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We previously reported that the inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor function of CD8+ T cells indirectly via restoring production of DC recruiting chemokines by cancer cells and subsequent induction of antitumor CD8+ T cells. In this study, we investigated the molecular mechanism of direct enhancing effects of SCD1 inhibitors on CD8+ T cells. In vitro treatment of CD8+ T cells with SCD1 inhibitors enhanced IFN-γ production and cytotoxic activity of T cells along with decreased oleic acid and esterified cholesterol, which is generated by cholesterol esterase, acetyl-CoA acetyltransferase 1 (ACAT1), in CD8+ T cells. The addition of oleic acid or cholesteryl oleate reversed the enhanced functions of CD8+ T cells treated with SCD1 inhibitors. Systemic administration of SCD1 inhibitor to MCA205 tumor-bearing mice enhanced IFN-γ production of tumor-infiltrating CD8+ T cells, in which oleic acid and esterified cholesterol, but not cholesterol, were decreased. These results indicated that SCD1 suppressed effector functions of CD8+ T cells through the increased esterified cholesterol in an ACAT1-dependent manner, and SCD1 inhibition enhanced T cell activity directly through decreased esterified cholesterol. Finally, SCD1 inhibitors or ACAT1 inhibitors synergistically enhanced the antitumor effects of anti-PD-1 antibody therapy or CAR-T cell therapy in mouse tumor models. Therefore, the SCD1-ACAT1 axis is regulating effector functions of CD8+ T cells, and SCD1 inhibitors, and ACAT1 inhibitors are attractive drugs for cancer immunotherapy.
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Neoplasias , Ácido Oléico , Ratones , Animales , Ácido Oléico/farmacología , Linfocitos T CD8-positivos , Acetiltransferasas , Colesterol , Estearoil-CoA DesaturasaRESUMEN
The concept of gastric-type mucinous carcinoma of the uterine cervix (GAS) has been accepted worldwide because of its aggressive clinical behaviour and the absence of high-risk human papilloma virus infection. The World Health Organization (WHO) 2020 classification divides cervical tumours into two categories: human papilloma virus-associated and human papilloma virus-independent. Hence, GAS is now classified as an human papilloma virus-independent gastric type. Because clinical studies have reported that GAS is refractory to conventional treatments such as chemotherapy and radiotherapy, especially at an advanced stage, and has aggressive features with widespread dissemination to unusual sites, such as the omentum, peritoneum and distant organs, it is urgent to establish new treatment strategies by comparing the molecular profiles of human papilloma virus-associated adenocarcinomas. A series of genetic mutations characteristic to GAS encourage the development of future treatment strategies such as targeted therapy and immunotherapy.
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Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/terapia , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Adenocarcinoma Mucinoso/terapia , Adenocarcinoma Mucinoso/patología , Adenocarcinoma/terapia , Adenocarcinoma/patología , Adenocarcinoma/genéticaRESUMEN
INTRODUCTION: The timing of prophylactic pegylated granulocyte colony-stimulating factor (G-CSF) administration during cancer chemotherapy varies, with Day 2 and Days 3-5 being the most common schedules. Optimal timing remains uncertain, affecting efficacy and adverse events. This systematic review sought to evaluate the available evidence on the timing of prophylactic pegylated G-CSF administration. METHODS: Based on the Minds Handbook for Clinical Practice Guideline Development, we searched the PubMed, Ichushi-Web, and Cochrane Library databases for literature published from January 1990 to December 2019. The inclusion criteria included studies among the adult population using pegfilgrastim. The search strategy focused on timing-related keywords. Two reviewers independently extracted and assessed the data. RESULTS: Among 300 initial search results, only four articles met the inclusion criteria. A meta-analysis for febrile neutropenia incidence suggested a potential higher incidence when pegylated G-CSF was administered on Days 3-5 than on Day 2 (odds ratio: 1.27, 95% CI 0.66-2.46, p = 0.47), with a moderate certainty of evidence. No significant difference in overall survival or mortality due to infections was observed. The trend of severe adverse events was lower on Days 3-5, without statistical significance (odds ratio: 0.72, 95% CI 0.14-3.67, p = 0.69) and with a moderate certainty of evidence. Data on pain were inconclusive. CONCLUSIONS: Both Day 2 and Days 3-5 were weakly recommended for pegylated G-CSF administration post-chemotherapy in patients with cancer. The limited evidence highlights the need for further research to refine recommendations.
