[The Usefulness of Preoperative Modified Glasgow Prognostic Score Evaluation in Elderly Colorectal Cancer Cases].

BACKGROUND: In cancer treatment of the elderly, it is important to grasp the"degree of inflammation"and"nutritional status"in advance. OBJECTIVE: This study aims to investigate the usefulness of preoperative modified Glasgow Prognostic score(mGPS)evaluation in elderly patients with colorectal cancer. PATIENT: 89 cases of primary resection of colorectal cancer over 80 years old were enrolled. METHODS: In the preoperative mGPS score normal group(score 0)and abnormal group (scores 1 or 2)were divided. Clinicopathological factors(patient-related 13 factors, treatment-related 6 factors, and tumor-related 4 factors)were compared, and the long-term results were also investigated. RESULTS: Between 42 cases in the normal group and 47 cases in the abnormal group, there were significant differences(p<0.05)in 6 factors: BMI, total protein, cholinesterase, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and Onodera prognostic nutritional index. The long-term results(5-year survival rate)were also significantly different in the normal group(76.8%)and the abnormal group(51.6%)(p=0.007). CONCLUSION: Even in elderly patients with colorectal cancer, preoperative suppression of inflammatory conditions and improvement of nutritional status may contribute to the improvement of long-term prognosis, so mGPS evaluation is useful.

[Long-Term Response of Nivolumab for Peritoneal Dissemination and Recurrent Liver Metastasis after Surgery for Perforated Gastric Cancer-A Case Report].

A 39-year-old woman was hospitalized because of lower abdominal pain and fatigue. A laboratory study indicated severe anemia(hemoglobin 2.5 g/dL). Computed tomography(CT)revealed a perforated gastric tumor and free air. Distal gastrectomy was performed as an emergency surgery. Histopathologic examination showed adenocarcinoma(moderately differentiated > poorly differentiated), and she was diagnosed as having a pT4b, pN0, pM1, pStage ⅣB tumor. Postoperatively, adjuvant chemotherapy with S-1 was administered. CT imaging 2 years after the operation showed peritoneal dissemination and liver metastasis, and XELOX therapy was initiated. Response evaluation after 3 courses was progressive disease (PD), and ramucirumab plus paclitaxel was initiated. After 5 courses, CT imaging revealed ascites and progression of peritoneal dissemination and liver metastasis; nivolumab was initiated. CT imaging after 74 courses showed peritoneal dissemination, and liver metastasis became unclear. The patient at present has responded well to nivolumab for 52 months.

[A Case of Advanced Breast Cancer in an Elderly Patient That Was Well Controlled by Mohs' Paste, Endocrine Therapy, and Denosumab].

We report a case of advanced left breast cancer with continuous bleeding from the primary tumor surface in an 81-year-old woman. Pathological findings showed invasive carcinoma with positive expression of hormone receptors. CT and bone scintigraphy showed primary tumor invasion of the greater pectoral muscle and multiple bone metastases. She received Mohs' chemosurgery, endocrine therapy, and denosumab. The bleeding was maintained by weekly treatment. Most of the bulging surface of the tumor decreased and dried up 2 months later. The tumor disappeared almost completely, and the bone metastases achieved stable status 3 months later. Until currently, the primary tumor and metastasis have been controlled for 1.5 years. Mohs' paste was effective for controlling bleeding and exudates of unresectable cancer bulging from the skin surface and played an important role in cancer treatment with systemic therapy.

[Investigation of Colorectal Cancer Cases among Patients Aged over 75 Years Who Received Postoperative Adjuvant Chemotherapy].

BACKGROUND: As the aging of the Japanese population progresses, the administration of postoperative adjuvant chemotherapy( AC)to the elderly is also expected to increase. OBJECTIVE: To examine the characteristics of AC in cases of colorectal cancer among elderly people aged over 75 years. PATIENTS: Forty-eight cases of colorectal cancer patients who received AC. METHODS: The clinicopathological factors, including 14 patient-related factors, 6 operation-related factors, and 2 AC-related factors, as well as the long-term outcomes, were compared between the elderly group of patients aged over 75 years(group O, 12 cases)and the non-elderly group(group Y, 36 cases). RESULTS: Significant differences were observed between groups in neutrophil count(p=0.044), operation time(p=0.044), AC regimen(p=0.006), and administration completion status (p=0.046). Compared to group Y, a higher proportion of oral drug alone(92% vs 39%)and completion rate of the initial setting dose(75% vs 39%)were observed in group O. There was no significant difference in the 2-year disease-free survival rate. CONCLUSION: Oral preparations of AC may be useful from the viewpoint of tolerability in the elderly.

