Research ArticleClinical Studies

Effects of Preoperative Immunochemoradiotherapy and Chemoradiotherapy on Immune Responses in Patients with Rectal Adenocarcinoma

SOTARO SADAHIRO, TOSHIYUKI SUZUKI, YUJI MAEDA, AKIRA TANAKA, AKEMI KAMIJO, CHIEKO MURAYAMA, YUKO NAKAYAMA and TAKESHI AKIBA
Anticancer Research March 2010, 30 (3) 993-999;

Abstract

Background: We previously reported that preoperative chemoradiotherapy (CRT) combined with intraoperative electron irradiation for cT3/T4 adenocarcinoma of the rectum reduced the local recurrence, with significant improvement of survival. Radiotherapy has been reported to reduce immune function. We examined the effects of PSK, a protein-bound polysaccharide, concomitant with preoperative CRT on immune responses. Patients and Methods: Thirty patients with cT3/T4 adenocarcinoma of the rectum were randomly assigned to 2 weeks' irradiation and 4 weeks' S-1 administration before surgery (control group), or the same CRT with simultaneous 4 weeks' PSK administration (PSK group). Both systemic and local immune responses were evaluated. Results: Significant increase of natural killer cell count in the peripheral blood and cytotoxic T-cell counts in the peri-tumoral and normal mucosa, and a significant decrease of serum immunosuppressive acidic protein level were observed in the PSK group. Conclusion: Combined use of PSK with preoperative CRT may improve immune function.

Multimodal therapies, preoperative short-term intensive radiotherapy (RT), and conventional long-term radiotherapy with 5-fluouracil-based chemotherapy have gained wide acceptance for the treatment of locally advanced rectal adenocarcinoma (1-5). However, no significant improvements in the disease-free and overall survival rates have been achieved, although these treatments improve local control. We have used preoperative chemoradiotherapy (CRT) combined with intraoperative electron beam irradiation (IOR) for cT3/T4 or TxN+ adenocarcinoma of the middle or lower rectum, and reported a reduction in local recurrence to 3%, with significant improvement of survival (6, 7). Our regimen requires only 4 weeks between the start of RT and radical surgery.

RT has been reported to be associated with significant suppression of the immune system. Both B and T lymphocytes in peripheral blood decrease and inflammatory reaction in the irradiated field is suppressed (8-12). Local wound infection has been reported to increase after multimodal therapy (13). These results demonstrated that immune function of patients with rectal carcinomas treated with preoperative RT or CRT was suppressed during the perioperative period.

PSK, a protein-bound polysaccharide obtained from cultured mycelia of the Basidiomycete coriolus versicolor, activates various immunological functions including the activities of natural killer (NK) cells (14) and dendritic cells (15), and improves the prognosis of gastric (16) and colorectal cancer (17, 18). In the present study, we assessed the systemic and local immune functions of patients with rectal adenocarcinoma who received preoperative multimodal therapy, and also evaluated the effect of the immunomodulator PSK in preventing immunosuppression.

Patients and Methods

Patients. Patients with histologically confirmed adenocarcinoma of the middle or lower rectum (cT3-T4, Tx N+, M0) were enrolled. Additional eligibility criteria were as follows: no prior chemotherapy and/or pelvic radiation; Eastern Cooperative Oncology Group performance status ≤1; age between 20 and 80 years; and adequate organ function, defined as leukocyte count ≥4,000/μl and ≤12,000/μl, neutrophil count ≥2,000/μl, platelet count ≥100,000/μl, hemoglobin ≥9 g/dl, serum creatinine ≤1.1 mg/dl, serum bilirubin ≤1.5 mg/dl, and serum aspartate aminotransferase and alanine aminotransferase ≤100 U/l.

A total of 30 patients were registered. The patients were randomized before treatment into a control group (n=15) and a PSK group (n=15). Pretreatment stage was determined by computed tomography (CT), transrectal ultrasonography and magnetic resonance imaging (MRI). Pathological stage was based on histopathological findings of the resected specimen. The patient and tumor characteristics of the 30 patients in the current study cohort are shown in Table I. During therapy, toxicity was assessed weekly according to the Common Toxicity Criteria of National Cancer Institute version 2.0.

Preoperative chemoradiotherapy with or without PSK and surgical procedure. All patients received preoperative CRT. External beam RT for a total dose of 20 Gy was delivered in daily fractions of 2.0 Gy, 5 days a week for two weeks using a four-field box technique (6, 7). At the same time when RT was initiated, the control group also started to take oral S-1 (Taiho Pharmaceutical Co., Japan) 80 mg/m2/day divided into 2 daily doses and the PSK group started to take the same dose of S-1 together with PSK (Kureha Corporation, Japan) 3.0 g/day divided into 3 daily doses, for 4 weeks until 3 days before surgery. Approximately 2 weeks after completion of RT, both groups underwent radical surgery. During surgery, electron beam irradiation of 15 Gy was delivered according to the methods we reported previously (6, 7, 19).

