scholarly journals Hyperprogressive Disease Caused by PD-1 Inhibitors for the Treatment of Pan-Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Shiyun Chen ◽  
Miaomiao Gou ◽  
Huan Yan ◽  
Mengjiao Fan ◽  
Yuting Pan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Tumor Markers ◽  
Malignant Tumors ◽  
Hepatic Metastases ◽  
Lactate Dehydrogenase Level ◽  
Tumor Growth Rate ◽  
Hyperprogressive Disease ◽  
Metastatic Sites ◽  
Pan Cancer

Background. Nowadays, PD-1/PD-L1 inhibitors are widely used to treat various malignant tumors. However, during the immunotherapy in a few patients, a flare-up of tumor growth occurred. This new pattern of progression is called hyperprogressive disease (HPD). Patients and Methods. The retrospective study included 377 patients with various malignant tumors treated with PD-1 inhibitors (nivolumab or pembrolizumab) in the Chinese PLA General Hospital from January 2015 to January 2019. Clinicopathologic variables, tumor growth rate (TGR), and treatment outcomes were analyzed in patients with pan-cancer treated with PD-1 inhibitors. HPD was defined as the difference of TGR before and during immunotherapy exceeding 50%. Results. In 38 of 377 patients (10.08%), HPD occurred after treatment with PD-1 inhibitors. Patients with HPD had lower overall survival (OS) than those without HPD (median OS, 3.6months (95% CI, 3.0–4.2) vs. 7.3 months (95% CI, 5.9–8.7); P < 0.01 ). Factors related to HPD include more than 2 metastatic sites, ECOG performance status ≥ 2 , hepatic metastases, and lactate dehydrogenase level greater than normal upper limit. KRAS status was significantly associated with HPD in patients with colorectal cancer. In the exploratory predictors’ analysis, the rapid increase of characteristic tumor markers (such as CEA in colorectal cancer, CA199 in pancreatic cancer and cholangiocarcinoma) within one month was found to be associated with the occurrence of HPD. Conclusions. HPD was developed with different rates in a variety of malignant tumor patients treated with PD-1 inhibitors and related to some clinicopathological features and poor prognosis. Tumor markers, especially CA199, might be served as early predictors of HPD.

scholarly journals Establishment of an Endoscopy-Guided Minimally Invasive Orthotopic Mouse Model of Colorectal Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3007
Author(s):  
Chen Chen ◽  
Jens Neumann ◽  
Florian Kühn ◽  
Serene M. L. Lee ◽  
Moritz Drefs ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mouse Model ◽  
Minimally Invasive ◽  
Tumor Growth ◽  
Hepatic Metastases ◽  
Specific Cell ◽  
Local Tumor ◽  
Orthotopic Mouse Model ◽  
Endoscopic Score ◽  
Local Tumor Growth

Open orthotopic mouse models of colorectal cancer have disadvantages such as the requirement for advanced surgical skills or the trauma caused by laparotomy. To overcome these drawbacks, this study aimed to evaluate the establishment of a minimally invasive model using murine colonoscopy. CT26 and MC38 CRC cells of different concentrations were injected into BALB/C and C57BL/6J mice, respectively. Follow-up endoscopies were performed to assign an endoscopic score to tumor growth. Gross autopsy, histologic and immuno-histochemical evaluation, and immune scoring were performed. To describe the learning curve of the procedures, a performance score was given. Local tumor growth with colorectal wall infiltration, luminal ulceration, the presence of tumor-infiltrating lymphocytes, lympho-vascular invasion, and early spontaneous lymph node, peritoneal, and hepatic metastases were observed. The tumors showed cytoplasmic immuno-staining for CK20. Compared to the MC38/C57BL/6J model, tumorigenicity and immunogenicity of the CT26/BALB/C model were higher. Tumor volume correlated with the endoscopic score. This endoscopy-guided orthotopic mouse model is easy to learn and quick to establish. It features early metastasis and enables the study of interactions with the immune system. When specific cell concentrations and cell lines are applied, controlled local tumor growth and metastasis can be achieved within short observation periods.

scholarly journals Long non-coding RNA MALAT1 regulates oxaliplatin-resistance via miR-324-3p/ADAM17 axis in colorectal cancer cells

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Changru Fan ◽  
Qiulan Yuan ◽  
Guifeng Liu ◽  
Yuliang Zhang ◽  
Maojun Yan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Malignant Tumors ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Western Blot Assay ◽  
Resistance Response ◽  
Non Coding Rna ◽  
Colorectal Cancer Cells ◽  
Long Non Coding Rna

