[Primary Small Intestinal Cancer-A Clinicopathological Study of Seven Cases].

The clinicopathological features of primarysmall intestinal cancer were assessed retrospectively. Seven patients underwent resection of small bowel cancer in our hospital between June 2011 and January 2019. The mean age of the patients was 62.9 years, and the male to female ratio was 4:3. Five patients were symptomatic, and the correct preoperative diagnosis rate was 28.6%. The average tumor diameter was 5.3 cm, and the median resected intestine length was 25 cm. Histopathological examination revealed that there were 2 patients with poorlydifferentiated tumors and 3 patients with pStage ⅡA, 3 with pStage ⅡB, and 1 with pStage ⅢA disease. Recurrence after surgeryoccurred in 4 patients, including local recurrence in 2 patients and lymph node recurrence in 1 patient. Median survival was 24.5 months. The resected intestinal length was longer and the mesenteric arterydissection was more extensive in survivors than in dead patients. In contrast, the dead patients were older than the survivors and had undifferentiated tumor, ly2/ly3, lymph node metastasis, and recurrence. Moreover, recur- rence occurred in 4 patients who had lymph node metastasis, and/or undifferentiated tumor type, and/or ly2/ly3. An adequate intestinal excision margin along with mesenteric lymph node dissection might be required to improve the survival of patients with primaryintestinal cancer.

[Perforated Marginal Ulcer after Subtotal Stomach Preserving Pancreaticoduodenectomy-Report of Five Cases].

PURPOSE: Perforated marginal ulcer after pancreaticoduodenectomy(PD)is a delayed complication. We evaluated the characteristics of the patients presenting perforated marginal ulcer after PD. METHODS: Five cases of perforated marginal ulcer after PD were reported at our hospital between 2008 and 2018, and the characteristics of these patients were evaluated. RESULTS: All 5 patients(4 females)with median age 73 years underwent subtotal stomach-preserving PD(SSPPD). In spite of the administration of gastric antisecretory medication, perforated marginal ulcer occurred in 3 patients(60%). All patients were treated with direct suture and omentum patch, and no mortality was reported. CONCLUSIONS: The perforating marginal ulcer after SSPPD occurred despite the administration of the gastric antisecretory medication. Treatment with direct suture and omentum patch was effective in perforated marginal ulcer after SSPPD.

Assessing the economic advantage of laparoscopic vs. open approaches for colorectal cancer by a propensity score matching analysis.

PURPOSES: This study investigated the surgical outcomes and potential economic advantage of open vs. laparoscopic surgery for colorectal cancer using a propensity score matching analysis. METHODS: We examined the surgical and economic outcomes of patients undergoing laparoscopic (N = 127) and open surgery (N = 253) for colorectal cancer and then compared these outcomes in two groups (N = 103 each) using a propensity score matching analysis. RESULTS: Compared to open surgery, the laparoscopic approach was associated with a significantly lower overall morbidity rate (14 vs. 40%; P < 0.001) and shorter mean (± standard deviation) postoperative hospital stay (12.6 ± 8.3 vs. 16.8 ± 9.9 days, respectively; P = 0.001). Despite generating higher mean surgical costs (Japanese yen) (985,000 ± 215,000 vs. 812,000 ± 222,000 yen; P < 0.001), utilizing a laparoscopic approach significantly reduced the non-surgical costs (773,000 ± 440,000 vs. 1075,000 ± 508,000 yen; P < 0.001). The mean total cost of laparoscopic-assisted surgery (1758,000 ± 576,000 yen) was decreased by approximately 130,000 yen compared with open surgery (1886,000 ± 619,000 yen), although the difference was not statistically significant (P = 0.125). CONCLUSIONS: Laparoscopic surgery for colorectal cancer is advantageous in reducing morbidity and facilitating an early discharge and does not increase hospital costs. These findings are consistent with the general consensus supporting the benefits of laparoscopic surgery as a minimally invasive approach.

[A Case of Intestinal Diverticular Perforation in Roux-en-Y Reconstruction after Laparoscopic Distal Gastrectomy].