Evaluation of systemic immunity in the peripheral blood. Before preoperative treatment was started and one day before surgery, the white blood cell count (WBC), neutrophil count, lymphocyte count, NK cell count and immunosuppressive acidic protein (IAP) level in the peripheral blood were determined.

Peripheral blood mononuclear cells were isolated from heparinized blood by density gradient centrifugation using Isolymph (Gallard-Schlesinger, NY, USA) according to the manufacturer's instructions. The proportion of NK cells were measured by direct immunofluorescence with fluorescein-conjugated monoclonal antibodies specific for CD16 (Beckman Coulter, FL, USA) and for CD57 (BD Bioscience, CA, USA) using flow cytometry. The proportion of CD16+/CD57+ cells among lymphocytes is shown as percentages. Serum IAP levels were measured by a turbidimetric immunoassay using San test IAP-N kits (Sanko Junyaku Co., Tokyo, Japan), according to the manufacturer's instructions.

Evaluation of local immunity in the resected specimen. Resected specimens containing rectal cancer were fixed in 4% (v/v) phosphate-buffered formalin, dehydrated and embedded in paraffin. Tumor tissue, peri-tumoral mucosa, and normal mucosa which was 5 cm or greater apart from the tumor, but within the radiation field were collected. Tissue sections of 4 μm were cut, mounted onto glass slides pretreated with 2% 3-aminopropyltriethoxysilane and dried overnight. Serial sections were stained with hematoxylin and eosin or processed for immunohistochemistry. Various inflammatory cells were assessed by immunohistochemical investigations with the following antibodies: anti-CD3 (monoclonal mouse anti-human T-cell, 1:200; DakoCytomation, Glostrup, Denmark), anti-CD4 (monoclonal mouse anti-human CD4, 1:40; Novocastra/Vision BioSystems, Norwell, MA, USA), anti-CD8 (monoclonal mouse anti-human CD8, 1:40; Novocastra/Vision BioSystems), anti-CD56 (monoclonal mouse anti-human N-CAM-16, 1:200; BD Pharmingen, BD Bioscience, San Diego, CA, USA), anti-AA1 (monoclonal mouse anti-human mast cell tryptase, 1:200; DakoCytomation), anti-CD68 (monoclonal mouse anti-human macrophage, 1:100; DakoCytomation), and anti-elastase (monoclonal mouse anti-human neutrophil elastase, 1:200; DakoCytomation).

For every tissue sample, cells were counted in 15-high power fields (2.1 mm2) according to the method of Nagtegaal et al. (20, 21), and expressed as number per mm2. Cell counting was conducted independently by two investigators (SS, AT), and the mean numbers were used for analyses.

View this table:
Table I.

Patient and tumor characteristics.

This study was approved by the Institutional Review Board of Tokai University and all patients provided written informed consent.

Statistical analysis. Data are presented as the mean±SD or number of patients. All statistical analyses were performed with SAS software (version 9.1.3, SAS Institute Inc., Cary, NC, USA). For statistical comparisons of the patient characteristics and immunological response in peripheral blood before preoperative treatment between the two groups, the chi-square test or unpaired t-test was used. The immunological response in peripheral blood was compared before and after treatment in the same group using paired t-test. The immunological response in the irradiated tissue was compared between the two groups using unpaired t-test. Two-sided p-values of less than 0.05 were considered statistically significant.

Results

Patient and tumor characteristics. No differences in male/female ratio and age were observed between the PSK and control groups (Table I). There were also no significant differences between the two groups in histological type determined from biopsies conducted before treatment, tumor diameter of resected specimens, or TNM staging of resection specimens.

Adverse effects during chemoradiotherapy. Adverse events of grade 3 or above were observed in one patient (7%) in the PSK group. All other adverse events observed in both groups were mild (Table II).

Immunological response in peripheral blood. No significant differences in peripheral blood values before preoperative treatment were observed between the control and PSK groups. The numbers of WBC, neutrophils, and lymphocytes were significantly reduced after chemoradiotherapy in both groups (Table III). The proportion of lymphocytes was significantly lower in the control group but did not change in the PSK group. No significant change in the proportion of NK cells was observed after chemoradiotherapy in the control group, while a significant increase in the proportion of NK cells was found in the PSK group. IAP level was significantly lowered in the PSK group.

View this table:
Table II.

Adverse effects during preoperative chemoradiotherapy and immunochemoradiotherapy.

