METHODS: A total of 162 eligible patients, progressing to IO, were enrolled from 16 Italian referral centers adhering to the Meet-Uro association. Baseline characteristics, outcome data and toxicities were retrospectively collected. Descriptive analysis was made using median values and ranges. Kaplan-Meier method and Mantel-Haenszel log-rank test were performed to compare differences between groups. RESULTS: A total of 111 patients (68.5%) were treated after IO progression. In all, 51 patients (31.5%) did not receive further treatment for clinical deterioration. Median IO progression free survival (PFS) was 4 months (95% confidence interval [CI]: 3.1-4.8). IO-PFS tends to be longer in patients reporting adverse events (AE) of any grade (5.03 [95% CI: 3.8-6.1] vs. 2.99 [95% CI: 2.4-3.5] months P=0.004). Subsequent therapies included cabozantinib (n=79, 48%), everolimus (n=11, 6.7%), and others (n=21, 12.9%).Median PFS post-IO was 6.5 months (95% CI: 5.1-7.8). Cabozantinib showed longer PFS compared with everolimus (7.6 mo [95% CI: 5.2-10.1] vs. 3.2 mo [95% CI: 1.8-4.5]) (hazard ratio: 0.2; 95% CI: 0.1026-0.7968) and other drugs (4.3 mo [95% CI: 1.3-7.4]) (hazard ratio: 0.6; 95% CI: 0.35-1.23). All grade AE were reported in 83 patients (74%) and G3 to G4 AE in 39 patients (35%). Target therapies post-IO showed median overall survival of 14.7 months (95% CI: 0.3-21.4). CONCLUSIONS: In our real world experience after progression to IO, vascular endotelial groth factor-tyrosine kinase inhibitors, given to patients, proved to be active and safe choices. Cabozantinib was associated with a better outcome in terms of median PFS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Idoso , Anilidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Progressão da Doença , Everolimo/administração & dosagem , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Itália , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Piridinas/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento
18.
Oncol Res ; 28(6): 631-644, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33208224

RESUMO

The benefit of adjuvant chemotherapy in the early stages of colorectal cancer (CRC) is still disappointing and the prediction of treatment outcome quite difficult. Recently, through a transcriptomic approach, we evidenced a role of PNN and KCNQ1OT1 gene expression in predicting response to fluoropyrimidine-based adjuvant chemotherapy in stage III CRC patients. Thus, the aim of this study was to validate in an independent cohort of stages IIIII CRC patients our previous findings. PNN and KCNQ1OT1 mRNA expression levels were evaluated in 74 formalin-fixed paraffin-embedded tumor and matched normal mucosa samples obtained by stages IIIII CRC patients treated with fluoropyrimidine-based adjuvant chemotherapy. PININ, the protein encoded by PNN, was immunohistochemically evaluated in 15 tumor and corresponding normal mucosa samples, selected on the basis of a low, medium, or high mRNA expression tumor/mucosa ratio. PNN and KCNQ1OT1 mRNA mean expression levels were significantly higher in tumor compared with normal tissues. Patients with high PNN or KCNQ1OT1 tumor mRNA levels according to ROC-based cutoffs showed a shorter disease-free survival (DFS) compared with patients with low tumor mRNA gene expression. Also, patients with tumor mRNA expression values of both genes below the identified cutoffs had a significantly longer DFS compared with patients with the expression of one or both genes above the cutoffs. In a representative large cohort of stages IIIII CRC untreated patients retrieved from GEO datasets, no difference in DFS was observed between patients with high and low PNN or KCNQ1OT1 gene expression levels. These data confirm our previous findings and underscore the relevance of PNN and KCNQ1OT1 expression in predicting DFS in early stages of CRC treated with fluoropyrimidine-based adjuvant chemotherapy. If further validated in a prospective case series, both biomarkers could be used to identify patients who benefit from this treatment and to offer alternative chemotherapy regimens to potential unresponsive patients. In relation to the suggested biological role of PNN and KCNQ1OT1 in CRC, they might also be exploited as potential therapeutic targets.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Moléculas de Adesão Celular/genética , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Proteínas Nucleares/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Moléculas de Adesão Celular/metabolismo , Quimioterapia Adjuvante/métodos , Estudos de Coortes , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Expressão Gênica , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Nucleares/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Prognóstico , Pirimidinas/uso terapêutico , RNA Mensageiro/metabolismo , Resultado do Tratamento
19.
Eur J Cancer ; 144: 101-112, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33341444

