[A Case of Sarcoid‒Like Reaction with Multiple Lymphadenopathy by Rectal Cancer after an Operation].

We are reporting on a case of lymphadenopathy after surgery for rectal cancer. The case was a 66‒year‒old female. Laparoscopic high anterior resection(D3 dissection)was performed for rectal cancer(pT1bpN0M0, pStage Ⅰ)in April 2018, and she was followed up with on an outpatient basis. In July of the same year, a painless mass had formed in the right groin. An abdominal contrast‒enhanced CT showed lymph node swelling around the right groin and external iliac artery, but the tumor markers, CEA 2.3 ng/mL and CA19‒9 <2 U/mL, were within the standard values. An inguinal lymph node biopsy was performed during the same month. Pathological examination revealed no cancer cells and formation of epithelioid granuloma with giant cells. There was no suspicion of systemic sarcoidosis based on the test results and clinical findings. From the above, the patient was diagnosed with sarcoid reaction due to the tumor. Abdominal contrast‒enhanced CT scan 2 months after the biopsy showed lymph node shrinkage and there was no recurrence 2 years after the biopsy.

Multiple stage IV colorectal cancers in a patient who received multidisciplinary treatment, including chemotherapy and Japanese Kampo medicine: A case report.

FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab is the preferred first-line treatment for right-sided metastatic colorectal cancer with RAS mutation. However, severe adverse events are common in Japanese patients. We report the successful management of multiple stage IV colorectal cancers in a patient who received multidisciplinary treatment, including chemotherapy and Japanese Kampo medicine. A 68-year-old man presented with epigastralgia and appetite loss and was diagnosed with multiple stage IV colorectal cancers. Colonoscopy identified type II tumors in the ascending colon, sigmoid colon, and upper rectum. Histopathological examination of a biopsy specimen revealed well- to moderately differentiated tubular adenocarcinoma. Enhanced computed tomography of the thorax and abdomen showed multiple pulmonary nodules and para-aortic lymph node swelling. Laparoscopic loop-ileostomy was performed to avoid bowel obstruction due to severe stenosis of ascending colon cancer. Intraoperative observation revealed two white nodules suggestive of metastasis in the lateral area of the liver. Therefore, we diagnosed multiple stage IV colorectal cancers with multiple metastases (lung, liver, and distant lymph nodes). His postoperative course was uneventful, and chemotherapy was started. Since the cancer cells harbored a RAS mutation, he received FOLFOXIRI plus bevacizumab. Japanese Kampo medicine consisting of Hangeshashinto and Juzen-taiho-to, to prevent diarrhea and fatigue, was administered daily. After 12 courses of chemotherapy, though circumferential stenosis still existed in the ascending colon, the tumors in the sigmoid colon and upper rectum were unclear. Enhanced computed tomography showed shrinkage of the pulmonary nodules and para-aortic lymph node; therefore, laparoscopic-assisted ileocecal resection was performed. The postoperative histopathological examination revealed moderately differentiated adenocarcinoma. The patient recovered uneventfully, and Kampo medicine consisting of Ninjin'yoeito was administered for postoperative weakness. Administration of adjuvant chemotherapy in this patient led to a near complete response that has been maintained without recurrence for 2 years and 8 months without reduced quality of life.

Postoperative Adjuvant Chemotherapy Regimen of CAPOX Combined With Ninjin'yoeito in an Elderly Patient With Stage III Colon Cancer: A Case Report.

We report the successful management of stage III colon cancer in an elderly patient who received an adjuvant chemotherapy regimen of capecitabine plus oxaliplatin (CAPOX) with the Japanese kampo medicine ninjin'yoeito (NYT). A 75-year-old woman with a medical history of hypertension presented at another institution with fecal occult blood, and a colonoscopy that showed a type II tumor in the sigmoid colon. She was referred to our hospital for tumor resection, where colonoscopy confirmed the location of the type II tumor in the sigmoid colon. Histopathology of the biopsy specimen indicated a moderately differentiated tubular adenocarcinoma. Enhanced computed tomography of the thorax and abdomen indicated thickening of the sigmoid colon wall. Regional lymph node metastasis was suspected, but distant metastasis was not indicated. A blood examination revealed an elevated carcinoembryonic antigen (CEA) concentration (32.7 ng/ml). Following a diagnosis of cancer of the sigmoid colon, clinical stage IIIb [cT4a, N1b, M0], a laparoscopic sigmoid colectomy was performed without complications. The postoperative histopathological examination revealed a moderately differentiated to mucinous adenocarcinoma. Three of 16 retrieved lymph nodes contained malignant cells. The final tumor classification was Stage IIIb [pT4a, pN1b, M0]. The patient recovered uneventfully, and was discharged 10 days after surgery with a recommendation for adjuvant chemotherapy with CAPOX starting 4 weeks after surgery. The patient also received 7.5 g of NYT daily throughout the adjuvant chemotherapy course. She did not report any loss of appetite, general fatigue, peripheral neuropathy, neutropenia, or febrile neutropenia. During a 1-year postoperative follow-up, she has not experienced any recurrence. We conclude that NYT might be useful for reducing the adverse effects of anticancer therapy, particularly in elderly patients.