View this table:
Table III.

Changes of immunological parameter in peripheral blood during preoperative chemoradiotherapy and immunochemoradiotherapy.

Immunological response in irradiated tissue. The numbers of T-cells, helper T-cells, cytotoxic T-cells, NK cells, mast cells, macrophages and neutrophils in tumor tissues showed great individual differences, and were not significantly different between the control and PSK groups (Table IV). In the PSK group, the number of cytotoxic T-cells in the peri-tumoral mucosa (p=0.005) and normal mucosa 5 cm or greater away from the tumor (p=0.003) was significantly greater than that of the resected control tissue (Figure 1). Furthermore, the NK cell count in normal mucosa tended to be higher in the PSK group, but the difference was only marginally significant (p=0.06).

Discussion

Bone marrow stem cells are extremely radiosensitive (22), and lymphopenia occurs almost immediately after RT with or without chemotherapy. During long-term RT for cancer of the breast (8, 9), prostate (8), testicles (8, 9, 12), lung (10) and uterus (11), the numbers of both B-cells and T-cells in the peripheral blood decrease after RT, and the number of naïve T-cells does not completely recover to normal even after several years (9).

In human adults, 40% of the total active bone marrow is distributed in the sacrum, hip bone and proximal femur (23). The radiation field of patients with anal cancer has been reported to include up to 50% of a patient's total hematopoietically active bone marrow (24). The proportion of active bone marrow distributed in the radiation field of patients with rectal cancer is also relatively large. In our present study, the numbers of WBC, neutrophils and lymphocytes were significantly reduced by fractionated RT at a total dose of 20 Gy delivered to the rectal region.

View this table:
Table IV.

Immune cell infiltration (n/mm2) in the resected specimen after preoperative chemoradiotherapy and immunochemoradiotherapy.

According to previous studies, although all subsets of peripheral lymphocytes decrease as a result of RT (10, 11), the degree of decrease, duration until recovery and degree of recovery differ among the subsets (9, 12). The decrease of NK cells has been reported to be relatively mild (11 12). In our study also, no significant change in the proportion of NK cells in peripheral blood was observed after CRT in the control group, while the proportion of NK cells significantly increased after therapy in the PSK group. The proportion of NK cells in peripheral blood before therapy did not reveal any significant differences between the two groups.

Although the mechanisms of action of the effects of PSK administration have not been elucidated, two possible mechanisms are speculated. The first possibility is that the decrease in NK cells is milder by PSK administration, based on the following findings: i) PSK alleviated leucopenia induced by chemotherapy in mice (25); and ii) PSK alleviated apoptosis of T-cells in peripheral blood induced by S-1 treatment in patients with gastric cancer (26). The second possibility is that PSK administration promotes the proliferation of NK cells, compensating for the decrease in the number of NK cells, based on the following reports: i) PSK showed in vitro mitogenic action against peripheral blood mononuclear cells of healthy individuals (27); ii) PSK promoted the proliferation of mouse splenic T-cells (28); iii) PSK promoted the proliferation of human NK cell line (29); iv) PSK promoted interleukin (IL)-2 production, although weakly, and increased IL-2 receptor expression in normal human lymphocytes (30, 31). Koda et al. (32) reported that rectal cancer patients with low NK cell activity before surgery had significantly lower metastasis-free survival, and that preoperative CRT impaired NK cell activity. The effect of any increase in the proportion of NK cells in the present study on clinical outcome has to be investigated in a larger scale randomized controlled study. Ohwada et al. (33) reported that PSK significantly prevented any decrease of the NK cell proportion in peripheral blood of colorectal cancer patients with curative resection, and the prognosis of patients with an increase of NK cell proportion was better than that of patients with a decrease or no change of NK cell proportion.

IAP is a protein that suppresses the immune response of lymphocytes against phytohemagglutinin (PHA) and other antigens. Serum IAP level has been reported to be elevated in cancer patients, and is related to cancer progression and prognosis (34, 35). Satomi et al. (36) reported a significant increase of IAP in the peripheral blood of patients with colorectal cancer compared to healthy controls. On the other hand, PSK has been reported to reduce IAP level (33, 37). In the present study, the IAP level was not changed in the control group but was significantly lowered by CRT with concomitant use of PSK. IAP level was reported to increase by IL-6 (38), and PSK has been shown to suppress IL-6 production (39). It is possible that the IAP level was reduced through suppression of IL-6 production. These results suggest that even under CRT, PSK is effective in improving the immunosuppressive state in cancer patients.

Figure 1.
Figure 1.

