Clinical Significance of Expression of Immunoadjuvant Molecules (LAG-3, TIM-3, OX-40) in Neoadjuvant Chemotherapy for Breast Cancer.

BACKGROUND/AIM: Various immunosuppressive factors that inhibit the immune response to cancer are present in cancer cells and the cancer microenvironment. Co-inhibitory and co-stimulatory receptors are dynamically expressed on T-cells as immunoadjuvant molecules that regulate the state of T-cell activity. In this report we focus on immunoadjuvant molecules such as LAG-3, TIM-3, and OX-40, for which there have been few published reports. We investigated the expression of LAG-3, TIM-3 and OX-40 in tumor-infiltrating lymphocytes (TILs), and clinically verified the significance of that expression in relation to neoadjuvant thermotherapy (NAC). PATIENTS AND METHODS: A total of 177 patients with resectable early-stage breast cancer were treated with NAC. Estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki67, LAG-3, TIM-3 and OX-40 status were assessed by immunohistochemistry. RESULTS: The group with low-LAG-3 expression was significantly smaller than the group with high expression in triple-negative breast cancer (TNBC) (p=0.038) and HER2-enriched breast cancer (HER2BC) (p=0.021), while the total number of pathological complete response (pCR) patients was greater (p<0.001). In TNBC and HER2BC, the pCR rate was significantly higher in the low-LAG-3 expression group than in the high-LAG-3 expression group (p<0.001 and p=0.02, respectively). Moreover, on multivariate analysis low-LAG-3 expression status was an independent predictor of favorable prognosis (TNBC: p=0.014, HR=8.124; HER2BC: p=0.048, HR=10.400). CONCLUSION: Our findings suggest that LAG-3 may become a biomarker in highly malignant breast cancers such as TNBC and HER2BC that can predict the therapeutic efficacy of NAC.

Verification of the effects of calcium channel blockers on the immune microenvironment of breast cancer.

BACKGROUND: A higher density of tumor-infiltrating lymphocytes (TILs) can lead to greater therapeutic effects and improved prognoses in cancer treatment. Similar results have been observed in breast cancer, particularly in triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2-enriched breast cancer. Calcium channel blockers (CCBs) are antihypertensive drugs (AHTs) that have also been reported to suppress the functions of T cells and macrophages. In this study, we evaluated TILs before pre-operative chemotherapy (POC) in breast cancer and retrospectively analyzed the correlation between CCBs and TILs or prognosis. METHODS: Of the patients treated with POC, 338 who had evaluable TILs were enrolled in this study. The correlations among TILs were evaluated according to standard methods, and CCB use and prognosis were investigated retrospectively. RESULTS: Before POC, 65 patients (19.2%) took AHTs (CCBs: 41/338, 12.1%). The TIL density was significantly lower among patients administered CCBs for the group of all patients and for patients with TNBC (p = 0.040, p = 0.009, respectively). Additionally, patients with TNBC who were administered CCBs showed significantly lower response rates for POC (p = 0.040). In all patients receiving POC, no significant differences in disease-free survival (DFS) or overall survival (OS) were observed in patients administered CCBs (p = 0.712, p = 0.478, log-rank tests, respectively). Furthermore, no significant differences were found, even in patients with TNBC (DFS: p = 0.441, OS: p = 0.727, log-rank tests, respectively). CONCLUSIONS: In patients with TNBC undergoing treatment for hypertension with CCBs, TILs in the needle biopsy specimens before treatment were significantly lower, and the response rate of POC was not sufficient. Thus, the immunosuppressive effects of CCBs may also affect the immune microenvironment.

[A Case of Curative Resection of Locally Advanced Gastric Cancer after Nutrition Therapy and Chemotherapy with S-1 and Oxaliplatin Using Elemental Diet Tube].