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Factor Estimulante de Colonias de Granulocitos , Neoplasias , Humanos , Esquema de Medicación , Filgrastim/uso terapéutico , Filgrastim/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Neoplasias/tratamiento farmacológico , Polietilenglicoles , Guías de Práctica Clínica como Asunto , Proteínas Recombinantes , Factores de TiempoRESUMEN
BACKGROUND: Docetaxel (DTX) is commonly used as a primary chemotherapy, and cabazitaxel (CBZ) has shown efficacy in patients who are DTX resistant. Primary prophylactic granulocyte colony stimulating factor (G-CSF) therapy is currently used with CBZ treatment in routine clinical care in Japan. METHODS: In this study, we performed a systematic review following the Minds guidelines to investigate the effectiveness and safety of primary prophylaxis with G-CSF during chemotherapy for prostate cancer and to construct G-CSF guidelines for primary prophylaxis use during chemotherapy. A comprehensive literature search of various electronic databases (PubMed, Cochrane Library, and Ichushi) was performed on January 10, 2020, to identify studies published between January 1990 and December 31, 2019 that investigate the impact of primary prophylaxis with G-CSF during CBZ administration on clinical outcomes. RESULTS: Ultimately, nine articles were included in the qualitative systematic review. Primary G-CSF prophylaxis during CBZ administration for metastatic castration-resistant prostate cancer was difficult to assess in terms of correlation with overall survival, mortality from infection, and patients' quality of life. These difficulties were owing to the lack of randomized controlled trials comparing patients with and without primary prophylaxis of G-CSF during CBZ administration. However, some retrospective studies have suggested that it may reduce the incidence of febrile neutropenia. CONCLUSION: G-CSF may be beneficial as primary prophylaxis during CBZ administration for metastatic castration resistant prostate cancer, and we made a "weak recommendation to perform" with an annotation of the relevant regimen.
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Factor Estimulante de Colonias de Granulocitos , Neoplasias de la Próstata , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Docetaxel/administración & dosificación , Docetaxel/uso terapéutico , Pueblos del Este de Asia , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Japón , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Taxoides/administración & dosificación , Taxoides/uso terapéuticoRESUMEN
Although granulocyte colony-stimulating factor (G-CSF) reduces the incidence, duration, and severity of neutropenia, its prophylactic use for acute myeloid leukemia (AML) remains controversial due to a theoretically increased risk of relapse. The present study investigated the effects of G-CSF as primary prophylaxis for AML with remission induction therapy. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis of pooled data was conducted, and the risk ratio with corresponding confidence intervals was calculated in the meta-analysis and summarized. Sixteen studies were included in the qualitative analysis, nine of which were examined in the meta-analysis. Although G-CSF significantly shortened the duration of neutropenia, primary prophylaxis with G-CSF did not correlate with infection-related mortality. Moreover, primary prophylaxis with G-CSF did not affect disease progression/recurrence, overall survival, or adverse events, such as musculoskeletal pain. However, evidence to support or discourage the use of G-CSF as primary prophylaxis for adult AML patients with induction therapy remains limited. Therefore, the use of G-CSF as primary prophylaxis can be considered for adult AML patients with remission induction therapy who are at a high risk of infectious complications.