Immunohistochemical staining for cytotoxic T-cells in the normal mucosa after preoperative chemoradiotherapy and immunochemoradiotherapy. CD8-positive cells (cytotoxic T-cells) in normal mucosa were assessed as described in the Patients and Methods. a: Immunochemoradiotherapy: Many positive cells (dark brown) can be seen in the normal mucosa of patients given PSK. b: Chemoradiotherapy: A few positive cells are observed in the normal mucosa of patients not given PSK.

Mast cells (40-46), macrophages (41, 47-49), lymphocytes (50, 51), T-cells (52, 53) and NK cells (54) in cancer tissues have been investigated as biomarkers indicating proliferation and invasion of cancer cells, and angiogenesis. For colorectal cancer, a good prognosis is associated with a high lymphocyte count (50) and high NK cell count (54) in tumor tissue. The clinical significance of mast cells and macrophages has not been clarified.

Among patients enrolled in the total mesorectal excision (TME) trial, patients who underwent RT before surgery had a significantly lower numbers of T-cells (CD3+), cytotoxic T-cells (CD8+) and neutrophils in tumor tissue, as well as lower numbers of T-cells (CD3+), helper T-cells (CD4+), cytotoxic T-cells and neutrophils in peri-tumoral tissues compared to patients who underwent surgery alone (21). In patients who underwent abdominoperineal resection in the TME trial, the wound infection rate was 18% in patients who underwent surgery alone, and this increased to 29% in patients who had RT before surgery (13). This result may be associated with the impaired inflammatory reaction in patients who receive preoperative RT. In addition, patients with large numbers of macrophages, T-cells and cytotoxic T-cells in the tumor, and patients with large numbers of mast cells and basophils in peri-tumoral tissues have been reported to have good prognosis (20).

In the present study, the effect of concomitant use of PSK on lymphocyte counts within the tumor tissue was not clear due to large individual differences. However, the present study demonstrated that concomitant use of PSK significantly increased cytotoxic T-cells in peri-tumoral mucosa and normal mucosa within the irradiation field, as well as marginally increasing NK cells in the normal mucosa, although no increase in neutrophils was observed. Although we did not measure cytotoxic T-cells in peripheral blood in the present study, Nio et al. (55) reported that PSK treatment increased the proportion of cytotoxic T-cells in peripheral blood of patients with gastrointestinal cancer. As mentioned above, since PSK promotes lymphocyte proliferation and alleviates chemotherapy-induced leucopenia, the increase of cytotoxic T-cells or NK cells in peripheral blood may allow their migration to peri-tumor and normal mucosa. These findings suggest that PSK may promote local immunity in normal tissues within the radiation field.

Further clinical studies with larger samples will be needed to confirm the beneficial effects of combined use of PSK with preoperative CRT both on perioperative morbidity and prognosis in patients with rectal adenocarcinoma.

Footnotes

    • Received September 26, 2009.
    • Accepted January 12, 2010.