We report a case of advanced gastric cancer with stenosis under severe malnutrition, in which nutritional treatment along with chemotherapy using an elemental diet(ED)tube led to complete resection of the tumor. A 66-year-old man who presented with difficulty in dietary intake came to our hospital. He was emaciated with a body mass index(BMI)score of 13.5 and a prognostic nutritional index(PNI)score of 33.8 and was admitted to the hospital for an emergency. He was diagnosed with advanced gastric cardia cancer invading the distal pancreas, spleen, and left diaphragm(U, type 3, tub2, cT4bN3M0, cStage ⅢC, HER2 score 0). There was obstruction of the passage of food due to the tumor, we performed nutrition therapy and chemotherapy consisting of 3 courses of S-1 and oxaliplatin using an ED tube. After chemotherapy, the primary tumor and lymph nodes were reduced, and we performed total gastrectomy with D2 lymph node, distal pancreas, spleen, and left partial diaphragm dissection. Histopathological diagnosis was ypT4aN1M0, ypStage ⅢA, indicating a pathological partial response(Grade 1). Adjuvant chemotherapy was performed for 6 months, and there has been no relapse for 3 years since the operation.

Cervical chylous leakage following esophagectomy that was successfully treated by intranodal lipiodol lymphangiography: a case report.

BACKGROUND: Chylous leakage is a well-known complication after esophagectomy, but cervical chylous leakage is relatively rare, and considerable controversy remains regarding the appropriate management strategies. We herein report a case of cervical chylous leakage treated successfully by lipiodol lymphangiography. CASE PRESENTATION: The patient, a 70-year-old man with middle thoracic esophageal cancer, underwent radical esophagectomy with 3-field lymph node dissection and subsequently developed cervical chylous leakage. From the second postoperative day (POD2), the amount of fluid in the cervical drainage tube increased by 200-300 ml/day. We started octreotide (300 µg/day) on POD5 and etilefrine (120 mg/day) on the POD6. However, the amount of cervical discharge did not decrease. We performed lipiodol lymphangiography on POD8. Thereafter, the amount of cervical discharge finally began to decrease. We removed the drainage tube on POD13, and the patient was discharged from the hospital on POD23. CONCLUSIONS: Our case suggests the clinical efficacy of lipiodol lymphangiography for cervical chylous leakage after esophagectomy.

Platelet-Lymphocyte Ratio as a Useful Predictor of the Therapeutic Effect of Neoadjuvant Chemotherapy in Breast Cancer.

BACKGROUND: The peripheral blood platelet-lymphocyte ratio (PLR) has been proposed as an indicator for evaluating systemic inflammatory responses in cancer-bearing patients. While some reports suggest a correlation between PLR and prognosis, few studies have examined the relationship between PLR and sensitivity to chemotherapy. We conducted a study on whether PLR could serve as a predictor of the therapeutic effects of neoadjuvant chemotherapy (NAC). METHODS: PLR was evaluated in 177 breast cancer patients treated with the NAC 5-fluorouracil, epirubicin and cyclophosphamide, followed by weekly paclitaxel and subsequent curative surgery. The correlation between PLR and prognosis, and between PLR and the efficacy of NAC, were evaluated retrospectively. RESULTS: The low PLR group had significantly more patients > 56 years old (p = 0.001) and postmenopausal women (p = 0.001) than the high PLR group. The low PLR group also had a higher pathologic complete response (pCR) rate (p = 0.019). On examining the correlation with prognosis, the low-PLR group was found to have significantly longer disease-free survival (p = 0.004) and overall survival (p = 0.032) than the high PLR group. Multivariate analysis also revealed that lymph node metastasis (p = 0.043, hazard ratio = 4.40) and a high PLR (p = 0.005, hazard ratio = 2.84) were independent, unfavorable prognostic factors. CONCLUSIONS: For patients with breast cancer treated with NAC, a low PLR indicated high chemotherapy sensitivity, suggesting that PLR could serve as a predictive marker of the therapeutic effect of NAC.

The significance and the predictive factors of microscopic lymph node metastasis in patients with clinically node negative papillary thyroid cancer: A retrospective cohort study.

