Combined Pre- and Postoperative Lymphocyte Count Accurately Predicts Outcomes of Patients with Colorectal Cancer.

BACKGROUND: Although preoperative lymphopenia is reportedly a prognostic factor in cancer patients, the association between postoperative lymphopenia and patient prognosis has not been widely studied. METHODS: We enrolled 379 patients who underwent surgery for colorectal cancer (CRC) to analyze correlations among pre- and postoperative lymphocyte counts (LCs) and prognosis in patients with CRC. RESULTS: Pre- and postoperative LCs were significantly correlated (r = 0.615, p < 0.0001). Based on results of receiver operating characteristic analysis, patients were subgrouped as preoperative LC ≥1,280 (pre-LCHigh, n = 234), preoperative LC < 1,280 (pre-LCLow, n = 145); and as postoperative LC ≥680 (post-LCHigh, n = 246), and postoperative LC < 680 (post-LCLow, n = 133). Five-year disease-specific survival rates significantly differed between pre-LCHigh (88.6%) and pre-LCLow (72.5%) groups (p < 0.0001); and also between the post-LCHigh (88.5%) and post-LCLow (71.1%) groups (p < 0.0001). Five-year disease-specific survival rates of patients who were both pre-LCLow and post-LCLow was significantly lower than those for patients who were either pre-LCHigh or post-LCHigh or pre-LCHigh/post-LCHigh (p = 0.0003). Multivariate analysis indicated that the combination of pre- and postoperative LC was an independent prognostic indicator. CONCLUSIONS: The combination of pre- and postoperative LC is a predictive factor for prognosis in CRC patients.

A prognostic index for colorectal cancer based on preoperative absolute lymphocyte, monocyte, and neutrophil counts.

PURPOSE: Associations between the preoperative absolute neutrophil count (NC), lymphocyte count (LC), and monocyte count (MC) in the peripheral blood and the prognosis of colorectal cancer (CRC) patients have not been widely studied. METHODS: We enrolled 361 patients who underwent surgery for CRC between January 2007 and December 2013 to analyze correlations among the LC, MC, and NC and prognosis. RESULTS: Based on cut-off values determined by a receiver operating characteristic analysis, patients were subgrouped as LymphHigh or LymphLow (cut-off: LC = 1460 cells/µL); as MonoHigh or MonoLow (cut-off: MC = 421 cells/µL); and as NeutHigh or NeutLow (cut-off: NC = 3247 cells/µL). Patients were then given lymphocyte-monocyte-neutrophil (LMN) scores by adding the points of their different subgroups (1 point each for LymphLow, MonoHigh and NeutHigh; 0 points for LymphHigh, MonoLow and NeutLow). The 5-year overall survival rates significantly differed by the LMN score (0: 89.7%, 1: 80.6%, 2: 68.8%, and 3: 57.4%; P < 0.0001). In the multivariate analysis, the LMN score was found to be an independent prognostic indicator. CONCLUSIONS: The combination of the preoperative absolute number of lymphocytes, monocytes, and neutrophils is a useful prognostic indicator in CRC patients.

Prognostic value of the combination of pre- and postoperative C-reactive protein in colorectal cancer patients.

PURPOSE: Inflammation is closely related to cancer development and progression. This retrospective study investigated the prognostic value of the combination of pre- and postoperative C-reactive protein (CRP) levels in patients with colorectal cancer (CRC). METHODS: The subjects of this study were 406 patients who underwent surgery for CRC. RESULTS: Based on receiver-operating characteristic analysis, patients were divided into the following groups: those with a preoperative CRP of ≥ 0.5 mg/dL (pre-CRPHigh), those with a preoperative CRP of < 0.5 mg/dL (pre-CRPLow), those with a postoperative CRP of ≥ 17.0 mg/dL (post-CRPHigh), and those with a postoperative CRP of < 17.0 mg/dL (post-CRPLow). They were then allocated to one of the following three groups: Group A, comprised of those in the pre-CRPHigh and post-CRPHigh groups; Group B, comprised of those in either the pre-CRPHigh and post-CRPLow or pre-CRPLow and post-CRPHigh groups; and Group C, comprised of those in the pre-CRPLow and post-CRPLow groups. The disease-specific 5-year survival rates were 53.8%, 72.8%, and 87.2% in Groups A, B, and C, respectively, and these differences were significant. Finally, multivariate analysis revealed that the combination of pre- and postoperative CRP levels was an independent prognostic indicator. CONCLUSIONS: The combination of pre- and postoperative CRP was predictive of the prognosis of CRC patients.

[Breast Cancer Patient with Bone Metastases Who Was Able to Return Home without Using Opioids after Administration of Strontium-89 Chloride].