Postoperative analgesia using fentanyl plus celecoxib versus epidural anesthesia after laparoscopic colon resection.

PURPOSE: Effective postoperative analgesia is essential to a patient's recovery after laparoscopic colon resection (LCR). We introduce a new analgesic protocol using fentanyl plus celecoxib following LCR. METHODS: The subjects of this retrospective comparative study were 137 patients who underwent LCR, 63 of whom were treated with 72 h of epidural anesthesia (group E), and 74 of whom were treated with 24 h of fentanyl intravenous injection followed by 7 days of oral celecoxib (group FC). We evaluated the safety and efficacy of this new protocol. RESULTS: The combination of fentanyl and celecoxib maintained a low postoperative pain score (<1.5, evaluated by the FACES Pain Scale) and reduced the need for rescue analgesic drugs for 7 days (groups E vs. FC: 5.39 ± 3.77 vs. 2.79 ± 2.92, p < 0.001). The postoperative hospital stay was almost equal for the two groups (E vs. FC: 11.1 ± 4.5 vs. 10.3 ± 4.8 days, p = 0.315). The operating room stay other than for surgery was significantly shorter for group FC (E vs. FC: 128.7 ± 30.5 vs. 107.2 ± 17.0 min, p < 0.001). Neither group experienced complications, apart from one group FC patient, who suffered transient nausea and vertigo. CONCLUSIONS: The new analgesic protocol using fentanyl plus celecoxib is an effective and time-saving strategy for LCR.

Solitary left axillary lymph node metastasis after curative resection of carcinoma at the colostomy site: a case report.

BACKGROUND: The incidence of axillary lymph node metastasis (ALNM) of colon cancer is very low, and there have been only a few reports of solitary ALNM. Neither the mechanism involved in solitary colon cancer ALNM nor the proper treatment has been elucidated. We encountered a case of solitary left ALNM after curative resection of carcinoma at the colostomy site. CASE PRESENTATION: A 53-year-old man underwent a Hartmann's operation for Hirschsprung disease during his adolescence. He complained of a mass of the descending colon and was diagnosed with colon cancer at the colostomy site with pagetoid spread to the adjacent skin. The cancer at the stoma site was resected, and a transverse colostomy was performed. Nine years later, his carbohydrate antigen (CA) 19-9 level was high during a health screening. On physical examination, adenopathy was palpated in the left axilla. Computed tomography (CT) demonstrated a lymph node in the left axillary fossa that was 33 mm in diameter, and (18)F-fluorodeoxyglucose positron emission tomography/CT showed high uptake in the lesion. We performed a curative resection of the left axillary lymph node. The lesion was pathologically diagnosed as left ALNM originating from the adenocarcinoma at the colostomy site. After lymph node resection, his serum CA19-9 level decreased compared to that observed at baseline. He has been receiving adjuvant chemotherapy (capecitabine plus oxaliplatin) without recurrence for 5 months after lymph node resection. CONCLUSIONS: The present case report shows that carcinoma at the colostomy site with pagetoid spread can metastasize to the axillary lymph nodes through superficial abdominal lymphatic pathways, and surgical resection followed by adjuvant chemotherapy may be a potent strategy to treat solitary colon cancer ALNM.

Successful treatment of rectovaginal fistula and rectal stenosis due to perianal Crohn's disease by dual-port laparoscopic abdominoperineal resection: a report of two cases.

BACKGROUND: The incidence of rectovaginal fistula in women with Crohn's disease has been reported to be 3-10 %. Although rectovaginal fistulas can be managed medically and surgically, they have high rates of recurrence and complications. Rectal stenosis is another condition that occurs due to perianal Crohn's disease. A novel, minimally invasive procedure, dual-port laparoscopic abdominoperineal resection using a multichannel port, has been shown effective in patients with lower rectal cancer and patients with medically uncontrolled ulcerative colitis. This report describes the use of the same method for two patients with Crohn's disease-related rectovaginal fistula and rectal stenosis. CASE PRESENTATION: The first patient, a 22-year-old woman, was diagnosed with rectovaginal fistula and rectal stenosis due to perianal Crohn's disease 2 years earlier. Induction therapy with infliximab and endoscopic balloon dilatation did not improve her symptoms. The second patient, a 33-year-old woman, was also diagnosed with rectovaginal fistula and rectal stenosis due to perianal Crohn's disease, and medical treatment was also unsuccessful. Both patients underwent dual-port laparoscopic abdominoperineal resection using a multichannel port, with no perioperative and postoperative complications. CONCLUSION: These findings show that this reduced port method can be used to successfully treat patients with Crohn's disease-associated rectovaginal fistula and rectal stenosis.