[Hemorrhage of Peritoneal Dissemination of the Ascending Colon Cancer Successfully Controlled by Palliative Radiotherapy-A Case Report].

An 81-year-old man underwent laparoscopic right hemicolectomy for ascending colon cancer. The postoperative diagnosis was tub1>tub2, pT4apN1bM0, pStage Ⅲb, ascending colon cancer. At 1 year 4 months after operation, abdominal CT showed dissemination around anastomosis. The patient has been treated with first-line systematic chemotherapy(capecitabine, oxaliplatin and bevacizumab). Epigastralgia and grade 4 anemia were observed at 5 years 7 months after initiation of chemotherapy when he was treated with second-line chemotherapy(capecitabine, irinotecan and bevacizumab). As abdominal CT showed that the dissemination progressed rapidly in size 30 mm to 100 mm, we diagnosed tumor bleeding in the dissemination. Palliative radiotherapy(30 Gy/10 Fr)for the dissemination was performed. Hemostasis and tumor shrinkage were achieved, and epigastralgia improved after receiving the radiation therapy. The patient discharged our hospital on 31 days form admission. We believe that palliative radiotherapy is effective to recurrent colon cancer with tumor bleeding.

[A Case of Intra-Abdominal Desmoid Tumors Occuring Four Years after Open Radical Prostatectomy].

Desmoid tumor is one kind of fibromatosis, and much occurs the abdominal wall and outside the abdominal wall. Intra- abdominal desmoid tumor is rare at about 8%. We experienced a case of intra-abdominal desmoid tumors occurring 4 years after open radical prostatectomy with some literature review. A 72-year-old man had undergone open radical prostatectomy for prostate cancer. Four years after that resection, multiple intra-abdominal tumors measuring 56 mm in maximum diameter was identified on follow-up computed tomography, and he was referred to our department for management. We performed laparotomy and investigation of the biopsy. Immunohistochemistry of the resected specimen indicated the tumor cells were positive for vimentin and ß-catenin, and the diagnosis was desmoid. We performed partial resection of the small intestine and ileocecal resection. His postoperative course was uneventful and he was discharged on the 12th postoperative day. He has shown no sign of recurrence in the 4 months follow-up since surgery. In the past, an operation was the best treatment for intra-abdominal desmoid tumor. But it is reported that watchful waiting is also possible by the case which has no symptom and dysfunction in NCCN guidelines 2019. Further research is needed.

[Hyperammonemia with Disturbance of Consciousness during 5-FU plus Nedaplatin Therapy for Esophageal Cancer-A Case Report].

Hyperammonemia is a rare adverse event of 5-FU. Here, we report a case of hyperammonemia with disturbance of consciousness during 5-FU plus nedaplatin therapy for esophageal cancer and present a literature review. A 69-year-old man was diagnosed with cT2N2M0, cStage Ⅲ esophageal cancer. He was administered with DCF therapy as the first-line neoadjuvant chemotherapy. After the first course, he showed renal dysfunction. Therefore, as the second-line neoadjuvant chemotherapy, he was administered with 5-FU plus nedaplatin. He vomited on treatment day 5 and suddenly presented with disturbance of consciousness on treatment day 6. Blood tests showed hyperammonemia(114 µg/dL). He was treated with rehydration and branched-chain amino acid solutions, resulting in a gradual improvement of symptoms. Hyperammonemia has been reported in patients with colorectal cancer but rarely in patients with esophageal cancer. A case of hyperammonemia during the 5-FU plus nedaplatin therapy has never been reported in Japan. We should be aware that 5-FU may cause hyperammonemia and resultant disturbance of consciousness during chemotherapy with 5-FU.