Abstract Background Colorectal cancer (CRC) is one of the most general malignant tumors. Accumulating evidence implied that long non-coding RNA Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) participated in the tumorigenesis of CRC. However, the effect of MALAT1 in drug-resistance needed to be further illustrated. Methods Levels of MALAT1, microRNA (miR)-324-3p, and a disintegrin and metalloprotease metallopeptidase domain 17 (ADAM17) were detected using quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assay. Cell Counting Kit 8 (CCK-8) was used to assess the half maximal inhibitory concentration (IC50) of oxaliplatin (Ox). Meanwhile, cell proliferation, migration and apoptosis were detected by CCK-8, transwell assay, and flow cytometry, respectively. The interaction between miR-324-3p and MALAT1 or ADAM17 was clarified by dual-luciferase reporter assay. Also, the effect of MALAT1 on tumor growth was detected in xenograft tumor mice treated with Ox. Results Significant up regulation of MALAT1 and ADAM17, and decrease of miR-324-3p were observed in Ox-resistant CRC tissues and cells. MALAT1 deficiency enhanced the sensitivity of Ox-resistant CRC cells response to Ox, while miR-324-3p repression or ADAM17 acceleration could overturn this effect. Moreover, MALAT1 silencing repressed tumor growth in Ox-treated nude mice. Mechanically, MALAT1 exerted promotion effect on the resistance response to Ox via miR-324-3p/ADAM17 axis in Ox-resistant CRC cells. Conclusion MALAT1 modulated the sensitivity of Ox through ADAM17 in Ox-resistant CRC cells by sponging miR-324-3p, thus MALAT1 might serve as a novel insight for the therapy of CRC.

Biomolecular, biochemical, and radiologic evaluation of patients on anti-VEGF treatment for mCRC.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 556-556
Author(s):  
L. Rossi ◽  
E. Veltri ◽  
M. Di Seri ◽  
S. Vari ◽  
M. Colonna ◽  
...  
Keyword(s):  
Ct Scan ◽  
Clinical Response ◽  
Tumor Markers ◽  
Objective Response ◽  
Hepatic Metastases ◽  
Response To Treatment ◽  
First Line ◽  
Ras Mutations ◽  
Ras Status ◽  
Metastatic Sites

556 Background: K-ras mutation is a negative predictor of clinical benefit (CB) from anti-EGFR treatment in mCRC. Bevacizumab combined with chemotherapy prolongs both PFS and OS in first-line treatment of mCRC. Previously data suggested that this results are independent of K-ras status. We conducted a study to investigate the CB of Bevacizumab in treatment of mCRC according to K-ras status and to evaluate timing of response to treatment trough the correlation between tumor markers values and clinical responses. Finally we evaluated CB in patients affected by mCRC with only hepatic metastases vs patients with multiple metastasis sites. Methods: 82 patients were enrolled and underwent first-line chemotherapy with Folfiri or FolFoX and bevacizumab. Tissue samples were analyzed for DNA sequencing in order to identify K-ras mutations in codons 12 and 13. Before therapy all patients were investigated with CT scan and with a blood sample to define tumor markers values; a new evaluation of tumor markers after 2 months of chemotherapy was performed and a CT scan after 3 months. Results: An overall objective response rate (RR) of 40% and a CB of 79% were obtained, with a correlation between tumor markers values and clinical response of 89%. 49% of population presented only hepatic metastases while other 51% showed multiple metastatic sites. RR in exclusive hepatic metastatic group was 45% vs 33% multiple metastatic sites group, CB was 90% vs 66% respectively. No grade 3 or 4 bevacizumab associated toxicity was showed in patients. K-ras mutations were investigated in 75 of 82 patients. 49 patients were wild-type (wt 65%) while 26 patients were mutated (mut 35%). RR in wt group was 45% vs 35% in mut group, while CB was 82% vs 81% respectively. Correlation between tumor markers values and clinical response was 90% in wt group vs 93% in mut group. Conclusions: RR in two K-ras groups was different with an advantage in K-ras wt group, but this difference does not observe in CB. Bevacizumab provides significant RR and CB after a short time of treatment and tumor markers values could be an optimal correlative parameters of early clinical response. Bevacizumab provides significant CB in patients with only hepatic metastases vs patients with multiple metastatic sites. No significant financial relationships to disclose.