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Factor Estimulante de Colonias de Granulocitos , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Inducción de Remisión , Guías de Práctica Clínica como Asunto , Quimioterapia de Inducción , Japón , Neutropenia/inducido químicamente , Neutropenia/prevención & controlRESUMEN
BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) reportedly reduces the risk of neutropenia and subsequent infections caused by cancer chemotherapy. Although several guidelines recommend using G-CSF in primary prophylaxis according to the incidence rate of chemotherapy-induced febrile neutropenia (FN), the effectiveness of G-CSF in digestive system tumor chemotherapy remains unclear. To address these clinical questions, we conducted a systematic review as part of revising the Clinical Practice Guidelines for the Use of G-CSF 2022 published by the Japan Society of Clinical Oncology. METHODS: This systematic review addressed two main clinical questions (CQ): CQ1: "Is primary prophylaxis with G-CSF effective in chemotherapy?", and CQ2: "Is increasing the intensity of chemotherapy with G-CSF effective?" We reviewed different types of digestive system tumors, including esophageal, gastric, pancreatic, biliary tract, colorectal, and neuroendocrine carcinomas. PubMed, Cochrane Library, and Ichushi-Web databases were searched for information sources. Independent systematic reviewers conducted two rounds of screening and selected relevant records for each CQ. Finally, the working group members synthesized the strength of evidence and recommendations. RESULTS: After two rounds of screening, 5/0/3/0/2/0 records were extracted for CQ1 of esophageal/gastric/pancreatic/biliary tract/colorectal/ and neuroendocrine carcinoma, respectively. Additionally, a total of 2/6/1 records were extracted for CQ2 of esophageal/pancreatic/colorectal cancer, respectively. The strength of evidence and recommendations were evaluated for CQ1 of colorectal cancer; however, we could not synthesize recommendations for other CQs owing to the lack of records. CONCLUSION: The use of G-CSF for primary prophylaxis in chemotherapy for colorectal cancer is inappropriate.
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Neoplasias del Sistema Digestivo , Factor Estimulante de Colonias de Granulocitos , Humanos , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Neoplasias del Sistema Digestivo/tratamiento farmacológico , Japón , Guías de Práctica Clínica como Asunto , Oncología Médica , Neutropenia Febril Inducida por Quimioterapia/prevención & control , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversosRESUMEN
BACKGROUD: Granulocyte colony-stimulating factor (G-CSF) is widely used for the primary prophylaxis of febrile neutropenia (FN). Two types of G-CSF are available in Japan, namely G-CSF chemically bound to polyethylene glycol (PEG G-CSF), which provides long-lasting effects with a single dose, and non-polyethylene glycol-bound G-CSF (non-PEG G-CSF), which must be sequentially administrated for several days. METHODS: This current study investigated the utility of these treatments for the primary prophylaxis of FN through a systematic review of the literature. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis or meta-analysis was conducted to evaluate six outcomes. RESULTS: Through the first and second screenings, 23 and 18 articles were extracted for qualitative synthesis and meta-analysis, respectively. The incidence of FN was significantly lower in the PEG G-CSF group than in the non-PEG G-CSF group with a strong quality/certainty of evidence. The differences in other outcomes, such as overall survival, infection-related mortality, the duration of neutropenia (less than 500/µL), quality of life, and pain, were not apparent. CONCLUSIONS: A single dose of PEG G-CSF is strongly recommended over multiple-dose non-PEG G-CSF therapy for the primary prophylaxis of FN.
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Factor Estimulante de Colonias de Granulocitos , Polietilenglicoles , Humanos , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Polietilenglicoles/administración & dosificación , Guías de Práctica Clínica como Asunto , Neutropenia Febril/prevención & control , Neutropenia Febril/inducido químicamente , Proteínas RecombinantesRESUMEN
BACKGROUND: The outcomes of relapsed or refractory acute myeloid leukemia (AML) remain poor. Although the concomitant use of granulocyte colony-stimulating factor (G-CSF) and anti-chemotherapeutic agents has been investigated to improve the antileukemic effect on AML, its usefulness remains controversial. This study aimed to investigate the effects of G-CSF priming as a remission induction therapy or salvage chemotherapy. METHODS: We performed a thorough literature search for studies related to the priming effect of G-CSF using PubMed, Ichushi-Web, and the Cochrane Library. A qualitative analysis of the pooled data was performed, and risk ratios (RRs) with confidence intervals (CIs) were calculated and summarized. RESULTS: Two reviewers independently extracted and accessed the 278 records identified during the initial screening, and 62 full-text articles were assessed for eligibility in second screening. Eleven studies were included in the qualitative analysis and 10 in the meta-analysis. A systematic review revealed that priming with G-CSF did not correlate with an improvement in response rate and overall survival (OS). The result of the meta-analysis revealed the tendency for lower relapse rate in the G-CSF priming groups without inter-study heterogeneity [RR, 0.91 (95% CI 0.82-1.01), p = 0.08; I2 = 4%, p = 0.35]. In specific populations, including patients with intermediate cytogenetic risk and those receiving high-dose cytarabine, the G-CSF priming regimen prolonged OS. CONCLUSIONS: G-CSF priming in combination with intensive remission induction treatment is not universally effective in patients with AML. Further studies are required to identify the patient cohort for which G-CSF priming is recommended.