A 46-year-old woman underwent mastectomy for right inflammatory breast cancer.Three years later, she was diagnosed with multiple bone metastases and was treated with systemic chemotherapy and zoledronic acid.Six years after the mastectomy, she complained of severe sacral pain, and 40 Gy external radiotherapy was applied to the sacral metastases.Oxycodone was also administered, but dose escalation was difficult because of severe nausea and fatigue.A bone scan showed increased uptake of Tc99m in an area consistent with the painful regions, and an injection of 89SrCl2 was administered.Five weeks after the injection, her severe pain was relieved and she was able to discontinue the use of opioids completely.She successfully lived at home for 100 days without using opioids.In this case, radionuclide therapy with 89SrCl2 led to remarkable pain relief with an improvement in the quality of life of the patient.

[A Case of Drug-Induced Lung Injury Associated with Paclitaxel plus Bevacizumab Therapy].

A 61-year old woman with recurrent breast cancer received combined treatment with paclitaxel (PTX) and bevacizumab (BV) as the third-line chemotherapy. During the administration of PTX in the 3 courses of chemotherapy, she suddenly developed respiratory failure, and both chest X-ray and CT revealed bilateral pulmonary infiltrates. Symptoms and radiographic findings responded dramatically to steroid pulse therapy. The history of onset and laboratory data showed no evidence of infection; therefore, we made a diagnosis of acute lung injury induced by the chemotherapy. It should be noted that lung injury may be induced by both PTX and BV, and is one of the important adverse events despite the low frequency of occurrence.

Role of Surgery in the Management for Gastric Cancer with Synchronous Distant Metastases.

Optimal treatment of patients with gastric cancer with synchronous distant metastases is palliative chemotherapy. However, occasionally gastrectomy should be selected due to control bleeding from tumors, perforation, or obstruction. The aim of this study is to evaluate the survival benefits of non-curative gastrectomy for patients with synchronous distant metastasis. Total 78 gastric cancer patients with synchronous distant metastasis treated in our hospital between 2003 and 2012 were enrolled in this study. Of these, 74 patients (95 %) received S1 based chemotherapy. During the treatment, 37 patients (47.4 %) underwent palliative gastrectomy because of bleeding from tumors (n = 15), tumor perforation (n = 6), and obstruction (n = 16). Survival benefits were compared in resected and non-resected patients, retrospectively. The two groups were clinicopathologically similar. Palliative gastrectomy was performed safely (morbidity: 10.8 % and mortality: 0) in resection group. However, resection showed survival benefits only in 13 patients (16.7 %) with single metastasis and without peritoneal metastasis. Their 2-year survival rate was 40 % and their median survival was 19 months. Non-curative gastrectomy with precise surgical techniques followed careful postoperative nutrition management may improve survival only for patients with a single metastatic site, except for peritoneal dissemination.

Tumor infiltration pattern into the surrounding tissue has prognostic significance in advanced gastric cancer.

Gastric cancer can be classified into three subgroups according to pattern of tumor infiltration into the surrounding tissue: INFa (expanding growth and a distinct border with the surrounding tissue), INFc (infiltrating growth and an indistinct border with the surrounding tissue), and INFb (in-between a and c). How the tumor infiltration pattern (INF) relates to prognosis and type of recurrence in advanced gastric cancer has not been sufficiently explored. We examined 805 consecutive advanced gastric adenocarcinoma patients who underwent curative gastrectomy at our institution between 1980 and 2005. Poor differentiation, serosal invasion, and lymph node metastasis were significantly more frequent in patients with INFc tumors than in those with INFa/b tumors. For patients with a T2 or T3 tumor, there was no significant difference in prognosis between those with INFa/b and with INFc. However, for patients with a T4a or T4b tumor, the prognosis of those with INFc was significantly worse than that of those with INFa/b. In multivariate analysis, INF was an independent prognostic indicator in T4a but not T2, T3, and T4b. Furthermore, the prognosis of T4 patients with INFc tumors was significantly worse than that of those with INFa/b, especially in node-negative but not in node-positive cases. In patients with a T4a or T4b tumor, peritoneal recurrence was significantly more frequent for those with INFc than for those with INFa/b. Our data indicate that INF is useful to predict the prognosis and recurrence pattern in T4a node-negative gastric cancer.

Changes in Standard Treatments and Postoperative Outcomes for Advanced Gastric Cancer at One Institute over an 11-Year Period.