BACKGROUND: The management of pathological lateral node involvement (pN1b) from papillary thyroid cancer (PTC) are controversial. METHODS: A consecutive series of 246 patients, diagnosed with clinically node negative (cN0) PTC who had undergone surgery with prophylactic lateral node dissection, and without postoperative radioactive iodine administration from 2001 to 11, were reviewed to clarify the significance of pN1b. RESULTS: Eighty-five (35%) patients had pN1b disease. One-half and 30% had pN1b in younger (age less than 45) and older patients (age 45 or over), respectively. Tumor size (≥ 21 mm) could predict pN1b disease in older patients. Patients with pN1b disease recurred more frequently (9 cases, 10.6%) than those without (4 cases, 2.4%), and 2 cases with pN1b died of the disease. CONCLUSIONS: pN1b disease was commonly found in patients with PTC even when they were diagnosed clinically as node negative. pN1b disease with prognostic meaning was often found in the older patients with larger PTC indicating the necessity for adjuvant treatments.

[A Patient with Recurrent Ulcerative Colitis-Associated Rectal Cancer Attaining a Complete Response with FOLFIRI plus Bevacizumab].

A 60-year-old man underwent laparoscopic total proctocolectomy with ileostomy for advanced ulcerative colitis-associated rectal cancer. The final diagnosis was advanced cancer pT3, pN2 and M0 (pStage Ⅲb). Adjuvant therapy with XELOX was performed. However, abdominal CT revealed a liver metastasis and lymph node metastases in the pelvis 6 months after surgery. The patient was treated with FOLFIRI plus bevacizumab. After 20 courses of chemotherapy, the patient was considered to have experienced a clinical CR, which has been maintained for 3 years 5 months.

Maintenance of the nutritional prognostic index predicts survival in patients with unresectable metastatic colorectal cancer.

PURPOSE: Nutrition and immunity significantly affect the progression of cancer in cancer patients. Therefore, the evaluation of the nutritional and immune status would be useful as a prognostic factor and to determine the optimal treatment strategy for patients with unresectable metastatic colorectal cancer who are receiving chemotherapy. The aim of this retrospective study was to evaluate the prognostic significance of the nutritional and immune status in patients with unresectable metastatic colorectal cancer treated with chemotherapy. METHODS: We retrospectively reviewed 80 patients with colorectal cancer. A total of 22 patients had metachronous unresectable cancer, and 58 patients had synchronous unresectable cancer. All patients underwent combination chemotherapy with oxaliplatin or irinotecan plus 5-fluorouracil/leucovorin as first-line chemotherapy. We then examined the correlations between the Onodera's prognostic nutritional index (OPNI) and the patients' clinicopathological features. The OPNI was calculated as follows: 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count (per mm(3)). According to the receiver operating characteristic (ROC) curve analysis, the cutoff value for OPNI was 44.5. RESULTS: Patients with a pretreatment OPNI of ≧44.5 demonstrated a longer OS than those with a pretreatment OPNI of <44.5. Moreover, we categorized these patients into four groups according to the combination of the pre- and post-treatment OPNI. The patients in the group with both OPNIs ≥44.5 exhibited a better prognosis compared to the other group (p = 0.001). CONCLUSION: The OPNI is considered to be a useful marker for predicting the long-term outcome in patients who receive chemotherapy for unresectable metastatic colorectal cancer.

[A case of a villous tumor of the rectum with electrolyte depletion syndrome].

We report a case of a villous tumor of the rectum with electrolyte depletion syndrome (EDS). A 76-year-old woman developed general fatigue, and on investigation, we found a large laterally spreading tumor of the rectum using bowel enema and colon fiber. Pathologically, the biopsy specimen was graded Group 4. We intended to perform a laparoscopy-assisted low anterior resection in the patient. However, the operation was interrupted by a short-run type of ventricular premature contraction (VPC) due to EDS-induced hypokalemia. After treating the hypokalemia, low anterior resection or laparotomy was performed. The tumor was 19 × 13 cm in size and occupied the circumference of the rectum. Histological examination revealed well differentiated tubular adenocarcinomas with tubulovillous adenoma. Pathological staging was pTis, pN0, M0, stage 0 according to the Japanese Classification of Colorectal Carcinoma (8th edition). It is now 6 months after the operation and hypokalemia has not recurred in the patient.

[Promising effects of pregabalin in the treatment of oxaliplatin-induced sensory neuropathy in patients with colorectal carcinoma].