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Factor Estimulante de Colonias de Granulocitos , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Inducción de Remisión , Guías de Práctica Clínica como Asunto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Japón , Terapia RecuperativaRESUMEN
Granulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression and thereby relieve symptoms, such as hematuria, infection, bleeding, and pain, as well as to prolong the survival. In this clinical question, we compared treatment with primary prophylactic administration of G-CSF to maintain therapeutic intensity with conventional standard therapy without G-CSF and examined the benefits and risks as major outcomes. A detailed literature search for relevant studies was performed using PubMed, Ichu-shi Web, and Cochrane Library. Data were extracted and evaluated independently by two reviewers. A qualitative analysis of the pooled data was performed, and the risk ratios with corresponding confidence intervals were calculated and summarized in a meta-analysis. Seven studies were included in the qualitative analysis, two of which were reviewed in the meta-analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, and one randomized controlled study showed a reduction in the incidence of FN. Primary prophylactic administration of G-CSF may be beneficial, as shown in a randomized controlled study of dose-dense MVAC therapy. However, there are no studies on other regimens, and we made a "weak recommendation to perform" with an annotation of the relevant regimen (dose-dense MVAC).
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Protocolos de Quimioterapia Combinada Antineoplásica , Factor Estimulante de Colonias de Granulocitos , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Cisplatino/administración & dosificación , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Neutropenia Febril/prevención & control , Neutropenia Febril/inducido químicamente , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Metotrexato/uso terapéutico , Metotrexato/administración & dosificación , Neoplasias Urológicas/tratamiento farmacológico , Vinblastina/administración & dosificación , Vinblastina/uso terapéutico , Vinblastina/efectos adversosRESUMEN
BACKGROUND: Febrile neutropenia represents a critical oncologic emergency, and its management is pivotal in cancer therapy. In several guidelines, the use of granulocyte colony-stimulating factor (G-CSF) in patients with chemotherapy-induced febrile neutropenia is not routinely recommended except in high-risk cases. The Japan Society of Clinical Oncology has updated its clinical practice guidelines for the use of G-CSF, incorporating a systematic review to address this clinical question. METHODS: The systematic review was conducted by performing a comprehensive literature search across PubMed, the Cochrane Library, and Ichushi-Web, focusing on publications from January 1990 to December 2019. Selected studies included randomized controlled trials (RCTs), non-RCTs, and cohort and case-control studies. Evaluated outcomes included overall survival, infection-related mortality, hospitalization duration, quality of life, and pain. RESULTS: The initial search yielded 332 records. Following two rounds of screening, two records were selected for both qualitative and quantitative synthesis including meta-analysis. Regarding infection-related mortality, the event to case ratio was 5:134 (3.73%) in the G-CSF group versus 6:129 (4.65%) in the non-G-CSF group, resulting in a relative risk of 0.83 (95% confidence interval, 0.27-2.58; p = 0.54), which was not statistically significant. Only median values for hospitalization duration were available from the two RCTs, precluding a meta-analysis. For overall survival, quality of life, and pain, no suitable studies were found for analysis, rendering their assessment unfeasible. CONCLUSION: A weak recommendation is made that G-CSF treatment not be administered to patients with febrile neutropenia during cancer chemotherapy. G-CSF treatment can be considered for patients at high risk.