RESUMO

BACKGROUND: Stratification of patients with stage III colon cancer into low (T1-3N1) and high (T4 and/or N2) risk groups is used to guide the duration of adjuvant chemotherapy. We determined the relative contribution of clinical and molecular features to survival by risk group. MATERIALS & METHODS: Stage III colon cancer (N = 5337) patients from two adjuvant trials of FOLFOX ± cetuximab [N0147 (Alliance), PETACC-8] were risk grouped, then subgrouped by clinical features and molecular variables [KRAS and BRAF/mismatch repair (MMR) combined variable]. Distributions of disease-free survival (DFS), overall survival (OS), and survival after recurrence (SAR) were estimated. In multivariable Cox models, backward elimination was performed for analysis of candidate predictors of outcomes. Relative contributions of model-selected variables to outcomes by risk group were calculated using χ2. RESULTS: Among low risk tumours, mutant KRAS and male gender were significantly associated with poorer OS multivariately. In high risk tumours, significantly poorer OS was observed for right sidedness and for mutant KRAS and BRAFV600E/pMMR, subgroups. Specifically, BRAFV600E/pMMR (OS: HR = 1.75; 95% CI: 1.36-2.24; Padj<.0001) and right- versus left-sidedness were associated with significantly poorer DFS, OS (HR = 1.56; 95% CI: 1.31-1.83; Padj<.0001), and SAR (HR = 1.64; 95% CI: 1.37-1.95; Padj<.0001). Poor prognosis of mutant KRAS for DFS and OS was similar among risk groups. BRAF/MMR and sidedness were associated with poorer SAR in both low and high risk tumours. Age, gender, and KRAS were the top three relative contributors to DFS and OS among low risk tumours; sidedness ranked first for DFS and OS, and second to BRAF/MMR for SAR among high risk tumours. CONCLUSION: Sidedness and BRAF/MMR contributed the most to survival outcomes among high risk tumours and should be interpreted in the context of risk group.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/mortalidade , Neoplasias do Colo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cetuximab/administração & dosagem , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem , Proteínas ras/genética
20.
Sci Rep ; 10(1): 19281, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-33159172

RESUMO

Neutropenia is a common side effect associated with nab-paclitaxel gemcitabine (Nab-Gem) therapy. We retrospectively investigated the association between neutropenia induced by first-line Nab-Gem and survival in metastatic pancreatic carcinoma patients. Metastatic pancreatic patients treated with first-line Nab-Gem were included in this retrospective analysis. Neutropenia was categorized using the National Cancer Institute Common Toxicity Criteria scale. Outcome measures were overall survival (OS), progression-free survival (PFS) and response rate. 115 patients were analyzed. Median PFS was 7 months (95% CI 5-8) for patients with grade ≥ 3 neutropenia and 6 months (95% CI 5-6) for patients with grade < 3 neutropenia [p = 0.08; hazard ratio (HR 0.68)]. Median OS was 13 months (95% CI 10-18) for patients with grade ≥ 3 neutropenia and 10 months (95% CI 8-13) for patients with grade < 3 neutropenia (p = 0.04; HR 0.44). In multivariate analysis, the occurrence of grade ≥ 3 neutropenia showed a statistically significant association with OS (HR 0.62; 95% CI 0.09-0.86; p = 0.05). Nab-Gem-induced neutropenia is associated with longer survival in metastatic pancreatic cancer patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neutropenia , Neoplasias Pancreáticas , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neutropenia/induzido quimicamente , Neutropenia/mortalidade , Neutropenia/patologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Taxa de Sobrevida
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