References

  1. ↵
    1. Sauer R,
    2. Becker H,
    3. Hohenberger W,
    4. Rödel C,
    5. Wittekind C,
    6. Fietkau R,
    7. Martus P,
    8. Tschmelitsch J,
    9. Hager E,
    10. Hess CF,
    11. Karstens JH,
    12. Liersch T,
    13. Schmidberger H,
    14. Raab R
    : Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351: 1731-1740, 2004.
    OpenUrlCrossRefPubMed
    1. Kapiteijn E,
    2. Marijnen CA,
    3. Nagtegaal ID,
    4. Putter H,
    5. Steup WH,
    6. Wiggers T,
    7. Rutten HJ,
    8. Pahlman L,
    9. Glimelius B,
    10. van Krieken JH,
    11. Leer JW,
    12. van de Velde CJ
    : Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345: 638-646, 2001.
    OpenUrlCrossRefPubMed
    1. Bujko K,
    2. Nowacki MP,
    3. Nasierowska-Guttmejer A,
    4. Michalski W,
    5. Bebanek M,
    6. Kryj M
    : Long-term results of a randomized trail comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 93: 1215-1223, 2006.
    OpenUrlCrossRefPubMed
    1. Bosset JF,
    2. Collette L,
    3. Calais G,
    4. Mineur L,
    5. Maingon P,
    6. Padosevic-Jelic L,
    7. Daban A,
    8. Bardet E,
    9. Beny A,
    10. Ollier JC
    : Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355: 1114-1123, 2006.
    OpenUrlCrossRefPubMed
  5. ↵
    1. Gérard JP,
    2. Conroy T,
    3. Bonnetain F,
    4. Bouché O,
    5. Chapet O,
    6. Closon-Dejardin MT,
    7. Untereiner M,
    8. Leduc B,
    9. Francois E,
    10. Maurel J,
    11. Seitz JF,
    12. Buecher B,
    13. Mackiewicz R,
    14. Ducreux M,
    15. Bedenne L
    : Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 24: 4620-4625, 2006.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Sadahiro S,
    2. Suzuki T,
    3. Ishikawa K,
    4. Yasuda S,
    5. Tajima T,
    6. Makuuchi H,
    7. Murayama C,
    8. Ohizumi Y
    : Intraoperative radiation therapy for curatively resected rectal cancer. Dis Colon Rectum 44: 1689-1695, 2001.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Sadahiro S,
    2. Suzuki T,
    3. Ishikawa K,
    4. Fukasawa M,
    5. Saguchi T,
    6. Yasuda S,
    7. Makuuchi H,
    8. Murayama C,
    9. Ohizumi Y
    : Preoperative radio/chemo-radiotherapy in combination with intraoperative radiotherapy for T3-4Nx Rectal Cancer. Eur J Surg Oncol 30: 750-758, 2004.
    OpenUrlPubMed
  8. ↵
    1. Hoppe RT,
    2. Fuks ZY,
    3. Strober S,
    4. Kaplan HS
    : The long term effects of radiation on T and B lymphocytes in the peripheral blood after regional irradiation. Cancer 40: 2071-2078, 1977.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Ruysscher DD,
    2. Waer M,
    3. Vandeputte M,
    4. Aerts R,
    5. Vantongelan K,
    6. vander Schueren E
    : Changes of lymphocyte subsets after local irradiation for early-stage breast cancer and seminoma testis: long-term increase of activated (HLA-DR+) T-cells and decrease of ‘naïve’ (CD4-CD45R) T lymphocytes. Eur J Cancer 28A: 1729-1734, 1992.
    OpenUrlPubMed
  10. ↵
    1. Nakayama Y,
    2. Makino S,
    3. Fukuda Y,
    4. Min KY,
    5. Ikemoto T,
    6. Shimizu A,
    7. Ohsawa N
    : Varied effects of thoracic irradiation on peripheral lymphocyte subsets in lung cancer patients. Inter Med 34: 959-965, 1995.
    OpenUrl
  11. ↵
    1. Louagie H,
    2. Van Eijkeren M,
    3. Philippe J,
    4. Thierens H,
    5. de Ridder L
    : Changes in peripheral blood lymphocyte subsets in patients undergoing radiotherapy. Int J Radiat Biol 75: 767-771, 1999.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Belka C,
    2. Ottinger H,
    3. Kreuzfelder E,
    4. Weinmann M,
    5. Lindermann M,
    6. Lepple-Wienhues A,
    7. Budach W,
    8. Grosse-Wilde H,
    9. Bamberg M
    : Impact of localized radiotherapy on blood immune cell counts and function in humans. Radiother Oncol 50: 199-204, 1999.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Marijnen CA,
    2. Kapiteijn E,
    3. van de Velde CJ,
    4. Martijn H,
    5. Steup WH,
    6. Wiggers T,
    7. Kranenbarg EK,
    8. Leer JW
    : Acute side-effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol 20: 817-825, 2002.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Algarra I,
    2. Collado A,
    3. Garrido F