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Neutropenia Febril , Factor Estimulante de Colonias de Granulocitos , Humanos , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Neutropenia Febril/tratamiento farmacológico , Neutropenia Febril/inducido químicamente , Neoplasias/tratamiento farmacológico , Neoplasias/complicaciones , Japón , Neutropenia Febril Inducida por Quimioterapia/tratamiento farmacológico , Oncología Médica , Guías de Práctica Clínica como AsuntoRESUMEN
BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) is an essential supportive agent for chemotherapy-induced severe myelosuppression. We proposed two clinical questions (CQ): CQ #1, "Does primary prophylaxis with G-CSF benefit chemotherapy for non-round cell soft tissue sarcoma (NRC-STS)?" and CQ #2, "Does G-CSF-based intensified chemotherapy improve NRC-STS treatment outcomes?" for the Clinical Practice Guidelines for the Use of G-CSF 2022 of the Japan Society of Clinical Oncology. METHODS: A literature search was performed on the primary prophylactic use of G-CSF for NRC-STSs. Two reviewers assessed the extracted papers and analyzed overall survival, incidence of febrile neutropenia, infection-related mortality, quality of life, and pain. RESULTS: Eighty-one and 154 articles were extracted from the literature search for CQs #1 and #2, respectively. After the first and second screening, one and two articles were included in the final evaluation, respectively. Only some studies have addressed these two clinical questions through a literature review. CONCLUSION: The clinical questions were converted to future research questions because of insufficient available data. The statements were proposed: "The benefit of primary G-CSF prophylaxis is not clear in NRC-STS" and "The benefit of intensified chemotherapy with primary G-CSF prophylaxis is not clear in NRC-STSs." G-CSF is often administered as primary prophylaxis when chemotherapy with severe myelosuppression is administered. However, its effectiveness and safety are yet to be scientifically proven.
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Factor Estimulante de Colonias de Granulocitos , Sarcoma , Humanos , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Sarcoma/tratamiento farmacológico , Japón , Guías de Práctica Clínica como Asunto , Oncología Médica , Calidad de Vida , Prevención Primaria/métodosRESUMEN
INTRODUCTION: Chemotherapy for breast cancer can cause neutropenia, increasing the risk of febrile neutropenia (FN) and serious infections. The use of granulocyte colony-stimulating factors (G-CSF) as primary prophylaxis has been explored to mitigate these risks. To evaluate the efficacy and safety of primary G-CSF prophylaxis in patients with invasive breast cancer undergoing chemotherapy. METHODS: A systematic literature review was conducted according to the "Minds Handbook for Clinical Practice Guideline Development" using PubMed, Ichushi-Web, and the Cochrane Library databases. Randomized controlled trials (RCTs) and cohort studies assessing using G-CSF as primary prophylaxis in invasive breast cancer were included. The primary outcomes were overall survival (OS) and FN incidence. Meta-analyses were performed for outcomes with sufficient data. RESULTS: Eight RCTs were included in the qualitative analysis, and five RCTs were meta-analyzed for FN incidence. The meta-analysis showed a significant reduction in FN incidence with primary G-CSF prophylaxis (risk difference [RD] = 0.22, 95% CI: 0.01-0.43, p = 0.04). Evidence for improvement in OS with G-CSF was inconclusive. Four RCTs suggested a tendency for increased pain with G-CSF, but statistical significance was not reported. CONCLUSIONS: Primary prophylactic use of G-CSF is strongly recommended for breast cancer patients undergoing chemotherapy, as it has been shown to reduce the incidence of FN. While the impact on OS is unclear, the benefits of reducing FN are considered to outweigh the potential harm of increased pain.