An 81-year-old woman who had undergone laparoscopic distal gastrectomy complained of abdominal pain 21 days after the operation.Blood tests showed a strong inflammatory reaction.Abdominal CT revealed a perforation in the small intestinal diverticula.Partial jejunectomy including the diverticulum was performed.The diverticular perforation was attributed to the presence of undigested food in the diverticulum.The patient had an uneventful postoperative course, and she was discharged on postoperative day 32.

Effects of the closing speed of stapler jaws on bovine pancreases.

BACKGROUND: The division of the pancreatic parenchyma using a stapler is important in pancreatic surgery, especially for laparoscopic surgery. However, this procedure has not yet been standardized. METHODS: We analyzed the effects of the closing speed of stapler jaws using bovine pancreases for each method. Furthermore, we assigned 10 min to the slow compression method, 5 min to the medium-fast compression method, and 30 s to the rapid compression (RC) method. The time allotted to holding (3 min) and dividing (30 s) was equal under each testing situation. RESULTS: We found that the RC method showed a high-pressure tolerance compared with the other two groups (rapid, 126 ± 49.0 mmHg; medium-fast, 55.5 ± 25.8 mmHg; slow, 45.0 ± 15.7 mmHg; p < 0.01), although the histological findings of the cut end were similar. The histological findings of the pancreatic capsule and parenchyma after the compression by staple jaws without firing also were similar. CONCLUSIONS: RC may provide an advantage as measured by pressure tolerance. A small series of distal pancreatectomy with a stapler that compares the speed of different stapler jaw closing times is required to prove the feasibility of these results after the confirmation of the advantages of the RC method under various settings.

The modified Glasgow Prognostic Score (mGPS) is a good predictor of indication for palliative bypass surgery in patients with unresectable pancreatic and biliary cancers.

BACKGROUND: Patients with unresectable pancreatic and biliary cancers sometimes need decompression due to obstruction of the gastrointestinal tract and/or biliary tract. The aim of this study was to determine the prognostic factors associated with an indication for palliative bypass surgery in patients with unresectable pancreatic and biliary cancers. METHODS: Between April 2005 and September 2011, 37 patients with unresectable pancreatic and biliary cancers underwent palliative bypass surgery. Prognostic factors were searched for among clinical characteristics, operation-related factors, and tumor-related factors using a prospective database. RESULTS: The median survival time (MST) of these patients was 4.6 months, with a 6-month survival rate of 40.5 %. A multivariate Cox proportional hazards regression analysis revealed that mGPS >2 was the only independent prognostic factor for bypass surgery. Patients with an mGPS of 2 had an MST of 1.7 months, and they had a significantly worse prognosis than mGPS 0-1 patients with an MST of 6.3 months. CONCLUSIONS: The mGPS is useful for predicting survival after surgical decompression due to gastrointestinal obstruction in patients with unresectable pancreatic and biliary cancers. Patients with a poor mGPS may not be indicated for palliative bypass surgery.

Glasgow Prognostic Score as a useful prognostic factor after hepatectomy for hepatocellular carcinoma.

BACKGROUND: Several previous studies have revealed that the Glasgow Prognostic Score (GPS) is a clinically useful scoring system to predict the prognosis of patients with various kinds of advanced cancers. However, there have been few reports on the relationship between the GPS and prognosis after hepatectomy for hepatocellular carcinoma (HCC). Therefore, we performed an analysis of the relationship between the GPS and prognosis after hepatectomy for HCC. METHODS: Between January 2005 and December 2009, 352 HCC patients underwent hepatectomy at Kumamoto University Hospital. Nineteen clinicopathologic factors were analyzed, using univariate and multivariate analyses. RESULTS: Univariate analysis showed that significant risk factors for poor survival included serum albumin level (<3.5 g/dL), tumor size (>35 mm), presence of ascites, portal vein invasion, operation time (>400 min), blood loss (>360 mL), requirement for blood transfusion, and GPS. Multivariate analysis revealed that tumor size [hazard ratio (HR) 3.355; p = 0.003], operation time (HR 2.634; p = 0.006), portal vein invasion (HR 2.419; p = 0.009), and GPS (HR 3.796; p < 0.001) were independent factors for poor prognosis. CONCLUSION: The GPS was demonstrated to be a statistically significant prognostic factor after hepatectomy for HCC.

