scholarly journals Metformin Combined with Local Irradiation Provokes Abscopal Effects in a Murine Rectal Cancer Model

2021 ◽  
Author(s):  
Mineyuki Tojo ◽  
Hedeyo Miyato ◽  
Koji Koinuma ◽  
Hisanaga Horie ◽  
Hidenori Tsukui ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
T Cells ◽  
Nk Cells ◽  
Lung Metastases ◽  
Combined Therapy ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Distant Metastases ◽  
Cell Mediated Immunity ◽  
Abscopal Effects

Abstract BackgroundAlthough preoperative chemoradiation therapy can down-stage locally advanced rectal cancer (LARC), it has little effect on distant metastases. Metformin exerts an anti-cancer effect partly through the activation of host immunity. MethodLuM1, a highly lung metastatic subclone of colon 26, was injected subcutaneously in BALB/c mice and treated with metformin and/or local radiation (RT). Lung metastases and the primary tumor were evaluated and the phenotypes of immune cells in the spleen and lung metastases were examined with flowcytometry and immunohistochemistry.ResultsLocal RT, but not metformin, partially delayed the growth of sc tumor which was augmented with metformin. Lung metastases was unchanged in metformin or RT alone, but significantly reduce in the combined therapy. The ratios of splenic T cells tended to be low in the RT group, which were increased by the addition of metformin. IFN-gamma production of the splenic CD4(+) and CD8(+) T cells was enhanced and CD49b (+) CD335(+) activated NK cells was increased after combined treatment group. Density of NK cells infiltrating in lung metastases was increased after combination treatment. ConclusionMetformin effectively enhances local and abscopal effects of RT though the activation of cell-mediated immunity and might be clinically useful for LARC.

scholarly journals CD73 blockade enhances the local and abscopal effects of radiotherapy in a murine rectal cancer model

2020 ◽  
Author(s):  
Hidenori Tsukui ◽  
Hisanaga Horie ◽  
Koji Koinuma ◽  
Hideyuki Ohzawa ◽  
Yasunaru Sakuma ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Lung Metastases ◽  
Locally Advanced ◽  
Intraperitoneal Administration ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Cancer Tissue ◽  
Antitumor Effects ◽  
Immunohistochemical Studies ◽  
Abscopal Effects

Abstract Background: Anti-tumor effects of radiation therapy (RT) largely depend on host immune function. Adenosine with its strong immunosuppressive properties is an important immune checkpoint molecule. Method: We examined how intra-tumoral adenosine levels modify anti-tumor effects of RT in a murine model using an anti-CD73 antibody which blocks the rate-limiting enzyme to produce extracellular adenosine. We also evaluated CD73 expression in irradiated human rectal cancer tissue. Results: LuM-1, a highly metastatic murine colon cancer, expresses CD73 with significantly enhanced expression after RT. Subcutaneous (sc) transfer of LuM-1 in balb/c mice developed macroscopic sc tumors and microscopic pulmonary metastases within 2 weeks. Adenosine levels in the sc tumor were increased after RT. Selective RT (12 Gy in 3 fractions) suppressed the growth of the irradiated sc tumor, but did not affect the growth of lung metastases which were shielded from RT. Intraperitoneal administration of anti-CD73 antibody (200 mg x 6) alone did not produce antitumor effects. However, when combined with RT in the same protocol, anti-CD73 antibody further delayed the growth of sc tumors and suppressed the development of lung metastases presumably through abscopal effects. Splenocytes derived from RT+ CD73 antibody treated mice showed enhanced IFN-g production and cytotoxicity against LuM-1 compared to controls. Immunohistochemical studies of irradiated human rectal cancer showed that high expression of CD73 in remnant tumor cells and/or stroma is significantly associated with worse outcome. Conclusion: These results suggest that adenosine plays an important role in the anti-tumor effects mediated by RT and that CD73/adenosine axis blockade may enhance the anti-tumor effect of RT, and improve the outcomes of patients with locally advanced rectal cancer.

scholarly journals CD73 blockade enhances the local and abscopal effects of radiotherapy in a murine rectal cancer model

2020 ◽  
Author(s):  
Hidenori Tsukui ◽  
Hisanaga Horie ◽  
Koji Koinuma ◽  
Hideyuki Ohzawa ◽  
Yasunaru Sakuma ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Lung Metastases ◽  
Locally Advanced ◽  
Intraperitoneal Administration ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Antitumor Effects ◽  
Immunohistochemical Studies ◽  
Remnant Tumor ◽  
Abscopal Effects