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Neoplasias de la Mama , Factor Estimulante de Colonias de Granulocitos , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Neutropenia Febril/prevención & control , Neutropenia Febril/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Multidrug chemotherapy for Ewing sarcoma can lead to severe myelosuppression. We proposed two clinical questions (CQ): CQ #1, "Does primary prophylaxis with G-CSF benefit chemotherapy for Ewing sarcoma?" and CQ #2, "Does G-CSF-based intensified chemotherapy improve Ewing sarcoma treatment outcomes?". METHODS: A comprehensive literature search was conducted in PubMed, Cochrane Library, and Ichushi web databases, including English and Japanese articles published from 1990 to 2019. Two reviewers assessed the extracted papers and analyzed overall survival (OS), febrile neutropenia (FN) incidence, infection-related mortality, quality of life (QOL), and pain. RESULTS: Twenty-five English and five Japanese articles were identified for CQ #1. After screening, a cohort study of vincristine, ifosfamide, doxorubicin, and etoposide chemotherapy with 851 patients was selected. Incidence of FN was 60.8% with G-CSF and 65.8% without; statistical tests were not conducted. Data on OS, infection-related mortality, QOL, or pain was unavailable. Consequently, CQ #1 was redefined as a future research question. As for CQ #2, we found two English and five Japanese papers, of which one high-quality randomized controlled trial on G-CSF use in intensified chemotherapy was included. This trial showed trends toward lower mortality and a significant increase in event-free survival for 2-week interval regimen with the G-CSF primary prophylactic use compared with 3-week interval. CONCLUSION: This review indicated that G-CSF's efficacy as primary prophylaxis in Ewing sarcoma, except in children, is uncertain despite its common use. This review tentatively endorses intensified chemotherapy with G-CSF primary prophylaxis for Ewing sarcoma.
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Protocolos de Quimioterapia Combinada Antineoplásica , Factor Estimulante de Colonias de Granulocitos , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Japón , Neoplasias Óseas/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Doxorrubicina/uso terapéutico , Doxorrubicina/efectos adversos , Doxorrubicina/administración & dosificación , Calidad de Vida , Etopósido/uso terapéutico , Etopósido/administración & dosificación , Ifosfamida/uso terapéutico , Ifosfamida/efectos adversos , Ifosfamida/administración & dosificación , Oncología Médica/métodos , Vincristina/uso terapéutico , Vincristina/efectos adversosRESUMEN
BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) is commonly administered to cancer patients undergoing myelosuppressive chemotherapy, especially when incidence rate of febrile neutropenia (FN) surpasses 20%. While primary prophylaxis with G-CSF has been proven effective in preventing FN in patients with cancer, there is limited evidence regarding its efficacy in specifically, lung cancer. Our systematic review focused on the efficacy of G-CSF primary prophylaxis in lung cancer. METHODS: We extracted studies on non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) using the PubMed, Ichushi Web, and Cochrane Library databases. Two reviewers assessed the extracted studies for each type of lung cancer and conducted quantitative and meta-analyses of preplanned outcomes, including overall survival, FN incidence, infection-related mortality, quality of life, and musculoskeletal pain. RESULTS: A limited number of studies were extracted: two on NSCLC and six on SCLC. A meta-analysis was not conducted owing to insufficient data on NSCLC. Two case-control studies explored the efficacy of primary prophylaxis with G-CSF in patients with NSCLC (on docetaxel and ramucirumab therapy) and indicated a lower FN frequency with G-CSF. For SCLC, meta-analysis of five studies showed no significant reduction in FN incidence, with an odds ratio of 0.38 (95% confidence interval 0.03-5.56, P = 0.48). Outcomes other than FN incidence could not be evaluated due to low data availability. CONCLUSION: Limited data are available on G-CSF prophylaxis in lung cancer. Primary prophylaxis with G-CSF may be weakly recommended in Japanese patients with NSCLC undergoing docetaxel and ramucirumab combination therapy.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Docetaxel/uso terapéutico , Calidad de Vida , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Ramucirumab , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Japan's health insurance covers multigene panel testing. This study aimed to determine the potential availability and utility of gene panel testing clinically in gynecologic oncology. METHODS: We analyzed the characteristics of patients with gynecologic cancer who underwent gene panel testing using FoundationOne® CDx or OncoGuide™ NCC Oncopanel between November 2019 and October 2022. RESULTS: Out of 102 patients analyzed, 32, 18, 43, 8, and 1 had cervical, endometrial, ovarian cancers, sarcoma, and vaginal cancer, respectively. Druggable gene alteration was found in 70 patients (68.6%; 21 with cervical cancer, 15 with endometrial cancer, 28 with ovarian cancer, 5 with sarcoma, and 1 with other). The most common druggable gene alteration was PIK3CA mutation (n = 21), followed by PTEN mutation (n = 12) and high tumor mutation burden (TMB-H) (n = 11). TMB-H was detected in 5 patients with cervical cancer, 5 with endometrial cancer, and 1 with endometrial stromal sarcoma. Eleven patients (10.8%) received molecularly targeted therapy according to their gene aberrations. Gene panel testing was mostly performed when the second-line treatment was ineffective. Of all 102 patients, 60 did not have recommended treatment, and 15 died or had worsened conditions before obtaining the test results. CONCLUSION: Through multigene panel testing, although many patients had druggable gene alterations, 10.8% of them received the recommended treatment. TMB-H was mainly observed in cervical/endometrial cancer, suggesting its potential as a therapeutic biomarker of immune checkpoint inhibitors. Furthermore, patients' prognosis and performance status should be considered before performing the test.