BACKGROUND: Reportedly, the recently established postoperative adjuvant chemotherapies (ADJs) with tegafur and uracil (UFT) or fluoropyrimidine S (S-1) show better survival than surgery alone in patients with advanced gastric cancer (GC). We analyzed chronological changes in postoperative prognosis of patients with advanced GC in our institute, and investigated the efficacy of ADJ in patients with stage II-III GC. METHODS: Of 143 patients with stage II-III GC who underwent curative gastrectomy at Tottori University Hospital between 1998 and 2008, three died with operative complications within 1 month after surgery. The remaining 140 patients were followed to the end of 2013. We compared disease-free survival (DFS) and clinicopathological differences between 82 patients who underwent gastrectomy during 1998-2002 (Group A) and 58 patients who underwent gastrectomy during 2003-2008 (Group B). RESULTS: Operative quality, as represented by number of dissected lymph nodes, was similar in both groups, but the recurrence rate of Group A (51.2%) was higher than in Group B (37.9%, P = 0.12) and the 5-year DFS rate of Group B (62.3%) was higher than that of Group A (50.2%, P = 0.095). In stage II, the 5-year DFS rate of patients in Group B (73.3%) was similar to Group A (77%), but at tumor stage III, the 5-year DFS rate of patients in Group B increased to 48.7%, compared with 33.1% of Group A. Between 2003 and 2008, S-1 was widely used as ADJ for stage II-III GC. CONCLUSION: Postoperative ADJ with S-1 improved DFS of patients with stage III gastric cancer.

Upregulation of Immune Checkpoint Molecules, PD-1 and LAG-3, on CD4+ and CD8+ T Cells after Gastric Cancer Surgery.

BACKGROUND: Surgery has been reported to suppress cell-mediated immunity; however, the detailed mechanisms responsible for this remain unclear. This study determined the expression of lymphocyte activation gene 3 (LAG-3) and programmed cell death 1 (PD-1) in lymphocytes following surgery for gastric cancer. METHODS: LAG-3 and PD-1 expression on both CD4+ and CD8+ T cells obtained pre- and post-operatively from gastric cancer patients were evaluated by multicolor flow cytometry. RESULTS: The total lymphocyte count decreased rapidly from preoperative levels, reaching a minimum on postoperative day 1 and remaining significantly decreased on days 3 and 7. PD-1(+)CD4(+) T cells significantly increased, reaching a maximum on postoperative day 1 and remaining significantly elevated on day 3. PD-1(+)CD8(+) T cells significantly increased and reached a maximum on day 7 before returning to the preoperative level on day 30. There were no statistically significant differences in the frequency of LAG-3(+)CD4(+) or LAG-3(+)CD8(+) T cells after surgery. There were significant positive correlations between PD-1 and LAG-3 expression on both CD4(+) andCD8(+) T cells. CONCLUSION: PD-1 and LAG-3 expression on both CD4(+) and CD8(+) T cells was up-regulated and might be related to impaired cell-mediated immunity after surgery for gastric cancer.

Clinical relevance of the number of interleukin-17-producing CD 8+ T cells in patients with gastric cancer.

PURPOSE: There is accumulating evidence that inflammation is linked to cancer development and progression. Interleukin-17 (IL-17), an inflammatory cytokine, is produced by CD 8+ T cells (Tc17 cells); however, the specific role of Tc17 cells in tumor immunity against gastric cancer remains unclear. METHODS: The prevalence of Tc17 cells in both peripheral blood mononuclear cells and gastric tissue was evaluated by multicolor flow cytometry and the concentration of IL-17 in sera was quantitated by an enzyme-linked immunosorbent assay. RESULTS: Circulating Tc17 cells were significantly more numerous in gastric cancer patients than in controls, and significantly more numerous before surgery than after surgery. IL-17 concentrations in gastric cancer patients and healthy controls were 0.51 ± 0.54 and 0.084 ± 0.084 pg/mL, respectively, with this difference being significant. The percentage of Tc17 cells was significantly related to serum IL-17 concentration. Tc17 cells were significantly more numerous than peripheral blood mononuclear cells in gastric cancer tissue. Furthermore, Tc17 cells were more numerous in cancerous gastric tissue than in normal gastric tissue. CONCLUSIONS: Tc17 cells may be the main source of IL-17 in gastric cancer patients and thus involved in the progression of gastric cancer.

Gastric adenocarcinoma with thymic metastasis after curative resection: a case report.