[A Case of Obstructing Rectal Cancer with Obstructive Colitis Resected after Neoadjuvant Chemotherapy to Avoid Anastomotic Leakage].

A 61-year-old male was referred to our department after decompression of the transanal ileus tube due to a rectal cancer obstruction. Colonoscopy revealed a circumferential type 2 tumor, 4 cm from the anal verge. The tumor was diagnosed as rectal cancer tub1-2, Group 5 on biopsy analysis. Longitudinal ulcers descending to the sigmoid colon were present and obstructive colitis was suspected. Enhanced computed tomography showed wall thickness in the Ra, Rb rectum and swelling of the mesorectum lymph node, but distant metastases were not identified. We diagnosed the patient with Ra, Rb rectal cancer cT4aN1aM0, cStage Ⅲb. Because of the risk of anastomotic leakage with obstructive colitis, we planned neoadjuvant chemotherapy(SOX therapy)after laparoscopic transverse colostomy. After neoadjuvant chemotherapy, colonoscopy revealed improvements in the obstructive colitis. The tumor was reduced in size and the chemotherapy appeared effective. We performed laparoscopic rectal super low anterior resection with resection of the D3 lymph node. Histopathological examination revealed tub1, ypT3, ypN0, and the chemotherapeutic outcome was rated as Grade 1a. The final diagnosis was Ra, Rb rectal cancer with ypT3ypN0M0, ypStage Ⅱa.

[A Case of Disseminated Carcinomatosis of the Bone Marrow with Carcinoma of the Rectum Diagnosed by Disseminated Intravascular Coagulation].

A 77-year-old man with rectal cancer was admitted to our hospital. After neoadjuvant chemotherapy, laparoscopic abdominoperineal resection of rectum with D3 dissection was performed. The pathological diagnosis was poorly differentiated carcinoma, pT3, N1a, M0, pStage Ⅲa. Adjuvant chemotherapy was not performed. Fifteen months after operation, his chief complaint was fatigue. Thrombocytopenia and elevation of tumor maker was detected by blood test and disseminated intravascular coagulation(DIC)was suspected. He was admitted to our hospital and we started anti DIC therapy immediately. Bone scintigraphy revealed multiple bone metastases, then we diagnosed disseminated carcinomatosis of the bone marrow. He died 10 days after hospitalization. Disseminated carcinomatosis of the bone marrow with colon cancer is rare and prognosis is very poor. It is important to diagnose and start treatment as early as possible.

[Effective Palliative Radiation for Hemostasis of Recurrent Colon Cancer in the Lymph Node with Gastric Wall Invasion].

A 76-year-old man underwent laparoscopic left hemicolectomy D3(pStage Ⅱb)for sigmoid colon cancer in 2015. Later, partial transverse colectomy D2(pStage Ⅱb)was performed because transverse cancer was also detected. Recurrent peritoneal dissemination was found in 2018. In 2019, hematemesis/black stool, as well as prominent anemia(Hb 3.1 g/dL)and bleeding from recurrent gastric wall invasion of the lymph nodes on the lesser curvature side of the stomach, was observed. Although hemostasis was performed endoscopically, palliative irradiation(30 Gy in 10 fractions)was performed to control bleeding because the risk of rebleeding was high. After irradiation, endoscopy showed that the ulcer in the infiltrated area of the gastric wall had a tendency to improve. No bleeding or progression of anemia was observed, and oral intake became possible. However, the patient's general condition deteriorated, and he died 80 days after palliative irradiation. For palliative radiation therapy, alleviation of pain owing to bone metastasis, as well as alleviation of the narrowed airway and esophagus, is known. Palliative radiation therapy has recently been performed for symptom relief and prognosis extension against tumor bleeding. Palliative radiation therapy for controlling bleeding has limited hemostatic effect compared with surgical resection, and it takes some time before hemostasis is achieved, but it is less invasive and less adverse event and may be an effective treatment option.

Change in PMI During Neoadjuvant Therapy Is a Predictive Prognostic Marker in Rectal Cancer.