Laparoscopic Observation of Adhesive Rectal Fixation after Gant-Miwa-Thiersch Procedure for Rectal Prolapse: A Case Report.

In our previous report, we have noted an increase of computed tomography (CT) attenuation values in perirectal fat tissue after Gant-Miwa-Thiersch (GMT) procedure for rectal prolapse. Based on these results, we hypothesized that the GMT procedure may have a rectal fixation effect due to inflammatory adhesions extending to the mesorectum. Herein, we report a case of laparoscopic observation of perirectal inflammation after GMT. A 79-year-old woman with a history of seizures, stroke, subarachnoid hemorrhage, and spondylosis underwent the GMT procedure under general anesthesia in the lithotomy position for rectal prolapse measuring 10 cm in length. But rectal prolapse recurred 3 weeks after surgery. Therefore, an additional Thiersch procedure was performed. However, rectal prolapse still recurred, and laparoscopic suture rectopexy was performed 17 weeks after initial surgery. During rectal mobilization, marked edema and rough membranous adhesions were observed in the retrorectal space. The average CT attenuation value obtained 13 weeks after initial surgery was found to be significantly elevated in the mesorectum compared with the subcutaneous fat, especially in the posterior side (P < 0.05). These findings suggest that the extension of inflammation to the rectal mesentery after the GMT procedure may have strengthened adhesions in the retrorectal space.

Risk factors associated with delayed haemorrhage after pancreatic resection.

BACKGROUND: Delayed haemorrhage (DH) is a life-threatening complication of pancreatic resection (PR) and the mortality rate for DH is very high. However, the risk factors and prognostic factors associated with DH are rarely evaluated. METHODS: A pancreatic resection was performed on 457 patients. Delayed haemorrhage was defined as bleeding from the surgical site ≥ 5 days after PR. Risk factors for DH were assessed according to demographics and pathological and operative parameters. Prognostic factors after DH were evaluated for the shock index (heart rate/systolic blood pressure) and systemic inflammatory response syndrome (SIRS) scores. RESULTS: Of the 457 patients, 11 (2.4%) experienced DH after PR. Logistic regression analysis showed that age >60 years and a diagnosis of malignant disease were risk factors for DH. The shock index and SIRS scores at the onset of DH were significantly higher in patients who died as compared with those patients that survived (P < 0.05). DISCUSSION: PR-associated DH carries an increased risk for patients aged >60 years with malignant disease. Prognostic factors were a shock index score ≥ 0.7 and SIRS at the onset of DH.

[A case of cancer of the pancreatic tail with disseminated carcinomatosis of the bone marrow].

Disseminated carcinomatosis of the bone marrow derived from solid cancer has a very poor prognosis, with disseminated intravascular coagulation(DIC). A 72-year-old man was admitted to our hospital after detection of a tumor in the pancreatic tail by CT imaging. Several images revealed that he suffered from cancer of the tail of the pancreas with multiple liver and bone metastases. Endoscopic ultra-sonography-guided fine needle aspiration detected adenocarcinoma cells from the tumor of the pancreatic tail. We also performed bone marrow aspiration, which confirmed adenocarcinoma cells in the bone marrow. We started to administer 1,000 mg/m2 of gemcitabine weekly. Laboratory data revealed that thrombocytopenia had occurred, and it developed into DIC after the first the administration of gemcitabine. In spite of the DIC state with thrombocytopenia, we were able to provide anticancer treatment using combination gemcitabine and S-1. He recovered from his DIC state, and the primary tumor was shrunk with a decrease of tumor markers after 2 courses of combination chemotherapy. Chemotherapy might be required for disseminated carcinomatosis of the bone marrow in order to promote tumor shrinkage and to prolonged expected survival, even if DIC was developed.

[Reduction of angialgia during peripheral administration of oxaliplatin mixed with dexamethasone].