Abstract Background Anti-tumor effects of radiation therapy (RT) largely depend on host immune function. Adenosine with its strong immunosuppressive properties is an important immune checkpoint molecule.Method We examined how intra-tumoral adenosine levels modify anti-tumor effects of RT in a murine model using an anti-CD73 antibody which blocks the rate-limiting enzyme to produce extracellular adenosine. We also evaluated CD73 expression in irradiated human rectal cancer tissue.Results LuM-1, a highly metastatic murine colon cancer, expresses CD73 with significantly enhanced expression after RT. After subcutaneous (sc) transfer of LuM-1, mice developed macroscopic sc tumors and microscopic pulmonary metastases within 2 weeks. Adenosine levels in the sc tumor were increased after RT. Selective RT (4Gyx3) suppressed the growth of the irradiated sc tumor, but did not affect the growth of lung metastases which were shielded from RT. Intraperitoneal administration of anti-CD73 antibody (200 μg x 6) alone did not produce antitumor effects. However, when combined with RT in the same protocol, anti-CD73 antibody further delayed the growth of sc tumors and suppressed the development of lung metastases presumably through abscopal effects. Splenocytes derived from RT+ CD73 antibody treated mice showed enhanced IFN-γ production and cytotoxicity against LuM-1 compared to controls. Immunohistochemical studies of irradiated human rectal cancer showed that high expression of CD73 in remnant tumor cells and/or stroma is significantly associated with worse outcome.Conclusion These results suggest that adenosine plays an important role in the anti-tumor effects mediated by RT and that CD73/adenosine axis blockade may enhance the anti-tumor effect of RT, and improve the outcomes of patients with locally advanced rectal cancer.

scholarly journals CD73 blockade enhances the local and abscopal effects of radiotherapy in a murine rectal cancer model

2020 ◽  
Author(s):  
Hidenori Tsukui ◽  
Hisanaga Horie ◽  
Koji Koinuma ◽  
Hideyuki Ohzawa ◽  
Yasunaru Sakuma ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Lung Metastases ◽  
Locally Advanced ◽  
Intraperitoneal Administration ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Cancer Tissue ◽  
Antitumor Effects ◽  
Immunohistochemical Studies ◽  
Abscopal Effects

Abstract Background Anti-tumor effects of radiation therapy (RT) largely depend on host immune function. Adenosine with its strong immunosuppressive properties is an important immune checkpoint molecule. Method We examined how intra-tumoral adenosine levels modify anti-tumor effects of RT in a murine model using an anti-CD73 antibody which blocks the rate-limiting enzyme to produce extracellular adenosine. We also evaluated CD73 expression in irradiated human rectal cancer tissue. Results LuM-1, a highly metastatic murine colon cancer, expresses CD73 with significantly enhanced expression after RT. After subcutaneous (sc) transfer of LuM-1, mice developed macroscopic sc tumors and microscopic pulmonary metastases within 2 weeks. Adenosine levels in the sc tumor were increased after RT. Selective RT (12Gy in 3fractions) suppressed the growth of the irradiated sc tumor, but did not affect the growth of lung metastases which were shielded from RT. Intraperitoneal administration of anti-CD73 antibody (200 μg x 6) alone did not produce antitumor effects. However, when combined with RT in the same protocol, anti-CD73 antibody further delayed the growth of sc tumors and suppressed the development of lung metastases presumably through abscopal effects. Splenocytes derived from RT+ CD73 antibody treated mice showed enhanced IFN-γ production and cytotoxicity against LuM-1 compared to controls. Immunohistochemical studies of irradiated human rectal cancer showed that high expression of CD73 in remnant tumor cells and/or stroma is significantly associated with worse outcome. Conclusion These results suggest that adenosine plays an important role in the anti-tumor effects mediated by RT and that CD73/adenosine axis blockade may enhance the anti-tumor effect of RT, and improve the outcomes of patients with locally advanced rectal cancer.