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Neoplasias Endometriales , Neoplasias de los Genitales Femeninos , Neoplasias Ováricas , Sarcoma , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias de los Genitales Femeninos/patología , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Biomarcadores de Tumor/genética , MutaciónRESUMEN
Recent cancer immunotherapy development with immune checkpoint inhibitors has shown durable clinical responses in a wide variety of tumor types. These drugs targeting programmed cell death 1, its ligand programmed death ligand 1 and cytotoxic T cell lymphocyte-associated antigen 4 have revolutionized the field of cancer treatment. It is of significant interest in optimizing the immunotherapy for cancer patients beyond the conventional treatments such as surgery, chemotherapy and radiation. Many clinical trials evaluating the safety and efficacy of various combined regimens with immune checkpoint inhibitors have been reported and are in progress. Among gynecologic malignancy, endometrial cancers have distinct subtypes with microsatellite instability-high status and polymerase É mutation. These types have been shown to immunogenic tumors and appropriated candidate for immune checkpoint inhibitors. Also, recurrent cervical cancer showed a promising objective response with single anti-PD1 Ab treatment. Despite their definite outcome and considerable potential of immunotherapy, not all patients received a survival benefit and further understanding of human tumor immunology is essential to improve this type of therapy. In this review, we have summarized the updated results of clinical trials of cancer immunotherapy for gynecologic malignancies and discussed the future perspectives.
Asunto(s)
Neoplasias de los Genitales Femeninos/inmunología , Neoplasias de los Genitales Femeninos/terapia , Inmunoterapia/tendencias , Antígeno CTLA-4/inmunología , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Terapia de Inmunosupresión , Microambiente TumoralRESUMEN
OBJECTIVES: To (i) identify correlations between selected immunogenic factors and clinicopathological characteristics, (ii) determine whether intratumoral abundance of various specific tumor-infiltrating lymphocytes (TILs) is a prognostic indicator in women with Stage II and III cervical cancer who undergo treatment with cisplatin-based concurrent chemoradiotherapy (CCRT), and (iii) investigate subtypes of FOXP3+ T cells in 15 fresh samples of cervical cancer. METHODS: In this retrospective study, intratumoral lesions in colposcopic biopsies from 55 women with advanced cervical cancer who subsequently underwent CCRT at our institution were subjected to automatic immunological staining using the following six mouse monoclonal antibodies: anti-CD3, anti-CD4, anti-CD8, anti-CD20, anti-CD206, and anti-FOXP3. Associations between the findings on automatic scoring of the number of each type of TIL in each specimen and various clinicopathological characteristics were analyzed, as were associations between the abundance of various specific types of TIL and survival. Subtypes of FOXP3+ TILs in 15 additional fresh tumor samples were also investigated using flow cytometry. RESULTS: Infiltration with CD8+ TILs was associated with pelvic lymph node metastasis. Abundant infiltration by CD3+, CD4+, CD8+, CD206+, and FOXP3+ TILs were statistically significant indicators of better progression-free and overall survival. Regarding subtypes of FOXP3+ TILs, non-Tregs (Fr-III) were found in all samples tested for this. CONCLUSIONS: The abundance of various specific intratumoral TILs may be prognostic indicators in patients with advanced cervical cancer undergoing CCRT.