Thirteen patients with metastatic colorectal cancer who suffered from oxaliplatin-induced sensory neuropathy were evaluated to determine the neuropathy Grade before and after the administration of pregabalin. All patients received oxaliplatin as adjuvant or first-line chemotherapy. The mFOLFOX6 and CapeOX groups included 3 and 10 cases, respectively, and the average treatment regimens were 8 and 5 doses, respectively. Before receiving pregabalin, sensory neuropathy was classified as Grade 3 in 2 patients, as Grade 2 in 8 patients, and as Grade 1 in 3 patient. The average amount of pregabalin administered to patients was 237 (range: 150-450) mg. After administering pregabalin, we observed improvements in 8 neuropathy cases (61. 5%)within approximately 2 weeks. All side effects were mild. In this study, pregabalin was shown to positively impact sensory neuropathy resulting from oxaliplatin treatment and to enable the long-term use of oxaliplatin-based chemotherapy.

[Day surgery of early breast cancer treated with breast-conserving operation following sentinel lymph node navigation biopsy under local anesthesia].

In the early stages of breast cancer when axillary lymph node dissection is avoidable, we performed same day surgery with a breast-conserving operation following sentinel lymph node navigation biopsy under local anesthesia. Initial sentinel lymph node biopsy under local anesthesia is performed to avoid false-negative sentinel lymph node metastasis. Resected sentinel lymph nodes were examined in fixed sections by hematoxylin-eosin staining and immunohistochemistry. The enrolled subjects were 20 patients with breast cancer whose diagnoses were confirmed before treatment. Two (10.0%) patients had metastasis.

[Lumpectomy and sentinel lymph node navigation surgery for breast cancer under local anesthesia].

We studied and analyzed therapeutic outcomes of a radical surgery under local anesthesia for breast cancer in our department. Subjects were 42 patients with breast cancer whose diagnoses were definitely made before surgery. Indications were: localized DCIS diagnosed preoperatively; invasive carcinoma less than 3 cm in tumor diameter on ultrasound; and clinically tumors with negative axillary lymph nodes. Operative procedures included lumpectomy associated with sentinel lymph node navigation biopsy. We could perform the operation under local anesthesia in all of the 42 patients, and were not demanded to shift from local to general anesthesia. Two patients had sentinel lymph nodes metastasis. Surgical stumps were positive in 14 patients( 33.3%). None of serious complications were encountered. Today's radical operation under local anesthesia for breast cancer is a useful procedure as minimally invasive surgery as for the indications employed in this study.

A meta-analysis of the short- and long-term results of randomized controlled trials that compared laparoscopy-assisted and conventional open surgery for rectal cancer.

PURPOSE: We conducted a meta-analysis to evaluate and compare the short- and long-term results of laparoscopy-assisted and open rectal surgery for the treatment of patients with rectal cancer. METHODS: We searched MEDLINE, EMBASE, Science Citation Index, and the Cochrane Controlled Trial Register for relevant papers published between January 1990 and April 2011 by using the search terms "laparoscopy," "laparoscopy assisted," "surgery," "rectal cancer," and "randomized controlled trials." We analyzed outcomes over short- and long-term periods. RESULTS: We identified 12 papers reporting results from randomized controlled trials that compared laparoscopic surgery with open surgery for rectal cancer. Our meta-analysis included 2,095 patients with rectal cancer; 1,096 had undergone laparoscopic surgery, and 999 had undergone open surgery. In the short-term period, 13 outcome variables were examined. In the long-term period, eight oncologic variables, as well as late morbidity, urinary function, and sexual function were analyzed. Laparoscopic surgery for rectal cancer was associated with a reduction in intraoperative blood loss and the number of transfused patients, earlier resumption of oral intake, and a shorter duration of hospital stay over the short-term, but with similar short-term and long-term oncologic outcomes compared to conventional open surgery. CONCLUSIONS: Laparoscopic surgery may be an acceptable alternative treatment option to conventional open surgery for rectal cancer.

[A case report of advanced rectal cancer showing a pathological complete response by neo-adjuvant FOLFOX chemotherapy].