EXPERIENCE OF THE APPLICATION OF THERMOCHEMIORRADIOTHERAPY IN COMBINED TREATMENT OF DYSTAL CANCER OF DIRECT INTESTINE

2019 ◽  
Vol 65 (1) ◽  
pp. 131-134
Author(s):  
Zhanna Startseva ◽  
Sergey Afanasev ◽  
Dina Plaskeeva
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Primary Tumor ◽  
Advanced Colorectal Cancer ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Chemoradiation Therapy ◽  
Locally Advanced Colorectal Cancer

The article describes the experience of using ther-mochioradiotherapy in the combined treatment of distal locally advanced colorectal cancer, as well as comparing the effectiveness of treatment with chemoradiation therapy. The use of the proposed method as a component of the combined treatment of patients with rectal cancer allowed to increase the percentage of organ-preserving operations. As a result of thermochemotherapy, the prevalence of the primary tumor was significantly reduced, as a result of which the number of sphincter-bearing operations was reduced by almost 2 times (p

Neoadjuvant Chemotherapy to Radiation and Concurrent Chemoradiation for Locally Advanced Squamous Cell Carcinoma of the Cervix: A Review of the Recent Literature

1998 ◽  
Vol 84 (2) ◽  
pp. 229-237 ◽  
Author(s):  
Alessandro Colombo ◽  
Fabio Landoni ◽  
Andrea Maneo ◽  
Gerardo Zanetta ◽  
Simonetta Nava ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Local Control ◽  
Randomized Trials ◽  
Recent Literature ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Distant Metastases ◽  
Integrated Treatment ◽  
Concurrent Chemoradiation ◽  
Late Morbidity

Radiotherapy is the standard treatment for locally advanced cervical cancer; nevertheless it fails to control disease progression within the irradiation fields in more than 40% of cases, particularly in patients with bulky tumor. Distant metastases are not infrequent in more advanced cases. Chemotherapy has been integrated with radiotherapy to improve local control and treat distant subclinical metastases. Schedules of combined treatment more frequently represented by neoadjuvant chemotherapy followed by radiation (NACT) and by concomitant chemotherapy and radiation (CT-RT). A review of the recent literature is presented. The role of NACT is controversial: high response rates are reported but doubtful advantages in terms of survival or local control have been shown. In randomized trials, hydroxyurea concomitant to radiation improves local control and survival, particularly in stage IIIB and IVA. Several randomized trials of concurrent chemoradiation with 5FU, cisplatin and mitomycin C are underway, but few have been published: no significative differences are reported in term of local control or survival. Acute toxicity is higher than in radiation alone, but usually manageable. For the analysis of late morbidity a longer follow-up is required. Large randomized trials of adequate radiotherapy versus concomitant chemoradiation are necessary to refine our understanding of the benefits of this integrated treatment.

Combined treatment with immunotherapy and chemotherapy using endoscopic ultrasonography guided injection for locally advanced pancreatic carcinoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 13503-13503
Author(s):  
K. Nonogaki ◽  
Y. Hirooka ◽  
A. Itoh ◽  
H. Kawashima ◽  
N. Ohmiya ◽  
...  
Keyword(s):  
Pancreatic Carcinoma ◽  
Peripheral Blood ◽  
Ductal Carcinoma ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Hematological Toxicity ◽  
Pancreatic Ductal Carcinoma ◽  
Cell Mediated Immunity ◽  
Locally Advanced Pancreatic Carcinoma ◽  
Advanced Pancreatic Carcinoma

13503 Background: Dendritic cells (DCs) play a pivotal role in T cell-mediated immunity. Usually, mature DCs were cultured using resected tumor tissue, but for inoperable cases, this method is impractical. The injection of immature DCs into the tumor after appropriate chemotherapy is reasonable, if DCs come to maturity capturing the specific cancer antigen . The aim of this study is to assess the toxicity and efficacy of combined treatment with immunotherapy and chemotherapy for locally advanced pancreatic carcinoma. Methods: Five patients with pathologically confirmed pancreatic ductal carcinoma using EUS-FNA were enrolled, median age 56 years (range, 46–70 years). All cases without distant metastasis were diagnosed as surgically unresectable . Patients underwent leukapheresis, immature DCs were prepared from peripheral blood by a culture with granulocyte macrophage colony-stimulating factor and interleukin 4. Lymphokine-activated killer (LAK) were also prepared from peripheral blood. Immature DCs were injected biweekly in the mass by endoscopic ultrasound-guided fine needle injection (EUS-FNI), LAK were administered intravenously. Patients received the treatment of gemcitabine 1000 mg / m2 by intravenous injection 3 days before the immunotherapy. One course with 6 times combined therapy was continued until the judgment of progressive diseases (PD) was given. The toxicity and efficacy of this treatment were assessed. We also assessed whether tumor associated antigen (TAA)-specific IFN-?producing cells increase after treatment. Results: Hematological toxicity occurred in one case, leucopenia of grade 2. No severe toxicities of grade 3 to 4 occurred. One had a partial response (PR), stable disease (SD) was observed in 2 patients for more than 6 months (long-term SD). PR patient could undergo curative operation after this therapy. The number of TAA-specific IFN-?producing cells in PR patient increased 12-fold higher than that seen before treatments. Conclusions: These results support the safety and efficacy of combined treatment with immunotherapy and chemotherapy for locally advanced pancreatic ductal carcinoma. This treatment may be a useful for the treatment of pancreatic ductal carcinoma. No significant financial relationships to disclose.