Seven patients who had been receiving capecitabine+oxaliplatin±bevacizumab(CapeOX±BV)therapy at our hospital between February 2010 and March 2011, had complained of angialgia during oxaliplatin(L-OHP)administration. Therefore, 3. 3 mg of dexamethasone(DEX)was added to their infusion solution. The patients were then asked to rate their angialgia severity using a numerical rating scale(NRS), when L-OHP in a 5% dextrose solution was administered with or without DEX. By changing the L-OHP in 5% dextrose solution without DEX to the solution containing 3. 3 mg of DEX, the mean NRS was improved to 2. 4 from 7. 1. These findings indicate that L-OHP in 5% dextrose solution mixed with 3. 3 mg of DEX seems to be useful in reducing angialgia during peripheral administration of L-OHP.

Effect of the Gant-Miwa-Thiersch Procedure for Rectal Prolapse on the Mesorectum.

Rectal prolapse (RP) most commonly occurs among elderly women and is caused by vulnerable suspensory tissue in the pelvis. In Japan, the Gant-Miwa-Thiersch procedure (GMT) is recommended for elderly people with poor general health. We retrospectively analyzed clinical data from 12 patients who underwent GMT at our hospital from September 2005 to July 2021 and investigated the effect of GMT on the mesorectum using abdominal-pelvic computed tomography (CT) performed for other diseases. The median age of the cohort was 82 years, and 92% of the subjects were women. The median RP length was 5 cm, and the median follow-up period was 60 months. Recurrence was observed in 1 of 12 patients (8.0%). CT conducted before and more than 6 months after GMT revealed no abnormal findings in the mesorectum, whereas CT within 5 months after GMT revealed hyperdense fat in the mesorectum in all three patients (100%; P < 0.05). The RP recurrence rate after the GMT was low. The mechanism of the effect of GMT may involve not only a direct mucosal plicating effect but also adhesional rectosacral fixation due to the presence of inflammation extending to the mesorectum.

The forkhead box M1 transcription factor as a candidate of target for anti-cancer immunotherapy.

The present study attempted to identify a target antigen for immunotherapy for cholangiocarcinoma. Forkhead box M1 (FOXM1) was selected as a candidate antigen based on the data of previous cDNA microarray analysis of clinical samples of cholangiocarcinoma. The level of FOXM1 mRNA was more than 4 times higher in cancer cells in comparison to adjacent normal epithelial cells, in all of 24 samples of cholangiocarcinoma tissues. An immunohistochemical analysis also detected FOXM1 protein in the cancer cells but not in the normal cells. Twenty-three human FOXM1-derived peptides predicted to bind to HLA-A2 were analyzed to determine their ability to induce HLA-A2-restricted T cells in HLA-A2 transgenic mice. FOXM1(362-370) (YLVPIQFPV), FOXM1(373-382) (SLVLQPSVKV), and FOXM1(640-649) (GLMDLSTTPL) peptides primed HLA-A2-restricted cytotoxic T lymphocytes (CTLs) in the HLA-A2 transgenic mice. Human CTL lines reactive to these 3 peptides could also be established from HLA-A2-positive healthy donors and cancer patients. Natural processing of the 3 epitopes from FOXM1 protein was confirmed by specific killing of HLA-A2-positive FOXM1-transfectants by peptide-induced CTLs. FOXM1 is expressed in various types of cancers and it is also functionally involved in oncogenic transformation and the survival of cancer cells. Therefore, FOXM1 may be a suitable target for immunotherapy against various cancers including cholangiocarcinoma.

Identification of SPARC as a candidate target antigen for immunotherapy of various cancers.