BACKGROUND/AIM: Neoadjuvant therapy is often administered to patients with locally advanced rectal cancer (LARC). The aim of this study was to investigate the correlation between the change in the psoas muscle index (PMI) during neoadjuvant therapy and the prognosis of LARC patients. PATIENTS AND METHODS: Forty-seven patients who underwent potentially curative surgery for LARC with neoadjuvant therapy were enrolled in this study. We evaluated the relationship between the prognosis and clinicopathological factors, including the prognostic value of a change in the PMI. RESULTS: A >10% decrease in the PMI value was observed in 15 of the 47 patients. A >10% decrease in the PMI value was associated with shorter OS and RFS compared to patients who did not show a >10% decrease in their PMI. The decrease in PMI after neoadjuvant therapy was an independent negative prognostic factor for patients undergoing neoadjuvant therapy for LARC. CONCLUSION: A decrease in PMI after neoadjuvant therapy might predict a poor prognosis in LARC patients undergoing neoadjuvant therapy.

The prognostic significance of the advanced lung cancer inflammation index in patients with unresectable metastatic colorectal cancer: a retrospective study.

BACKGROUND: Growing evidence indicates that inflammation contributes to cancer progression, and several inflammatory markers have been reported to be associated with the clinical outcomes in patients with various types of cancer. Recently, the advanced lung cancer inflammation index (ALI) has been developed as a prognostic marker in patients with lung cancer. The difference between the ALI and the inflammatory markers reported in the previous studies is that the ALI contains not only indices related to inflammation but also the body mass index (BMI), which was reported to correlate with the sarcopenic status. The aim of this study was to evaluate the prognostic significance of the ALI in patients with unresectable metastatic colorectal cancer. METHODS: We retrospectively reviewed a database of 159 patients who underwent combination chemotherapy for unresectable metastatic colorectal cancer between 2008 and 2016. The BMI was calculated by dividing the weight by height squared. The neutrophil-to-lymphocyte ratio (NLR) was calculated from a blood sample by dividing the absolute neutrophil count by the absolute lymphocyte count. The ALI was defined as follows: ALI=BMI × serum albumin concentration/NLR. RESULTS: The overall survival rate was significantly worse in the low-ALI group than in the high-ALI group (p < 0.0001). Furthermore, the ALI was an independent prognostic factor for the overall survival (hazard ratio: 2.773, 95% confidence interval: 1.773-4.335, p < 0.001). CONCLUSIONS: A newly developed prognostic marker, the ALI, was found to be a novel prognostic marker in patients with unresectable metastatic colorectal cancer as well as in patients with lung cancer.

Prognostic Significance of the C-Reactive Protein-to-Albumin Ratio in Patients With Metastatic Colorectal Cancer Treated With Trifluridine/Thymidine Phosphorylase Inhibitor as Later-line Chemotherapy.

BACKGROUND/AIM: New drugs for metastatic colorectal cancer (mCRC) have been recently developed for use in later-line chemotherapy and have contributed to further prolongation of the survival of patients. However, in later-line chemotherapy, treatment failure may lead to discontinuation of chemotherapy and the transition to best supportive care. Therefore, a biomarker able to predict the effects of later-line chemotherapy is required. The C-reactive protein-to-albumin ratio (CAR), which is an inflammatory marker, has been reported to correlate with therapeutic outcome in patients with mCRC who underwent first-line chemotherapy. However, the significance of the CAR as a marker for predicting the chemotherapeutic outcome in patients with mCRC treated with later-line chemotherapy is unknown. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 40 patients with mCRC who were treated with trifluridine/thymidine phosphorylase inhibitor (FTD/TPI) as a later-line chemotherapy. The CAR was calculated from the blood samples obtained within 1 week before the initiation of FTD/TPI by dividing the serum C-reactive protein level by the serum albumin level. RESULTS: According to the receiver operating characteristic curve analysis, we set 0.122 as the CAR cut-off, and patients were classified into groups with high or low CAR. The low-CAR group had a significantly higher disease control rate than the high-CAR group. The progression-free and overall survival rates were significantly better in the low-CAR group than in the high-CAR group. A high-CAR was associated with a greater number of prior regimens, higher serum lactate dehydrogenase level and more organs with metastases, considered to be correlated with the rate of disease progression. However, no significant differences were observed in the incidence of grade 3 or more adverse events, the relative dose intensity, or the rate of discontinuing chemotherapy between the two groups. CONCLUSION: The CAR may be a useful indicator for predicting the chemotherapeutic outcome in patients with mCRC treated with FTD/TPI as a late-line chemotherapy. The correlation between a high-CAR and poor prognosis was presumed to be due to the rate of cancer growth and increased resistance to chemotherapy rather than an insufficient dose of the drug.