Pelvic side wall nodes in locally advanced rectal cancer as a prognostic indicator.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 613-613
Author(s):  
Kirsten Elizabeth Jean Laws ◽  
Christina Wilson ◽  
Stephen Harrow
Keyword(s):  
Rectal Cancer ◽  
Overall Survival ◽  
Locally Advanced ◽  
Side Wall ◽  
Distant Metastases ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Pre Treatment ◽  
Long Course ◽  
Patterns Of Recurrence

613 Background: Neoadjuvant long course chemoradiotherapy is a well recognised treatment in locally advanced rectal cancer. Patients with pelvic side wall nodes are often considered for neoadjuvant treatment. We investigated whether pelvic side wall nodes identified on pre-treatment imaging is a poor prognostic factor and whether there are different patterns of recurrence compared to patients without pelvic side wall node involvement. Methods: All patients treated with long course chemoradiotherapy between January 2008 and December 2009 were identified. Patients were excluded if treatment indication was for inoperable disease, postoperative, recurrence, or palliative intent. 231 patients were identified and a retrospective analysis performed investigating patterns of recurrence and survival for patients with pelvic side wall nodes identified on pre-treatment imaging. Results: Kaplan Meier curves are presented showing patients with pelvic side wall nodes identified on pre-treatment imaging appear to have poorer outcomes and overall survival compared with those with only mesorectal nodes or no nodes. Patterns of recurrence are presented, showing patients with pelvic side wall nodes identified on pre-treatment imaging have a non significant trend to increased rates of disease recurrence (local and distal recurrence combined, 45.7% versus 27.9% for pelvic side wall nodes versus no pelvic side wall nodes). Patients with pelvic side wall nodes identified on pre-treatment imaging appear to be more likely to develop distant metastases compared to those patients who have mesorectal nodes or no nodal involvement (37% versus 23%). Conclusions: Our study highlights that patients with pelvic side wall nodes identified on pre-treatment imaging appear to have a trend to poorer overall survival, are more likely to recur and develop distant metastases. These results were not statistically significant, due to the small number of patients, and the data is consequently limited. We intend to further investigate current management strategies for this subgroup of patients, with assessment of radiotherapy treatment plans, current use of integral boosts, and surgical procedures for this subgroup of patients.

Rectal admission of chemotherapeutic drugs in neoadjuvant treatment schemes of locally advanced rectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15168-e15168
Author(s):  
Luiza Korytova
Keyword(s):  
Rectal Cancer ◽  
Sodium Alginate ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Control Group ◽  
Treatment Results ◽  
Similar Treatment

e15168 Background: High incidence and steady rise of rectal cancer morbidity, unsatisfactory treatment results, amount of disabling surgery, high rate of local recurrents advocate for searching for new methods of combined treatment of locally advanced rectal cancer. Methods: We had suggested to rectally install sterile hydrogel material based on sodium alginate with incorporated 5-FU for radio modification purposes during neoadjuvant chemo radiotherapy. 39 patients with histologically confirmed diagnosis were included into our study. 19 patients received preoperative radiotherapy with summary dose of 50-56 Gy and systemic chemotherapy with fluorpirimidines and rectally admitted hydrogel material with incorporated 5-FU twice per day. Control group consisted of 20 patients who had similar treatment, excluding rectal hydrogel installations. Results: There was no increase in early radiotherapy complications noticed. Three study group patients had complete response, 16 had partial response (versus 1 CR, 15 PR, 3 stabilization and 1 progression in control group). This allowed reduction of surgical assistance volume in seven patients - sphincter-preserving operations were performed. Grade 3-4 pathomorphosis by Dworak’s scale was identified in 17 out of 19 patients (13 out of 20 in control group). Conclusions: Use of hydrogel material based on sodium alginate with incorporated 5-FU does not increase amount and intensity of radiation induced complications, allows to improve patients quality of life and treatment results.

Sign in / Sign up

Export Citation Format

Share Document