Asunto(s)
Carcinoma de Células Escamosas/terapia , Quimioradioterapia/métodos , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias del Cuello Uterino/terapia , Adulto , Linfocitos T CD8-positivos , Carcinoma de Células Escamosas/patología , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Microambiente Tumoral , Neoplasias del Cuello Uterino/patologíaRESUMEN
OBJECTIVE: To determine the involvement of homeobox D9 (HOXD9) in the survival, proliferation, and metastasis of cervical cancer cells through regulating the expression of human papillomavirus (HPV) 16 E6/E7 genes using the P97 promoter. METHODS: One hundred cases of cervical cancer (CC), CC cell lines SKG-I, SKG-II, SKG-IIIa, SKG-IIIb, HeLa, and SiHa, and a human tumor xenograft mouse model were used to examine the roles of HOXD9 in CC. Knockdown experiments employed RNA interference of HOXD9. qPCR, functional assays, western blotting, DNA microarray, and luciferase and ChIP assays were applied for assessments. RESULTS: All CC cell lines expressed HOXD9 mRNA and protein. In uterine CC, HOXD9 gene expression was significantly higher than in normal cervical tissues. A positive correlation of lymphovascular space invasion and lymph node metastasis with high levels of HOXD9 expression was found in patient samples. HOXD9-knockdown cells in the mouse xenograft model only formed small or no tumors. Knockdown of HOXD9 markedly reduced CC cell proliferation, migration and invasion, induced apoptosis, increased P53 protein expression, and suppressed HPV E6/E7 expression by directly binding to the P97 promoter of HPV16 E6/E7 genes. A positive correlation between HOXD9 and HPV16 E6 expression was found in CC patients. CONCLUSIONS: HOXD9 promotes HPV16 E6 and E7 expression by direct binding to the P97 promoter, which enhances proliferation, migration, and metastasis of CCr cells. Our results suggest that HOXD9 could be a prognostic biomarker and potential therapeutic target in CC.
Asunto(s)
Proteínas de Homeodominio/fisiología , Proteínas de Neoplasias/fisiología , Infecciones por Papillomavirus/genética , Regiones Promotoras Genéticas/genética , Neoplasias del Cuello Uterino/virología , Animales , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Papillomavirus Humano 16/genética , Humanos , Ratones Endogámicos BALB C , Metástasis de la Neoplasia , Proteínas Oncogénicas Virales/metabolismo , Oncogenes , Proteínas E7 de Papillomavirus/metabolismo , Fenotipo , Proteínas Represoras/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias del Cuello Uterino/genéticaRESUMEN
OBJECTIVE: Liquid-based cytology (LBC) and conventional cytology (CS) are routine diagnostic techniques in cervical cytology, but few studies have compared their diagnostic performances with each other and with histologic diagnosis. This study aimed to compare the diagnostic performances of these techniques in subjects with abnormal cervical cytology of atypical cells of undetermined significance (ASC-US) or worse. METHODS: A total of 312 patients diagnosed with ASC-US or worse were enrolled in this prospective study in Japan from 2013 to 2014. LBC and CS samples were prepared by a split-sampling technique and evaluated blindly. The results were classified using the Bethesda System 2001. Colposcopy and biopsy were conducted simultaneously or within 4 weeks of cytology-specimen collection in all cases. Diagnostic performance was calculated in terms of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for detection of CIN2 or worse, with a cut-off ASC-US or worse. RESULTS: There was one unsatisfactory CS sample and the remaining 311 cases were evaluated. The sensitivities of LBC and CS were 100.0% and 98.8%, specificities were 17.2% and 23.8%, PPVs were 56.1% and 57.9% and NPVs were 100.0% and 94.7%, respectively. LBC had slightly higher sensitivity and NPV for detection of CIN2, but there was no significant difference between the two methods. CONCLUSIONS: There was no significant difference in the diagnostic performances of LBC and CS in patients with ASC-US or worse. LBC may therefore be an alternative approach to CS for cervical cancer screening.