The peritoneum is the most frequent site of recurrence for gastric cancer after gastrectomy, followed by the liver and lymph nodes. In contrast, metastasis to the thymus is rare. Annual surveillance with computed tomography was performed on a 67-year-old man who previously underwent a distal gastrectomy and D2 lymph node dissection for gastric cancer at Tottori University. Five years after the initial operation, an anterior mediastinal tumor was detected by computed tomography. The patient underwent video-assisted thoracic surgery to remove the tumor. Histopathology revealed adenocarcinoma cells similar to those of the gastric cancer resected 5 years previously. Thymic metastasis was considered likely based on the location of the tumor. The recognition that gastric cancer can metastasize to unusual anatomic locations, such as the thymus, can facilitate an accurate, prompt diagnosis and appropriate treatment.

Clinicopathologic characteristics and prognosis of advanced gastric cancer simulating early gastric cancer.

BACKGROUND: Although the clinicopathologic features and prognosis of Borrmann type advanced gastric cancer has been well characterized, those of advanced gastric cancer simulating early gastric cancer (AGC simulating EGC) still remains unclear. METHODS: We reviewed 1985 gastric cancer patients who had undergone gastrectomy at our hospital to determine the clinicopathologic characteristics, susceptible sites for lymph node metastasis, and prognosis of AGC simulating EGC in comparison with Borrmann type advanced gastric cancer. RESULTS: Among 102 patients with AGC simulating EGC, 100 patients (98%) had tumors with depressed type appearance. The frequencies of serosal invasion, lymph node metastasis, lymphatic vessel invasion, blood vessel invasion, and liver metastasis were significantly lower in AGC simulating EGC than in Borrmann type tumors. The prognosis of AGC simulating EGC was significantly better than that of the Borrmann type tumors. Multivariate analysis indicated that the gross appearance was an independent prognostic factor. In patients with AGC simulating EGC which invaded to the the muscularis propria (MP), most lymph node metastasis was restricted with the perigastric lymph nodes (1st-titer lymph nodes) and lymph node metastasis to 2nd-titer lymph nodes was only observed at station 8a. CONCLUSION: AGC simulating EGC is less advanced in comparison with Borrmann type advanced gastric cancer. Based on the results of susceptible sites for lymph node metastasis in the current study, limited lymph node dissection could be indicated for AGC simulating EGC whose depth of invasion is MP.

Increased apoptosis and elevated Fas expression in circulating natural killer cells in gastric cancer patients.

BACKGROUND: Immune cells undergo extensive apoptosis in patients with cancer, which may be related to immune evasion by cancerous cells. The present study was designed to investigate the relationship between natural killer (NK) cell apoptosis and Fas expression in gastric cancer patients. METHODS: NK cell apoptosis and Fas expression were evaluated by multicolor flow cytometry. Soluble Fas ligand (sFasL) was quantitated by enzyme-linked immunosorbent assay. RESULTS: The frequency of apoptotic NK cells in gastric cancer patients was significantly higher than in normal controls (p = 0.0016). Moreover, their frequency was related to the progression of gastric cancer. Fas-positive NK cells were significantly more common in gastric cancer patients compared with normal controls (p = 0.034). Furthermore, Fas expression was closely related to the frequency of NK cell apoptosis (r = 0.6, p < 0.0001). The frequency of tumor-infiltrating NK cell apoptosis was significantly higher than that of circulating NK cell apoptosis (p = 0.035). Furthermore, Fas-positive NK cells in gastric cancer tissues occurred significantly more often than in peripheral blood (p = 0.029). FasL concentration in gastric cancer patients was lower than that in normal controls, and the difference tended to be significant (p = 0.057). Apoptotic circulating NK cells significantly decreased after surgery compared to before surgery (p = 0.023). Furthermore, Fas expression on circulating NK cells also significantly decreased after surgery compared with before surgery (p = 0.021). CONCLUSIONS: Upregulation of Fas expression on NK cells is related to increased apoptosis of circulating NK cells in gastric cancer patients.

Treatment of patients with stage IV gastric cancer.

PURPOSE: Treatment of patients with stage IV gastric cancer is controversial. This study was retrospectively designed to elucidate the best treatment for these patients. METHODS: Between 2003 and 2010, a total of 558 patients with gastric cancer were treated at the Department of Surgery, Tottori University Hospital, 96 (17.2 %) of whom were diagnosed with stage IV. Among 96, 54 underwent palliative gastrectomy while 42 underwent chemotherapy, exploratory laparotomy, or gastrojejunostomy for unresectable cases. Surgical morbidity, mortality, and patient survival were analyzed with respect to several factors. RESULTS: Among resected cases, high age, R2 operation, and neoadjuvant chemotherapy did not increase the occurrence of postoperative complications. Patient age, R1 operation, and sufficient chemotherapy were indicated as better prognostic factors for resected stage IV gastric cancers. Even after R2 operation, continuous chemotherapy with changing regimens prolonged R2 resected patients' survival to 25 months (mean). In unresectable cases, bypass operation did not affect patients' survival. But, chemotherapy with changing regimens prolonged the survival of unresectable cases. CONCLUSIONS: Adequate management can resolve surgery-related morbidity, and continuous chemotherapy may be one of the most important prognostic factors in stage IV gastric cancer.