To establish efficient anticancer immunotherary, it is important to identify tumor-associated antigens (TAAs) directing the immune system to attack cancer. A genome-wide cDNA microarray analysis identified that secreted protein acidic and rich in cysteine (SPARC) gene is overexpressed in the gastric, pancreatic and colorectal cancer tissues but not in their noncancerous counterparts. This study attempted to identify HLA-A24 (A*2402)-restricted and SPARC-derived CTL epitopes. We previously identified H-2K(d)-restricted and SPARC-derived CTL epitope peptides in BALB/c mice, of which H-2K(d)-binding peptide motif is comparable with that of HLA-A24 binding peptides. By using these peptides, we tried to induce HLA-A24 (A*2402)-restricted and SPARC-reactive human CTLs and demonstrated an antitumor immune response. The SPARC-A24-1(143-151) (DYIGPCKYI) and SPARC-A24-4(225-234) (MYIFPVHWQF) peptides-reactive CTLs were successfully induced from peripheral blood mononuclear cells by in vitro stimulation with these two peptides in HLA-A24 (A*2402) positive healthy donors and cancer patients, and these CTLs exhibited cytotoxicity specific to cancer cells expressing both SPARC and HLA-A24 (A*2402). Furthermore, the adoptive transfer of the SPARC-specific CTLs could inhibit the tumor growth in nonobese diabetic/severe combined immunodeficient mice bearing human cancer cells expressing both HLA-A24 (A*2402) and SPARC. These findings suggest that SPARC is a potentially useful target candidate for cancer immunotherapy.

Clinical significance of dihydropyrimidine dehydrogenase and thymidylate synthase expression in patients with pancreatic cancer.

BACKGROUND: Little is known about the clinical significance of TS and DPD in pancreatic cancer. We aimed to evaluate TS and DPD expression levels in not only pancreatic cancer but also surrounding normal pancreatic tissues to assess the clinical implications of the expression of TS and DPD in this study. PATIENTS AND METHODS: Pancreatic cancer and normal pancreatic tissues were obtained from 18 patients with pancreatic cancer who underwent pancreatic resection to measure TS and DPD activities. The TS and DPD activities were determined by enzyme-linked immunosorbent assay using non-fixed fresh-frozen specimens. RESULTS: Pancreatic cancer tissues had significantly higher DPD and TS enzyme activities than surrounding normal tissue. Anaplastic ductal carcinoma had higher DPD and TS activities than the other histological types. Patients with high DPD in this study demonstrated poorer prognosis than those with low DPD. On the other hand, there was no statistically significant difference in survival between the high and the low TS groups. CONCLUSIONS: The efficacy of 5-FU may be lower in pancreatic cancer tissue than in normal tissue because DPD activity is upregulated in pancreatic cancer tissue compared to normal pancreatic tissue. It is necessary to develop an effective 5-FU delivery system and/or 5-FU combined with an inhibitor for DPD that can be used when 5-FU must be administered to patients with pancreatic cancer. High DPD activity may be a prognostic factor in patients with pancreatic cancer.

Identification of the H2-Kd-restricted cytotoxic T lymphocyte epitopes of a tumor-associated antigen, SPARC, which can stimulate antitumor immunity without causing autoimmune disease in mice.

We previously reported that the secreted protein acidic and rich in cystein (SPARC) was overexpressed in melanoma in humans, and the serum SPARC level was useful as a novel tumor marker for melanoma. SPARC was also reported to be overexpressed in various human cancers. In this study, we asked whether SPARC-specific cytotoxic T lymphocytes (CTL) could induce antitumor immunity to SPARC-expressing tumor in mice or not as a preclinical study of SPARC-directed anticancer immunotherapy. Because of similarities in the structural motifs of major histocompatibility complex-binding peptides between H2-Kd and HLA-A24 (A*2402), the most common human leukocyte antigen class I allele in the Japanese population, we attempted to identify the H2-Kd-restricted SPARC epitope for CTL in BALB/c mice and we found that the mouse SPARC143-151 (DYIGPCKYI) and SPARC225-234 (MYIFPVHWQF) peptides could induce peptide-reactive CTL in BALB/c mice without causing autoimmune diseases. The immunization of mice with SPARC225-234 peptide-pulsed bone marrow-derived dendritic cells (BMDC) inhibited the growth of s.c. inoculated mouse mammary cancer cell line, N2C, expressing SPARC and these mice lived longer than the mice immunized with peptide-unpulsed BMDC. In conclusion, our study indicated that SPARC peptide-based cancer immunotherapy was effective and safe at least in a mouse tumor prevention model.