    : Protein bound polysaccharide PSK abrogates more efficiently experimental metastasis derived from H-2-negative than from H-2-positive fibrosarcoma tumor clones. J Exp Clin Canc Res 16: 373-380, 1997.
    OpenUrl
  15. ↵
    1. Kanazawa M,
    2. Mori Y,
    3. Yoshihara K,
    4. Iwadate M,
    5. Suzuki S,
    6. Endoh Y,
    7. Ohki S,
    8. Takita K,
    9. Sekikawa K,
    10. Takenoshita S
    : Effect of PSK on the maturation of dendritic cells derived from human peripheral blood monocytes. Immunol Lett 91: 229-238, 2004.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Nakazato H,
    2. Koike A,
    3. Saji S,
    4. Ogawa N,
    5. Sakamoto J
    : Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Lancet 343: 1122-1126, 1994.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Mitomi T,
    2. Tsuchiya S,
    3. Iijima N,
    4. Aso K,
    5. Suzuki K,
    6. Nishiyama K,
    7. Amano T,
    8. Takahashi T,
    9. Murayama N,
    10. Oka H,
    11. Oya K,
    12. Noto T,
    13. Ogawa N
    : Randomized, controlled study on adjuvant immunochemotherapy with PSK in curatively resected colorectal cancer. Dis Colon Rectum 35: 123-130, 1992.
    OpenUrlCrossRefPubMed
  18. ↵
    1. Ohwada S,
    2. Ikeya T,
    3. Yokomori T,
    4. Kusaba T,
    5. Roppongi T,
    6. Takahashi T,
    7. Nakamura S,
    8. Kakinuma S,
    9. Iwazaki S,
    10. Ishikawa H,
    11. Kawate S,
    12. Nakajima T,
    13. Morishita Y
    : Adjuvant immunochemotherapy with oral tegafur/uracil plus PSK in patients with stage II or III colorectal cancer: a randomized controlled study. Br J Cancer 90: 1003-1010, 2004.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Sadahiro S,
    2. Suzuki T,
    3. Ishikawa K,
    4. Mukai M,
    5. Tokunaga N,
    6. Tajima T,
    7. Makuuchi H,
    8. Tsuda M,
    9. Murayama C,
    10. Mori T,
    11. Abe H
    : Development of an irradiation method of intraoperative radiation therapy for curatively resected rectal cancer. Int J Clin Oncol 4: 210-214, 1999.
    OpenUrlCrossRef
  20. ↵
    1. Nagtegaal ID,
    2. Marijnen CAM,
    3. Kranenbarg EK,
    4. Mulder-Stapel A,
    5. Hermans J,
    6. van de Velde CJ,
    7. van Krieken JH
    : Local and distant recurrences in rectal cancer patients are predicted by the nonspecific immune response; specific immune response has only a systemic effect – a histopathological and immunohistochemical study. BMC Cancer 1: 7, 2001.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Nagtegaal ID,
    2. Marijnen CAM,
    3. Kranenbarg EK,
    4. Mulder-Stapel A,
    5. Hermans J,
    6. van de Velde CJ,
    7. van Krieken JH
    : Short-term preoperative radiotherapy interferes with the determination of pathological parameters in rectal cancer. J Pathol 197: 20-27, 2002.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Mauch P,
    2. Constine L,
    3. Greenberger J,
    4. Knospe W,
    5. Sullivan J,
    6. Liesveld JL,
    7. Deeg HJ
    : Hematopoietic stem cells compartment: acute and late effects of radiation therapy. Int J Radiat Oncol Biol Phys 31: 1319-1339, 1995.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Ellis RE
    : The distribution of active bone marrow in the adult. Phys Med Biol 5: 255-258, 1961.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Mell LK,
    2. Schomas DA,
    3. Salama JK,
    4. Devisetty K,
    5. Aydogan B,
    6. Miller RC,
    7. Jani AB,
    8. Kindler HL,
    9. Mundt AJ,
    10. Roeske JC,
    11. Chmura SJ
    : Association between bone marrow dosimetric parameters and acute hematologic toxicity in anal cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 70: 1431-1437, 2008.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Mizuno D,
    2. Chihara G,
    3. Fukuoka F,
    4. Yamamoto T,
    5. Yamamura Y
    1. Tsukagoshi S
    : Fundamental approaches to cancer immunotherapy using a protein-bound polysaccharide, PS-K, with special reference to its clinical application. In: Host Defense against Cancer and Its Potentiation. Mizuno D, Chihara G, Fukuoka F, Yamamoto T, Yamamura Y (eds.). Tokyo, University of Tokyo Press, pp. 365-377, 1975.
  26. ↵
    1. Kono K,
    2. Kawaguchi Y,
    3. Mizukami Y,
    4. Mimura K,
    5. Sugai H,