Usefulness of palliative prognostic score in the treatment of patients with non-resectable gastric cancer.

The aim of this study was to evaluate the clinical usefulness of the palliative prognostic (PaP) score in patients with non-resectable advanced gastric cancer. The PaP score was calculated prior to each course of chemotherapy in 44 consecutive patients with non-resectable advanced gastric cancer between 2003 and 2010 at the Tottori University Hospital, Yonago, Japan. The prognosis was evaluated according to the PaP score and the different chemotherapeutic agents. The median survival time (MST) was 10 months. The PaP score classified the heterogeneous patient sample into three isoprognostic groups with regard to the possibility of a 1-month survival period, with 28 patients in group A (>70% chance), 12 in group B (30-70% chance) and 4 in group C (<30% chance). The MST of the three groups was 11, 3 and 1 months for group A, B and C, respectively. In group A, chemotherapeutic regimens did not affect patient survival, although the docetaxel regimen prolonged survival of patients in group B. In conclusion, the PaP score may be useful in selecting the best chemotherapeutic regimen in patients with non-resectable gastric cancer.

Prognosis of patients with gastric cancer who underwent proximal gastrectomy.

Proximal gastrectomy (PG) has been introduced for patients who are preoperatively diagnosed with early gastric cancer located in the upper third of the stomach. In the present study, we compared the prognosis of patients who underwent PG with that of patients who underwent total gastrectomy (TG). Between 1997 and 2006, 51 patients were diagnosed with early gastric cancer located in the upper third of the stomach and underwent PG. In the same period, 35 patients were diagnosed with early gastric cancer and underwent TG. Of these, in 24 patients, the cancer was localized in the middle to upper part of the stomach, and 11 patients had multiple cancers. We compared the clinicopathologic differences and prognoses between the two groups. Significantly fewer lymph nodes were dissected in the PG group (mean, 18.2) than in the TG group (mean, 36.6;P < 0.001). Complications were detected in 17.6% of patients in the PG group and in 14.3% of patients in the TG group, which was not significant (P = 0.678). The overall and disease-specific 5-year survival rates in the 51 patients who underwent PG (88.7% and 97.1%, respectively) were not different from those in the 35 patients who underwent TG (87.6% and 93.4%; P = 0.971 and P = 0.553; respectively). These findings indicate that PG can be performed safely and may have various advantages compared with TG in terms of patients' daily lives.

Clinicopathologic characteristics and prognosis of gastric cancer in young patients.

To determine the clinicopathologic characteristics and prognosis of gastric cancer in young patients, a total of 1985 gastric cancer patients who had undergone gastrectomy at our hospital were reviewed. The male-to-female ratio was significantly lower in the young patients than in either the middle-aged (P < 0.0001) or elderly patients (P < 0.0001). Undifferentiated carcinoma was observed more frequently in the young patients compared with either the middle-aged (P < 0.0001) or elderly patients (P < 0.0001). Furthermore, peritoneal metastasis was observed more frequently in the young patients than in either the middle-aged (P < 0.005) or elderly patients (P < 0.005). Five-year survival rates were 61.0, 73.6 and 68.1% in the young, middle-aged and elderly patients, respectively. The prognosis of the middle-aged patients was significantly better than that of either the young or the elderly patients (P < 0.05). Multivariate analysis indicated that age was an independent prognostic factor. Peritoneal recurrence was more frequently observed in the young patients than either the middle-aged or the elderly patients (P < 0.05). Gastric cancer in young patients has unique characteristics, namely, a predominance of female patients and a high frequency of undifferentiated cancer and peritoneal metastasis and recurrence.

[A case of complete response of gemcitabine (GEM) monotherapy-refractive liver metastatic pancreatic cancer treated with GEM+S-1 combined chemotherapy].

A 75-year-old man with pancreatic body cancer underwent distal pancreatectomy and was treated with gemcitabine (GEM) as an adjuvant therapy. Multiple liver metastases appeared three months after the surgery. With GEM+S-1 combined chemotherapy, liver metastatic lesions became unidentifiable upon imaging 7 months later. Complete response status had continued as long as 13 months. Though grade 3 neutropenia appeared after 2 courses of the combined therapy, the patient well tolerated it after controlling the dosing schedule. The GEM+S-1 combined chemotherapy was expected to have synergistic effects for GEM monotherapy-refractive pancreatic cancer.