Impact of the occurrence of new lesions on the survival of patients who undergo chemotherapy for metastatic colorectal cancer.

In clinical practice, the efficacy of chemotherapy for metastatic colorectal cancer (mCRC) is typically evaluated according to the Response Evaluation Criteria in Solid Tumours (RECIST) criteria, and an appropriate treatment plan is determined. In the case of progressive disease (PD), the components of the treatment are altered; however, PD, as defined by the RECIST criteria, includes various types of progression. While detailed consideration regarding the impact of the growth pattern of measurable target lesions on survival has been performed, the impact of the occurrence of new lesions on survival is unclear. The aim of the present study was to assess the impact of the occurrence of new lesions on the survival of patients who underwent chemotherapy for mCRC. Among the patients who received doublet chemotherapy for mCRC as a first-line treatment between 2008 and 2016, 81, who stopped the chemotherapy due to PD, were enrolled in the present study. The types of progression were classified according to the definitions of RECIST. Subsequently, the following criteria were considered: The growth of measurable target lesions, the occurrence of new lesions and the unequivocal progression of non-target disease. Furthermore, the developing patterns of new lesions were also assessed. The association between the type of progression and the survival after the failure of the first-line chemotherapy was explored. Forty (49.4%) patients only experienced growth of measurable target lesions, 41 (50.6%) of the patients had new lesions and 3 (3.7%) of the patients had unequivocal progression of non-target disease. The survival rate from the discontinuation of first-line chemotherapy in patients with new lesions was significantly worse than that in patients without new lesions (P=0.0068); however, the developing patterns of new lesions were not associated with survival. Regardless of the developing patterns of new lesions, patients who stopped chemotherapy due to new lesions had worse survival rates from the discontinuation of first-line chemotherapy compared with those who stopped chemotherapy due only to the growth of measurable target lesions. Because the occurrence of new lesions represents severe progressive disease, patients with new lesions may require more intensive chemotherapy. The type of progression may be useful information for selecting the appropriate treatment following the failure of first-line chemotherapy.

Tumor-infiltrating Immune Cells in H&E-stained Sections of Colorectal Cancer Tissue as a Reasonable Immunological Biomarker.

BACKGROUND: The density of tumor-infiltrating lymphocytes has been reported to reflect the antitumor immune status, and many reports have shown that tumor-infiltrating CD8+ and total T-lymphocytes may be strong prognostic biomarkers in colorectal cancer. We previously reported that the density of tumor-infiltrating immune cells in hematoxylin and eosin (H&E)-stained sections may be an easily available prognostic biomarker. However, it remains unclear whether the density of tumor-infiltrating immune cells in H&E-stained sections accurately reflects the antitumor immune status. PATIENTS AND METHODS: A total of 308 patients who underwent curative resection for stage II/III colorectal cancer were enrolled. The density of both tumor-infiltrating immune cells in H&E-stained sections and tumor-infiltrating lymphocyte subsets was assessed by immunohistochemistry. RESULTS: The density of tumor-infiltrating immune cells in H&E-stained sections was significantly and positively correlated with that of tumor-infiltrating CD4+/CD8+/total T-lymphocytes. CONCLUSION: The density of tumor-infiltrating immune cells in H&E-stained sections may be a reasonable immunological biomarker.

Complete Response of Pulmonary Metastases from Rectal Cancer to Tegafur-Uracil/Leucovorin plus Bevacizumab in an Elderly Patient: A Case Report.

As a result of recent major advances in chemotherapy for metastatic colorectal cancer, the prognosis for patients with metastatic colorectal cancer has improved. However, elderly patients often cannot receive intensive therapy. There are still many problems to solve regarding treatment for elderly patients with metastatic colorectal cancer. We herein report a case of complete response of pulmonary metastases from rectal cancer to tegafur-uracil (UFT)/leucovorin (LV) + bevacizumab (Bmab) in an elderly patient. An 80-year-old woman who had undergone curative surgery for rectal cancer 5 years ago was diagnosed with pulmonary metastases. Taking into account her advanced age and low renal function (creatinine clearance: 41.2 mL/min), UFT/LV + Bmab therapy was selected. The patient received UFT (300 mg/m2/day) and LV (75 mg/day) on days 1-5, 8-12, and 15-19 and Bmab (7.5 mg/kg) on day 1. The treatment cycle was repeated every 21 days. Following 17 courses of treatment without adverse events, a complete response was observed. Furthermore, there was no recurrence within 6 months after the final course of therapy. This case indicates that UFT/LV + Bmab is suitable for the treatment of elderly patients with metastatic colorectal cancer.