Hyperprogressive disease during treatment with immune checkpoint inhibitors in patients with advanced non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21664-e21664 ◽  
Author(s):  
Pablo Ayala de Miguel ◽  
Javier López Gallego ◽  
Itziar Gorospe García ◽  
Pablo René Rivera Vargas ◽  
Andrea Posada Restrepo ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Tumor Growth ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Cox Regression ◽  
Checkpoint Inhibitors ◽  
Eastern Cooperative Oncology Group ◽  
Hyperprogressive Disease ◽  
Metastatic Sites

e21664 Background: Hyperprogressive disease (HPD) is a new pattern of progressión during immunotherapy and is described as an acceleration of tumor growth during treatment with immune checkpoint inhibitors (ICI). The rate of HPD in advanced solid tumors remains unknown, but it has been reported in 9% to 29% of patients in two recent series. Our aim was to study prognostic factors of HPD. Methods: We collected data of 104 patients diagnosed of advanced NSCLC and treated with ICI in monotherapy at our institution between December 2015 and December 2019. Several variables as clinical, tumour-related and therapeutical were included in the analysis. The variables were compared by chi-square and Fisher test, then we performed a multivariate logistic regression model to analyse the effects of the covariates, and finally we performed a Kaplan Meier survival analysis. We described HPD as disease progression at first evaluation with an increase in tumor growth rate exceeding 50%, according to Gustave Roussy criteria previously reported. Results: Cohort of 84 men and 20 women, median age of 67 years and 86% with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 89% were active or ex-smokers and 11% had never smoked. 60% of patients had adenocarcinoma histology, 39% scamous and 1% had not otherwise specified (NOS) carcinoma histology. 3% of patients had III-B stage at the moment of start of immunotherapy, 37% M1a, 30% M1b and 30% M1c. 2 patients had driver mutations in EGFR gene. 41% of patients had unknown PDL1 status; 14% had no PDL1 expression, 14% low expression and 31% high expression. 78% of patients had progressed to prior line of treatment, while 22% were treatment-naive. Nine of 104 patients (8.7%) in our population developed HPD during treatment with ICI. HPD occured within the first two months of treatment in all 9 patients, and was associated with worse overall survival in the multivariate analysis by Cox regression (12.6 vs 2.6 months; HR 13.94, p < 0.001). The presence of 2 or more metastatic sites was related to the development of HPD in the multivariate analysis (HR 8.59, p = 0.026). Conclusions: The incidence of HPD in our population is concordant with previous report about this topic. As previously described by Ferrara et al, HPD was significantly associated with a high number of metastatic sites before start treatment with ICI and correlated with poor outcomes in patients with advanced NSCLC.

scholarly journals Effect of meglumine acridonacetate on growth of experimental colon adenocarcinoma and tumor-associated changes in the blood of BALB/c mice

2019 ◽  
pp. 51-61
Author(s):  
А.П. Трашков ◽  
А.Л. Коваленко ◽  
Е.И. Дрогомирецкая ◽  
Я.Д. Бараков ◽  
М.Г. Хотин ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Therapeutic Effect ◽  
Malignant Tumors ◽  
Treatment Plan ◽  
Colon Adenocarcinoma ◽  
Inhibitory Effect ◽  
Blood System ◽  
Tumor Growth Rate ◽  
Tumor Dissemination ◽  
Organ Systems