    6. Akaike H,
    7. Fujii H
    : Protein-bound polysaccharide K partially prevents apoptosis of circulating T-cells induced by anti-cancer drugs S-1 in patients with gastric cancer. Oncology 74: 143-149, 2008.
    OpenUrlPubMed
  27. ↵
    1. Ohno R,
    2. Yokomaku S,
    3. Wakayama K,
    4. Sugiura S,
    5. Yamada K
    : Blastoid transformation of human lymphocytes cultured with protein-bound polysaccharide preparation, PS-K, in vitro. Gann 67: 713-716, 1976.
    OpenUrlPubMed
  28. ↵
    1. Hirai R,
    2. Oguchi Y,
    3. Sugita N,
    4. Matsunaga K,
    5. Nomoto K
    : Enhancement of T-cell proliferation by PSK. Int J Immunopharmacol 15: 745-750, 1993.
    OpenUrlCrossRefPubMed
  29. ↵
    1. Jimenez-Medina E,
    2. Berruguilla E,
    3. Romero I,
    4. Algarra I,
    5. Collado A,
    6. Garrido F,
    7. Garcia-Lora A
    : The immunomodulator PSK induces in vitro cytotoxic activity in tumor cell lines via arrest of cell cycle and induction of apoptosis. BMC Cancer 8: 78, 2008.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Ueda Y,
    2. Yamagishi H,
    3. Naito K,
    4. Kobayashi M,
    5. Hamagashira K,
    6. Komichi H,
    7. Omori K,
    8. Oka T
    : Effects of OK-432 or PSK on in vitro activation of T-lymphocytes from human peripheral blood. Biotherapy 4: 712-716, 1990.
    OpenUrl
  31. ↵
    1. Yamaguchi Y,
    2. Minami K,
    3. Ohshita A,
    4. Kawabuchi Y,
    5. Noma K,
    6. Toge T
    : Enhancing effect of PS-K on IL-2-induced lymphocyte activation: possible involvement of antagonistic action against TGF-beta. Anticancer Res 24: 639-64, 2004.
    OpenUrlAbstract/FREE Full Text
  32. ↵
    1. Koda K,
    2. Saito N,
    3. Oda K,
    4. Seike K,
    5. Kondo E,
    6. Ishizuka M,
    7. Takiguchi N,
    8. Miyazaki M
    : Natural killer cell activity and distant metastasis in rectal cancers treated surgically with and without neoadjuvant chemoradiotherapy. J Am Coll Surg 197: 254-260, 2003.
    OpenUrlCrossRefPubMed
  33. ↵
    1. Ohwada S,
    2. Ogawa T,
    3. Makita F,
    4. Tanahashi Y,
    5. Ohya T,
    6. Tomizawa N,
    7. Satoh Y,
    8. Kobayashi I,
    9. Izumi M,
    10. Takeyoshi I,
    11. Hamada K,
    12. Minaguchi S,
    13. Togo Y,
    14. Toshihiko T,
    15. Koyama T,
    16. Kamio M
    : Beneficial effects of protein-bound polysaccharide K plus tegafur/uracil in patients with stage II or III colorectal cancer: Analysis of immunological parameters. Oncol Rep 15: 861-868, 2006.
    OpenUrlPubMed
  34. ↵
    1. Tamura K,
    2. Shibata Y,
    3. Matsuda Y,
    4. Ishida N
    : Isolation and characterization of an immunosuppressive acidic protein from ascitic fluids of cancer patients. Cancer Res 41: 3244-3252, 1981.
    OpenUrlAbstract/FREE Full Text
  35. ↵
    1. Kikuchi S
    : Serum levels of immunosuppressive acidic protein (IAP) in various disease states and its clinical significance. J Jpn Surg Soc 85: 283-299, 1984.
    OpenUrl
  36. ↵
    1. Satomi A,
    2. Murakami S,
    3. Ishida N,
    4. Matsuki M,
    5. Hashimoto T,
    6. Sonoda M
    : Significance of increased neurophils in patients with advanced colorectal cancer. Acta Oncol 34: 69-73, 1995.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Inokuchi K,
    2. Kumashiro R
    : Chemotherapy for gastric cancer. Surg Therapy 42: 40-46, 1980.
    OpenUrl
  38. ↵
    1. Ikuta S,
    2. Miki C,
    3. Tanaka K,
    4. Konishi N,
    5. Mohri Y,
    6. Tonouchi H,
    7. Kusunoki M
    : Serum immunosuppressive acidic protein as an interleukin-6 related index of deteriorating condition in gastric cancer patients. Dig Surg 20: 532-538, 2003.
    OpenUrlPubMed
  39. ↵
    1. Ooshiro M,
    2. Sugishita Y,
    3. Tanaka H,
    4. Koide K,
    5. Nagashima M,
    6. Katoh R
    : Regulation of perioperative immunological changes following laparotomy: effects of biological response modifier (BRM) on surgical stress. Immunol Lett 93: 33-38, 2004.
    OpenUrlCrossRefPubMed
  40. ↵
    1. Reynolds JL,
    2. Akhter J,
    3. Adams WJ,
    4. Morris DL
    : Histamine content in colorectal cancer. Are there sufficient levels of histamine to affect lymphocyte function? Eur J Surg Oncol 23: 224-227, 1997.
    OpenUrlPubMed
  41. ↵