A 72-year-old man was admitted with melena. Colonoscopy detected an advanced rectal cancer. CT scan revealed the prostate was invaded. We decided to start a systemic chemotherapy (mFOLFOX6). The chemotherapy (mFOLFOX6) was performed six times. After the treatment with chemotherapy, the tumor shrunk. Abdominoperineal resection of rectum was done, and a final pathological examination revealed a complete response of the main tumor.

[The outcome of chemotherapy by sorafenib in advanced hepatocellular carcinoma].

We analyzed the treatment outcome and effect of sorafenib in advanced hepatocellular carcinoma. Nine patients were received the therapy of sorafenib between June 2009 and October 2009. The overall incidence of treatment-related adverse events was 87.5%. Grade 3 drug-related adverse events included a hand-foot skin reaction (two patients) and fatigue (one patient). Grade 2 hypertension (three patients), grade 1 diarrhea (two patients) and anorexia (four patients) occurred at this study. The response rate was 0% (CR/PR 0, SD 2, PD 6) and median overall survival length was 101 days. Now there are two patients undergoing the therapy of sorafenib. Effect of sorafenib in advanced hepatocellular carcinoma was not good in this study, and drug-related adverse events had a high rate. However, the continuous treatment was possible with dose modified chemotherapy.

[Results of neo-adjuvant chemotherapy by FOLFOX and FOLFIRI for colorectal liver metastasis].

We analyzed a treatment outcome and the effect of FOLFOX and FOLFIRI neo-adjuvant chemotherapy (NAC) for patient with liver metastasis of colorectal cancer. Eleven patients undergoing hepatectomy after NAC were investigated. FOLFOX was performed for 8 patients, and FOLFIRI was for 3 patients. The response rate was 45.5% (PR 5, SD 6), and the reduction rate was 37.7%. The average ICG R15 value before hepatectomy was 13.7%. A complication during and after operations was not recognized. The average observation period was 19.8 months (8-45 months). Now, 9 patients are alive with no recurrence. NAC by FOLFOX for liver metastasis of colorectal cancer showed a high reduction rate, and there was a little influence to hepatectomy indicating that FOLFOX could be an effective therapy.

DNA methyltransferase inhibitor 5-aza-CdR enhances the radiosensitivity of gastric cancer cells.

The National Comprehensive Cancer Network guidelines recommend radiotherapy as a standard treatment for patients with a high risk of recurrence in gastric cancer. Because radiation is harmful to the surrounding organs, a radiation sensitizer might therefore be useful to decrease the side effects of patients with advanced gastric carcinoma. The aim of the current study was to clarify the effect of a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (CdR), on radiation sensitivity in gastric cancer cells. Five gastric cancer cell lines, OCUM-2M, OCUM-12, KATO-III, MKN-45, and MKN-74, were used. The effects of 5-aza-CdR with irradiation on the growth activity, cell-cycle distribution, apoptosis, and apoptosis-associated gene expression were examined. 5-aza-CdR sensitized three of five gastric cancer cell lines to radiation. A combination of irradiation and 5-aza-CdR significantly (P<0.05) decreased the growth activity compared with irradiation alone in OCUM-2M, OCUM-12, and MKN-45 cells, but not in KATO-III and MKN-74 cells. The percentage of cells in G2-M phase and the apoptotic rate with irradiation in combination with 5-aza-CdR were increased in OCUM-2M, OCUM-12, and MKN-45 cells compared with irradiation alone, but not in KATO-III and MKN-74 cells. 5-aza-CdR increased the expression of p53, RASSF1, and death-associated protein kinases (DAPK) genes compared with the control or irradiation alone. These findings suggest that 5-aza-CdR might therefore be useful as a radiation sensitizer to treat some types of gastric carcinoma. The arrest at G2-M phase and increased apoptotic rate might be partly mediated by enhanced expression of the p53, RASSF1, or DAPK gene families by 5-aza-CdR.

Alternative pharmacokinetics of S-1 components, 5-fluorouracil, dihydrofluorouracil and alpha-fluoro-beta-alanine after oral administration of S-1 following total gastrectomy.