Neoadjuvant Radiotherapy with Capecitabine Plus Bevacizumab for Locally Advanced Lower Rectal Cancer: Results of a Single-institute Phase II Study.

BACKGROUND/AIM: A single-arm phase II clinical trial was conducted to evaluate the safety and efficacy of adding bevacizumab to standard capecitabine-based neoadjuvant chemoradiotherapy (CRT) for the treatment of locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Twenty-five patients were enrolled. Patients received capecitabine-based CRT for 5 weeks and 3 days. Bevacizumab was administered every 2 weeks during CRT. Within 6-10 weeks after completion of CRT, surgery was performed. RESULTS: With regard to CRT-related acute toxicities, most of the adverse events were limited to grade 1. A pathological complete response was obtained in four (16%) patients. In total, six patients (24%) developed postoperative complications. Six out of five (83%) patients healed without the need for surgical intervention. CONCLUSION: Although acute toxicity during CRT with bevacizumab was minimal and postoperative complications do not seem to increase, the addition of bevacizumab apparently offers no clinically-significant benefit for patients with LARC.

The prognostic value of the systemic inflammatory score in patients with unresectable metastatic colorectal cancer.

Inflammation has been widely recognized as a contributor to cancer progression and several inflammatory markers have been reported as associated with the clinical outcomes in patients with various types of cancer. Recently, a novel inflammatory marker, the systemic inflammatory score (SIS), which is based on a combination of the lymphocyte-to-monocyte ratio (LMR) and the serum albumin concentration has been reported as a useful prognostic marker. The aim of the present study was to assess the prognostic value of the SIS in patients with unresectable metastatic colorectal cancer (mCRC). The retrospective cohort study included 160 patients who underwent combination chemotherapy for unresectable mCRC between January 2008 and December 2016. The SIS was used to classify the patients into three groups based on their LMR and the serum albumin concentration. Patients with high-LMR and high serum albumin level were given a score of 0; patients with low-LMR or low serum albumin level were given a score of 1; patients with low-LMR and low serum albumin level were given a score of 2. There were significant differences in the overall survival among the three SIS groups and the SIS was an independent prognostic factor for the overall survival. Although the SIS was significantly associated with the overall survival rate even when using the original cut-off values, the SIS according to the new cut-off values had a more accurate prognostic value. The present study determined that the SIS was a useful biomarker for predicting the survival outcomes in patients with unresectable mCRC, although the optimum cut-off value of the SIS according to the patients' background needs to be examined in further studies.

A comparison of the local immune status between the primary and metastatic tumor in colorectal cancer: a retrospective study.

BACKGROUND: The anticancer immune response has been reported to correlate with cancer progression. Tumor-infiltrating lymphocytes (TILs), which are one of the indicators of host immunity, affect the tumor growth, metastasis and chemoresistance. Both TILs in the primary tumor and those in the metastatic tumor have been reported to be a useful predictor of the survival and therapeutic outcome. However, the correlation between the density of TILs in the primary and metastatic tumor is unclear. The aim of this study was to elucidate the correlation between the density of TILs in the primary and metastatic tumor. METHODS: A total of 24 patients with stage IV colorectal cancer who underwent concurrent resection of the primary tumor and liver metastasis were enrolled in order to assess the correlation between the density of TILs in the primary tumor and that in the metastatic tumor. Hematoxylin and eosin (HE)-stained tumor sections were used for the evaluation of TILs. The density of TILs was assessed by the measurement of the area occupied by mononuclear inflammatory cells over the total stromal area at the invasive margin. In addition, to evaluate TIL subsets and the activation/suppression status of the lymphocytes, immunohistochemistry for CD4, CD8, Forkhead boxprotein P3 (FOXP3), programmed cell death 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), inducible T-cell co-stimulator (ICOS), Glucocorticoid induced tumor necrosis factor receptor related protein (GITR), Human Leukocyte Antigen - antigen D Related (HLA-DR) and Granzyme B was performed, and the number of immunoreactive lymphocytes was counted. RESULTS: According to the evaluation using the HE-stained sections, the density of tumor-infiltrating mononuclear inflammatory cells in the primary tumor was significantly associated with that in the metastatic tumor. In addition, according to the immunohistochemistry evaluation, the density of CD4+, CD8+ and FOXP3+ TILs in the primary tumor and that in the metastatic tumor were significantly correlated with that in the metastatic tumor. Furthermore, the activation/suppression marker values of the lymphocytes (i.e., such as PD-1, ICOS, Granzyme B and the PD-1/CD8 ratio) in the primary tumor were correlated with values in the metastatic tumor. CONCLUSIONS: The local immune status of the primary tumor was revealed to be similar to that of the metastatic tumor. This suggests that the evaluation of the local immunity of the primary tumor may be a substitute for the evaluation of the local immunity of the metastatic lesion. Therefore, information on the primary tumor may be useful when considering treatment strategies for metastatic lesions.