По мере своего роста злокачественные новообразования оказывают выраженное токсическое воздействие на работу всех органов и тканей организма, способствуя развитию разнообразной сопутствующей патологии, изменяя тактику лечения и ухудшая прогноз заболевания. Дополнительным фактором, усиливающим степень тяжести сопутствующей патологии или провоцирующим обострение хронических заболеваний, являются проводимые лечебные процедуры, в том числе, цитостатическая терапия. Это определяет актуальность комплексной оценки лекарственных препаратов, применяющихся в онкологии, в отношении влияния и на опухолевый процесс, и на работу систем жизнеобеспечения организма. Цель исследования: комплексный анализ влияния на развитие экспериментальной опухоли и состояние системы крови потенциального противоопухолевого средства - меглюмина акридонацетата, в том числе, на фоне цитостатической терапии. Материалы и методы. Исследование проведено на 256 самцах мышей линии BALB/c. В качестве модели опухолевого процесса использовали аденокарциному толстой кишки (АКАТОЛ). Экспериментальную химиотерапию проводили на 2-е и 5-е сутки после трансплантации опухоли препаратом циклофосфан в дозе 175 мг/кг массы тела. Меглюмина акридонацетат применяли ежедневно в дозе 100 мг/кг на протяжении 5 суток после трансплантации АКАТОЛ. Оценивали динамику роста опухоли и её метастатическую активность. Осуществляли общий клинический анализ крови. Результаты. Циклофосфан оказал выраженное ингибирующее действие на рост первичного опухолевого узла АКАТОЛ и процесс распространения новообразования в организме животного. При этом наблюдалось сильное гемотоксическое действие цитостатической терапии, имеющее временный, краткосрочный характер. Включение в экспериментальную схему лечения меглюмина акридонацетата потенциировало терапевтические эффекты циклофосфана и в значительной степени нивелировало его токсическое действие в отношении системы крови. На фоне монотерапиии новообразования меглюмина акридонацетатом наблюдалось выраженное ингибирование метастазирования АКАТОЛ и увеличение продукции форменных элементов крови. Выводы. Включение меглюмина акридонацетата в схему терапии циклофосфаном экспериментальной модели колоректального рака усиливает эффективность цитостатика и улучшает профиль его безопасности в отношении влияния на состояние системы крови. Монотерапия новообразования меглюмина акридонацетатом показала умеренный терапевтический эффект в отношении роста опухолевого узла и клинически значимый эффект в отношении ингибирования интенсивности метастазирования опухоли. Growing malignant tumors exert a pronounced toxic effect on all organs and tissues. Thereby, they contribute to various concomitant pathology, change the treatment tactics, and aggravate prognosis for the disease. The treatment itself, specifically a cytotoxic therapy, may also worsen the associated pathology and provoke exacerbation of chronic conditions. These factors determine a need for complex assessment of the drugs used in oncology, both regarding their effect on the neoplasm and side effects on functioning of vital organ systems. Aim: Complex evaluation of the effect of a candidate antitumor drug, meglumine acridonacetate, on experimental tumor growth and the blood system, including the effect on the background of cytostatic therapy. Material and methods. The study was performed on 256 male BALB/c mice. Colon adenocarcinoma (CAC) was used as an experimental model of tumor growth. The experimental chemotherapy with cyclophosphane (175 mg/kg) was administered on days 2 and 5 of tumor implantation. Meglumine acridonacetate (100 mg/kg) was administered daily for 5 days after the CAC implantation. The studied parameters included the tumor growth rate and metastatic activity. Clinical blood tests were also performed. Results. Cyclophosphane exerted a pronounced inhibitory effect on the growth of CAC primary node and tumor dissemination. The cytotostatic therapy produced a severe but brief hemotoxic effect. Addition of meglumine acridonacetate to the experimental treatment plan potentiated the therapeutic effect of cyclophosphane and considerably compensated for its hemotoxic effect. The monotherapy with meglumine acridonacetate significantly inhibited CAC metastasis and stimulated hematopoiesis. Conclusion: Supplementation of the cyclophosphane treatment plan with meglumine acridonacetate enhanced the cytostatic efficacy and improved its safety with respect of the blood system. The meglumine acridonacetate monotherapy exerted a moderate therapeutic effect on tumor growth and a clinically significant inhibitory effect on tumor metastasis.

scholarly journals FAM65A as a novel prognostic biomarker in human tumors reveal by a pan-cancer analysis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wenken Liang ◽  
Chune Mo ◽  
Jianfen Wei ◽  
Wei Chen ◽  
Weiwei Gong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Biomarker ◽  
Malignant Tumors ◽  
Sequence Similarity ◽  
Human Tumor ◽  
Colon Adenocarcinoma ◽  
Human Tumors ◽  
The Cancer Genome Atlas ◽  
Different Types ◽  
Pan Cancer

Abstract Background Family with sequence similarity 65 member A (FAM65A), also known as RIPOR1, is differentially expressed between human tumor and non-tumor tissues in kinds of cancers. In addition, it was reported that the product of FAM65A may be a biomarker for cholangiocarcinoma patients. However, there is still no evidence on the relationship between the FAM65A and different types of tumors. Our study is mainly for exploring the prognostic values of FAM65A in pan-cancer and for further discovering a potential therapeutics target. Methods We analyzed FAM65A expression, prognostic values, genetic alteration, protein phosphorylation, immune infiltration and enrichment analysis across different types of human malignant tumors based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Additionally, Real-Time PCR (RT-qPCR) was performed to further confirm the roles of FAM65A in the pathogenesis of colorectal cancer. Results We found that FAM65A expression was associated with the prognosis of multiple human tumors, especially colorectal cancer. Moreover, we also observed that FAM65A was highly expressed in colorectal cancer through RT-qPCR. We observed that decreasing phosphorylation level of the S351 locus in colon adenocarcinoma, uterine corpus endometrial carcinoma and lung adenocarcinoma. And the expression of FAM65A was positively related to cancer-associated fibroblasts (CAFs) infiltration in many tumors, such as colon adenocarcinoma. Therefore, FAM65A may be a potential prognostic biomarker of human tumors.

scholarly journals Carcinoembryonic antigen-targeted photodynamic therapy in colorectal cancer models