Identification of a novel tumor-associated antigen, cadherin 3/P-cadherin, as a possible target for immunotherapy of pancreatic, gastric, and colorectal cancers.

PURPOSE: To establish cancer immunotherapy, it is important to identify the tumor-associated antigens (TAA) that are strongly expressed in the tumor cells but not in the normal cells. In this study, to establish an effective anticancer immunotherapy, we tried to identify the useful TAA of pancreatic cancer. EXPERIMENTAL DESIGN: Based on a previous genome-wide cDNA microarray analysis of pancreatic cancer, we focused on cadherin 3 (CDH3)/P-cadherin as a novel candidate TAA for anticancer immunotherapy. To identify the HLA-A2 (A*0201)-restricted CTL epitopes of CDH3, we used HLA-A2.1 (HHD) transgenic mice (Tgm). Furthermore, we examined the cytotoxicity against the tumor cells in vitro and in vivo of CTLs specific to CDH3 induced from HLA-A2-positive healthy donors and cancer patients. RESULTS: CDH3 was overexpressed in the majority of pancreatic cancer and various other malignancies, including gastric and colorectal cancers, but not in their noncancerous counterparts or in many normal adult tissues. In the experiment using HLA-A2.1 Tgm, we found that the CDH3-4(655-663) (FILPVLGAV) and CDH3-7(757-765) (FIIENLKAA) peptides could induce HLA-A2-restricted CTLs in Tgm. In addition, peptides-reactive CTLs were successfully induced from peripheral blood mononuclear cells by in vitro stimulation with these two peptides in HLA-A2-positive healthy donors and cancer patients, and these CTLs exhibited cytotoxicity specific to cancer cells expressing both CDH3 and HLA-A2. Furthermore, the adoptive transfer of the CDH3-specific CTLs could inhibit the tumor growth of human cancer cells engrafted into nonobese diabetic/severe combined immunodeficiency mice. CONCLUSIONS: These results suggest that CDH3 is a novel TAA useful for immunotherapy against a broad spectrum of cancers, including pancreatic cancer.

Cancer cells spread through lymph vessels in the submucosal layer of the common bile duct in gallbladder carcinoma.

INTRODUCTION: In the present study, we performed immunohistochemical staining with a lymphatic epithelium-specific marker, D2-40, to analyze the status of lymphatic spreading in the hepatoduodenal ligament in T2 gallbladder carcinoma (GC). METHODS: One hundred and eighty-six paraffin-embedded specimens from 15 T2 GC patients were reviewed. RESULTS: Lymph vessels lined with D2-40 were visualized in the submucosal layer of the common bile duct in all cases. In 3 of 15 patients, clusters of cancer cells were identified in the submucosal lymph vessels of the extrahepatic bile duct, and this lymphatic invasion of cancer cells failed to be detected with only conventional hematoxylin-eosin staining. The frequency of the invasion to the submucosal lymph vessels in T2 GC correlated with presence of microscopic invasion to hepatoduodenal ligament and perineural invasion. CONCLUSION: There were lymph vessels in the submucosal layer of the common bile duct, and cancer cells can spread through these channels in addition to the large lymph vessels in subserosal layer around the extrahepatic bile duct in GC. The present results would support the concept of en bloc resection of the extrahepatic bile duct in curative resection for T2 GC.

Multiple gastrointestinal stromal tumors in neurofibromatosis type 1: report of a case.

This report presents a case of multiple gastrointestinal stromal tumors (GIST) with neurofibromatosis type 1 (NF1). A 68-year-old woman was admitted to the hospital because of a tumor close to the head of the pancreas. Imaging studies revealed submucosal tumors of the duodenum. The retroperitoneal tumor was diagnosed before surgery. Besides the main tumor in the duodenum, multiple small submucosal tumors were found in the duodenum and upper part of the jejunum during the operation. All of these tumors were resected. The histological diagnosis of all these tumors was GISTs. These tumors were immunohistochemically positive for KIT, but they demonstrated no mutation in c-kit exons 9, 11, 13, and 17, and platelet-derived growth factor receptor alpha exons 12 and 18. No recurrence occurred for a year after surgery.