Verification of the methodology for evaluating tumor-infiltrating lymphocytes in colorectal cancer.

BACKGROUND: The density of tumor-infiltrating lymphocytes (TILs) have been reported to reflect antitumor immune response and correlate with prognosis in malignancy. However, the methodology for evaluating the density of TILs by an immunohistochemical analysis differs among reports. The aim of this study was to verify the methodology for evaluating the density of TILs by immunohistochemical analysis and thereby identify the optimum methodology in clinical setting. METHODS: Three-hundred-thirteen patients who underwent curative operation for stage II/III colorectal cancer were enrolled. We retrospectively examined the density of TILs using immunohistochemical staining according to each method as follows: 1) subset of lymphocytes (i.e. CD4+/CD8+), 2) selected fields (i.e. at random or focusing on hot spots), 3) location in low-power field (i.e. the invasive margin [TILsIM] or the center of the tumor [TILsCT] or the surface of the tumor [TILsST]), and 4) location in high-power field (i.e. in tumor stroma [sTILs] or intra-tumor cells [iTILs] or total TILs [tTILs: sTILs+iTILs]). We then assessed the prognostic value of the density of TILsIM evaluated as described above. We also evaluated the correlation between the density of TILsIM and that of TILsCT/TILsST. RESULTS: Only the densities of CD8+sTILsIM and CD8+tTILsIM evaluated in randomly selected fields were significantly associated with the survival. Furthermore, the density of CD8+TILsIM was significantly associated with that of CD8+TILsCT and CD8+TILsST. CONCLUSIONS: We concluded that best and easiest way to evaluate the density of TILs in the clinical setting may be to assess the density of CD8+tTILsIM in randomly selected fields.

A new method for evaluating tumor-infiltrating lymphocytes (TILs) in colorectal cancer using hematoxylin and eosin (H-E)-stained tumor sections.

PURPOSE: Numerous reports indicate that tumor-infiltrating lymphocytes (TILs) are a prognostic factor in various cancers and that they must be good biomarkers. However, the methods of evaluating TILs differ in each study; thus, there is not yet a standardized methodology for evaluating TILs. The purpose of this study is to evaluate the prognostic significance of tumor-infiltrating lymphocytes (TILs) in patients with colorectal cancer (CRC) using the new method proposed by the International TILs Working Group in breast cancer and to standardize the method of evaluating TILs in CRC. METHODS: We retrospectively reviewed a database of 160 patients with Stage II or III CRC. The density of TILs was assessed by measuring the area occupied by mononuclear cells over the stromal area on hematoxylin and eosin (H-E)-stained sections. We set 42% as the cut-off percentage of the area occupied by TILs according to the receiver operating characteristic curve, and we classified patients into the high-TILs and the low-TILs groups. RESULTS: The rates of relapse-free survival (RFS) and overall survival (OS) in the high-TILs group were significantly higher than those in the low-TILs group. A multivariate analysis showed that the density of TILs was independently associated with RFS and OS. Moreover, the density of TILs assessed by an observer was significantly associated with the density of TILs assessed by the automated imaging software program. CONCLUSIONS: The new method for evaluating TILs, which was recommended by the International TILs Working Group in breast cancer, might be a useful predictive factor in colorectal cancer patients.