    1. Dabbous MK,
    2. North SM,
    3. Haney L,
    4. Tipon DA,
    5. Nicolson GL
    : Effects of mast cell-macrophage interactions on the production of collagenolytic enzymes by metastatic tumor cells and tumor-derived and stromal fibroblasts. Clin Exp Metastasis 13: 33-41, 1995.
    OpenUrlPubMed
    1. Dimitriadou V,
    2. Koutsilieris M
    : Mast cell-tumor cell interactions: for or against tumor growth and metastasis? Anticancer Res 17: 1541-1549, 1997.
    OpenUrlPubMed
    1. Lachter J,
    2. Stein M,
    3. Lichtig C,
    4. Eidelman S,
    5. Munichor M
    : Mast cells in colorectal neoplasias and premalignant disorders. Dis Colon Rectum 38: 290-293, 1995.
    OpenUrlCrossRefPubMed
    1. Fisher ER,
    2. Paik SM,
    3. Rockette H,
    4. Jones J,
    5. Caplan R,
    6. Fisher B
    : Prognostic significance of eosinophils and mast cells in rectal cancer: findings from the National Surgical Adjuvant Breast and Bowel Projects (protocol R-01). Hum Pathol 20: 159-163, 1989.
    OpenUrlCrossRefPubMed
    1. Nielsen HJ,
    2. Hansen U,
    3. Christensen IJ,
    4. Reimert CM,
    5. Brünner N,
    6. Moesgaard F
    : Independent prognostic value of eosinophil and mast cell infiltration in colorectal cancer tissues. J Pathol 189: 487-495, 1999.
    OpenUrlCrossRefPubMed
  46. ↵
    1. Pretlow TP,
    2. Keith EF,
    3. Cryar AK,
    4. Bartolucci AA,
    5. Pitts AM,
    6. Pretlow TG 2nd,
    7. Kimball PM,
    8. Boohaker EA
    : Eosinophil infiltration of human colonic carcinomas as a prognostic indicator. Cancer Res 43: 2997-3000, 1983.
    OpenUrlAbstract/FREE Full Text
  47. ↵
    1. Håkansson L,
    2. Adell G,
    3. Boeryd B,
    4. Sjögren F,
    5. Sjödahl R
    : Infiltration of mononuclear inflammatory cells into primary colorectal carcinomas: an immunohistological analysis. Br J Cancer 75: 374-380, 1997.
    OpenUrlPubMed
    1. Skinner JM,
    2. Jarvis LR,
    3. Whitehead R
    : The cellular response to human colonic neoplasms: macrophage numbers. J Pathol 139: 97-103, 1983.
    OpenUrlPubMed
  49. ↵
    1. Higgins CA,
    2. Hatton WJ,
    3. McKerr G,
    4. Harvey D,
    5. Carson J,
    6. Hannigan BM
    : Macrophages and apoptotic cells in human colorectal tumours. Biologicals 24: 329-332, 1996.
    OpenUrlPubMed
  50. ↵
    1. Ropponen KM,
    2. Eskelinen MJ,
    3. Lipponen PK,
    4. Alhava E,
    5. Kosma VM
    : Prognostic value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 182: 318-324, 1997.
    OpenUrlCrossRefPubMed
  51. ↵
    1. Jass JR,
    2. Love SB,
    3. Northover JM
    : A new prognostic classification of rectal cancer. Lancet 1: 1303-1306, 1987.
    OpenUrlCrossRefPubMed
  52. ↵
    1. Dolcetti R,
    2. Viel A,
    3. Doglioni C,
    4. Russo A,
    5. Guidoboni M,
    6. Capozzi E,
    7. Vecchiato N,
    8. Macrì E,
    9. Fornasarig M,
    10. Boiocchi M
    : High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol 154: 1805-1813, 1999.
    OpenUrlCrossRefPubMed
  53. ↵
    1. Goedegebuure PS,
    2. Eberlein TJ
    : The role of CD4+ tumor-infiltrating lymphocytes in human solid tumors. Immunol Res 14: 119-131, 1995.
    OpenUrlCrossRefPubMed
  54. ↵
    1. Coca S,
    2. Perez-Piqueras J,
    3. Martinez D,
    4. Colmenarejo A,
    5. Saez MA,
    6. Vallejo C,
    7. Martos JA,
    8. Moreno M
    : The prognostic significance of intratumoral natural killer cells in patients with colorectal cancer. Cancer 79: 2320-2328, 1997.
    OpenUrlCrossRefPubMed
  55. ↵
    1. Nio Y,
    2. Tsubono M,
    3. Chen-Chiu T,
    4. Morimoto H,
    5. Kawabata K,
    6. Masai Y,
    7. Shiraishi T,
    8. Imai S,
    9. Ohgaki K,
    10. Tobe T
    : Immunomodulation by orally administered protein-bound polysaccharide PSK in patients with gastrointestinal cancer. Biotherapy 4: 117-128, 1992.
    OpenUrlPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Effects of Preoperative Immunochemoradiotherapy and Chemoradiotherapy on Immune Responses in Patients with Rectal Adenocarcinoma
SOTARO SADAHIRO, TOSHIYUKI SUZUKI, YUJI MAEDA, AKIRA TANAKA, AKEMI KAMIJO, CHIEKO MURAYAMA, YUKO NAKAYAMA, TAKESHI AKIBA
Anticancer Research Mar 2010, 30 (3) 993-999;
Twitter logo Facebook logo Mendeley logo

Jump to section