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Fortuné M. K. Elekonawo ◽  
Desirée L. Bos ◽  
David M. Goldenberg ◽  
Otto C. Boerman ◽  
Mark Rijpkema
Keyword(s):  
Colorectal Cancer ◽  
Photodynamic Therapy ◽  
Tumor Growth ◽  
Carcinoembryonic Antigen ◽  
Tumor Growth Rate ◽  
Incomplete Resection ◽  
Radiant Exposure ◽  
Antibody Conjugate ◽  
Targeted Photodynamic Therapy

Abstract Background In colorectal cancer, survival of patients is drastically reduced when complete resection is hampered by involvement of critical structures. Targeted photodynamic therapy (tPDT) is a local and targeted therapy which could play a role in eradicating residual tumor cells after incomplete resection. Since carcinoembryonic antigen (CEA; CEACAM5) is abundantly overexpressed in colorectal cancer, it is a potential target for tPDT of colorectal cancer. Methods To address the potential of CEA-targeted PDT, we compared colorectal cancer cell lines with different CEA-expression levels (SW-48, SW-480, SW-620, SW-1222, WiDr, HT-29, DLD-1, LS174T, and LoVo) under identical experimental conditions. We evaluated the susceptibility to tPDT by varying radiant exposure and concentration of our antibody conjugate (DTPA-hMN-14-IRDye700DX). Finally, we assessed the efficacy of tPDT in vivo in 18 mice (BALB/cAnNRj-Foxn1nu/nu) with subcutaneously xenografted LoVo tumors. Results In vitro, the treatment effect of tPDT varied per cell line and was dependent on both radiant exposure and antibody concentration. Under standardized conditions (94.5 J/cm2 and 0.5 μg/μL antibody conjugate concentration), the effect of tPDT was higher in cells with higher CEA availability: SW-1222, LS174T, LoVo, and SW-48 (22.8%, 52.8%, 49.9%, and 51.9% reduction of viable cells, respectively) compared to cells with lower CEA availability. Compared to control groups (light or antibody conjugate only), tumor growth rate was reduced in mice with s.c. LoVo tumors receiving tPDT. Conclusion Our findings suggest cells (and tumors) have different levels of susceptibility for tPDT even though they all express CEA. Furthermore, tPDT can effectively reduce tumor growth in vivo.

Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 550-550 ◽  
Author(s):  
Hongjae Chon ◽  
Chang Gon Kim ◽  
Sangeun Yoon ◽  
Chan Kim ◽  
Beodeul Kang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Real World ◽  
Progressive Disease ◽  
Objective Response ◽  
Tumor Growth Rate ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Dismal Prognosis ◽  
Hyperprogressive Disease

550 Background: Immune checkpoint blockade with PD-1 inhibitors has shown promising clinical efficacy in patients with hepatocellular carcinoma (HCC). However, emerging evidences show that PD-1 blockade can sometimes lead to a flare-up of tumor growth with rapid clinical deterioration (hyperprogressive disease, HPD). This study aimed to evaluate the incidence and pattern of HPD in a multicenter, real-world cohort of East Asian patients with advanced HCC treated with PD-1 blockade. Methods: We enrolled 148 advanced HCC patients treated with nivolumab between March 2016 and December 2018 in Korea. Clinicopathologic variables, tumor growth dynamic, and treatment outcomes were comprehensively analyzed. Progressive disease was assessed using tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF), and patient with HPD were defined as those who met the criteria of progressive disease by both TGK and TGR. Results: In this large cohort of HCC patients, the median age was 60 years and the majority were male (85%) and HBV-infected (72%). The objective response rate was 17.6% including two complete responders (1.4%). Ongoing responses were seen in 46% of responders at data cut-off. The incidence of HPD after PD-1 blockade was 23%. HCC patients with HPD had dismal prognosis with worse progression-free survival (PFS) and overall survival (OS) (HR, 1.947; 95% CI, 1.226-3.093 and HR, 1.839; 95% CI, 1.108-3.055, respectively) than progressive disease without HPD. Among various baseline clinicopatholgic parameters, elevated neutrophil-to-lymphocyte ratio (NLR) was only significantly associated with HPD. The optimal cut-off value of NLR for HPD prediction was 3.74 determined by ROC curves, and NLR > 3.74 was associated with worse PFS and OS. Conclusions: The real-world efficacy of PD-1 blockade in HCC patients was consistent with previous studies. However, there was also a corresponding risk of HPD as well as a clinical benefit. Therefore, careful patient selection using immunologic biomarkers, such as NLR, could enhance the therapeutic benefit of PD-1 blockade in clinical trials and real-world practice of HCC

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