Use of transabdominal ultrasonography to preoperatively determine T-stage of proven colon cancers.

PURPOSE: Although noninvasive and highly informative, transabdominal ultrasonography (US) is not yet an accepted means of staging colorectal cancer preoperatively. This prospective study evaluated the diagnostic accuracy of US in preoperative staging of patients with resectable colon cancers. METHODS: A total of 98 patients with primary colon cancer diagnosed by colonoscopy at our institute between January, 2011 and June, 2014 underwent preoperative ultrasonographic tumor staging. Depth of tumor infiltration (T-stage) was assessed by standard means (i.e., extent of mural involvement), analyzing agreement in US and histopathology determinations. RESULTS: All but two colon cancers (at splenic flexure) were detected by US (98%, 96/98). Compared with histopathology, overall accuracy of US in determining T-stage was 64% (61/96), indicating moderate reproducibility (κ coefficient 0.48; 95% CI 0.35-0.62; p < 0.001). Using a three-tier approach of graded muscularis propria (MP) involvement (Tis/T1, below MP; T2, within MP; and T3/T4, beyond MP), diagnostic agreement increased to 89% (85/96), with good agreement (κ coefficient 0.77; 95% CI 0.64-0.90; p < 0.001). No tumor characteristics or patient demographics influenced diagnostic agreement at any site in the colon. CONCLUSIONS: Given the potential to yield valuable information while limiting patient discomfort, US should be reconsidered as a means of assessing colon cancer.

[S-1+gemcitabine (GEM) therapy was effective in a case of unresectable pancreatic head carcinoma].

OBJECTIVE: Treatment results of pancreatic head carcinoma are not good and long-term survival, especially in nonresectable cases is extremely difficult to obtain. The case reported here is of nonresectable pancreatic head carcinoma in which S-1+gemcitabine (GEM) proved to be effective. CASE: A 70-year-old male. The patient initially complained of epigastralgia. Jaundice was also noted and upon further study, pancreatic head carcinoma, portal vein and common hepatic artery infiltration along with duodenal infiltration were diagnosed. Gastrojejunostomy and cholecystectomy were performed with a preoperative diagnosis of Phb, TS2 infiltrative type T4, CH (+), DU (+), S (+), RP (-), PV (+), Ach (+), PLX, OO (-), N0, M0, and Stage IVa. Perioperative findings showed no hepatic or peritoneal metastases. Following surgery, S-1+ GEM (S-1 100 mg/day, day 1-14; GEM 1,000 mg/m(2) was administered on day 8 and day 15 for 2 weeks followed by one week of no administration) was started. After completing 2 courses, there was no change in the tumor, but after finishing the sixth course, there was a notable reduction in tumor size, and after finishing the 10th course, a further reduction was noted. Currently at the end of the 14th course, the tumors are unidentifiable upon imaging. At 1 year and 5 months from the initial diagnosis, there has been no recurrence and chemotherapy is being continued. In the case reported here, there have been no adverse side-effects from the S-1+GEM therapy, it is a safe method which does not lower QOL in patients with unresectable pancreatic carcinoma, and we can look forward to the possibility of extended survival times. CONCLUSION: In the case of unresectable pancreatic carcinoma, S-1+GEM therapy may be able to provide an improved long-term prognosis.

[Successful emergency surgery for acute mitral regurgitation due to total rupture in the anterior papillary muscle after acute myocardial infarction; report of a case].

A 32-year-old male was admitted with dyspnea Severe dyspnea and hypoxemia developed the next day and blood examination indicated acute myocardial infarction. Echocardiogram revealed massive mitral regurgitation with prolapse of the anterior mitral leaflet due to rupture in the papillary muscle. Percutaneous coronary intervention for total occlusion in the right coronary artery was successfully performed, but progressive heart failure continued to develop. Surgery for the papillary muscle rupture was performed on the 3rd day. Complete head rupture of the anterior papillary muscle was found and the mitral valve was replaced with a prosthetic valve (St. Jude Medical valve: #31). Pathological findings showed necrosis in the papillary muscle with inflammatory changes. The postoperative course was uneventful and the patient was discharged on the 43rd day after surgery.

Selection of a novel drug-response predictor in esophageal cancer: a novel screening method using microarray and identification of IFITM1 as a potent marker gene of CDDP response.