We studied whether total gastrectomy for gastric cancer would affect the pharmacokinetics of 5-fluorouracil (5-FU) and its degradation products, such as dihydrouracil (FUH(2)) and alpha-fluoro-beta-alanine (FBAL), after oral administration of the fluorouracil derivative S-1, composed of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP; a dihydropyrimidine dehydrogenase inhibitor) and potassium oxonate. Blood and urine samples were obtained, both preoperatively and at least 2 weeks postoperatively, from six patients with advanced gastric cancers who were undergoing total gastrectomy. Plasma levels of tegafur, 5-FU, CDHP, potassium oxonate, FUH(2) and FBAL were measured prior to and at 1, 2, 4, 6 and 10 h after oral administration of 40 mg/m(2) S-1. The total amounts of 5-FU, FUH(2) and FBAL excreted into urine during the 24-h period after S-1 administration were also measured. Total gastrectomy significantly increased the maximum concentration and the area under the curve until 10 h after administration (AUC(1-10h)) of plasma 5-FU. The plasma AUC(1-10h) of CDHP was significantly higher than the preoperative value. In terms of clinical efficacy, the higher AUC(1-10h) of 5-FU after total gastrectomy may be beneficial to S-1 administered as adjuvant chemotherapy, and might be caused by the higher postoperative AUC(1-10h) of CDHP relative to preoperative values. However, the dose of S-1 for patients who have undergone total gastrectomy might be diminished to avoid severe adverse events and to continue the treatment for a long period.

[A case of gastric cancer with peritoneal recurrence which developed during adjuvant administration of TS-1 showing complete response by weekly docetaxel regimen].

A 62-year old man had undergone total gastrectomy for Borrmann type 4 gastric cancer. No peritoneal dissemination was observed at the laparotomy. Pathological examination revealed that the tumor involved the subserosal layer, and that the lymph node metastasis extended to the left gastric nodes. Vascular and lymphatic involvement was also observed. One hundred mg/body of TS-1, an oral 5-fluorouracil (5-FU) anticancer agent, which consisted of tegafur (a prodrug of 5-FU), and two modulators (gimeracil and oteracil potassium) was given from the 16th post-operative day. A course of TS-1 consisted of consecutive administration for 4 weeks followed by 2 weeks rest. The patient complained of abdominal fullness after administration of the second course of TS-1. Computed tomography (CT) revealed massive ascites. The serum carcinoembryonic antigen (CEA) titer was elevated to 13.5 ng/ml. From these findings, the occurrence of peritoneal dissemination was suspected. Weekly docetaxel of 30 mg/m2 (40 mg/body) was given for 3 weeks followed by a week cessation. At the start of the 6th course, the serum CEA was normalized, and CT scan detected the disappearance of ascites without any new lesion. Administration of docetaxel was continued until the 10th course then stopped without relapse of the disease. No dose reduction or postponement of administration were required. The patient has survived without disease one year after cessation of the treatment. Weekly docetaxel is a safe and effective regimen for gastric cancer worth using for a second-line therapy after failure of the 5-FU-based regimen.

[Analysis of microsatellite instability and p53 LOH in advanced colorectal cancers--first report of the No. 3 protocol].

In order to establish the most appropriate protocol of adjuvant chemotherapy for colorectal cancers, several cooperative studies have been undertaken by the Kinki Cooperative Study Group of Chemotherapy for Colorectal Carcinoma (KCSGCCC). In the No. 3 protocol of KCSGCCC, several cancer-associated molecular markers were analyzed to investigate a possible correlation with chemosensitivity and/or patient's prognosis. Here, we report the preliminary results of the analysis of microsatellite instability (MSI) and p53 LOH in 559 cases of Stage II, III colorectal cancer. The MSI was detected in 51 cases (9%) and was shown to have a significant correlation with right-sided localization and histology (poorly differentiated, mucinous). p53 LOH was positive in 225 cases (40%) and was shown to have a significant correlation with left-sided localization and histology (well to moderately differentiated). These results might support the concept of 2 distinct pathways of colorectal carcinogenesis, e.g., RER pathway and LOH pathway.