Prior laboratory prediction of individual drug response is of key importance in esophageal squamous cell carcinoma (ESCC), because of the extremely narrow therapeutic index of chemotherapy. However, very few critical markers have been validated to date for ESCC. We previously demonstrated that simultaneous performance of two different types of comprehensive gene expression analysis might provide a way to identify potent marker genes for drug sensitivity from the expression-sensitivity correlation analysis alone, but the screening method appeared not to be always effective. Therefore, we attempted to identify novel potent marker genes using a new statistical analysis of oligonucleotide microarray expression data, based on a two-dimensional mixed normal model, and selected 3 and 7 novel candidates for 5-fluorouracil (5-FU) and cis-platinum (CDDP), respectively. Interferon induced transmembrane protein 1 (IFITM1) gene alone, being suggested as a key gene of Wnt pathway, was commonly selected in both screening methods. The transfection analyses and siRNA-mediated knock-down experiments revealed that expression of IFITM1 closely related to cellular sensitivity to CDDP. Considering the fact that drug sensitivity is determined by multiple genes, we established the best linear model using quantified expression data of a set of all the selected marker genes including IFITM1, which converted the quantified expression data of ESCC cell lines into an IC50 value of each drug. In the same way, using the representative genes selected in vitro, we developed highly predictive formulae for disease-free survival (DFS) of the CDDP/5-FU combination after curative operation in esophageal cancer patients (R=0.917). A two-dimensional mixed normal model can be a powerful tool to identify novel drug-response determinants, and the IFITM1 gene selected by the statistical method a novel critical biomarker of CDDP response in ESCC.

Human carboxylesterase 1A2 expressed from carboxylesterase 1A1 and 1A2 genes is a potent predictor of CPT-11 cytotoxicity in vitro.

BACKGROUND: The conversion of CPT-11 to its active form, SN-38, by carboxylesterases (CESs) is a critical event in CPT-11-induced cytotoxicity. Among the CESs, CES1 and CES2 probably play a major role in the metabolism, but the functional significance and molecular basis of CES1 on CPT-11 response remain unclear. METHODS AND RESULTS: We investigated CES1A1 (AB119997) and CES1A2 (AB187225), whose coding sequences were recently registered in GenBank, for CPT-11-induced cytotoxicity, anticipating novel biomarkers of CPT-11 response. Their coding sequences showed high homology, with only four amino acid differences in the N-terminal region, but our sequencing study of the 5' regions revealed that CES1A1 and CES1A2 had distinctive consensus sequences for transcription factors in the regions, implying differences in transcriptional regulation of the genes. We also identified three isoforms of CES1A1 gene--CES1A1a, CES1A1b and CES1A1c--and developed a detection method for CES1A1 and CES1A2 types of mRNA expression. Interestingly, CES1A2 type of mRNA was found to be expressed from both CES1A1b and CES1A1c isoforms and CES1A2, the promoter activity of the former was higher than that of the original CES1A2 gene. Finally, CES1A2 type of mRNA expression correlated with CPT-11 sensitivities of cancer cells. CONCLUSION: We demonstrated novel sequence structures and a functional role of CES1A genes in CPT-11 responses. We believe that our novel findings will be of key importance in developing a really useful prediction method for CPT-11 chemosensitivity.

[Complete recovery obtained with combined S-1 + CDDP therapy in a patient with multiple lung metastases from esophageal cancer].

PURPOSE: There are numerous reports on the subject of effectiveness in radio-chemotherapy with regard to esophageal cancer, suggesting especially the combination therapy of 5-FU + CDDP aimed for recovery. Treatment becomes difficult when distal metastases appear during an adjuvant therapy followed by surgery. Our report here is a case in which a complete recovery was obtained after changing to S-1, a prodrug of 5-FU, in response to multiple lung metastases which appeared during the combined 5-FU + CDDP therapy followed by surgery for esophageal cancer. CASE: The patient was a 71-year-old male. Endoscopy during a physical examination showed a Type 1 tumor 27-30 cm from the anterior teeth. Detailed tests provided a preoperative diagnosis of esophageal cancer: Ut Type 1, T2-T3, N2, MO, IMO. A right thoracolaparotomic subtotal esophagectomy and retrosternal reconstruction were performed. Pathological findings showed well-differentiated squamous cell carcinoma, pT1b (sm), pN1 (106-rec R), pStage II. Postoperative combination of 5-FU + CDDP (day 1-5, 5-FU 500 mg; CDDP 10 mg/body) was started. Because of the appearance of multiple lung metastases after the completion of 3 courses, 2 courses of S-1 + CDDP (S-1 120 mg/body day 1-14; CDDP 5 mg/body day 1-5, day 8-12) were performed. After completing the chemotherapy, CT revealed the resolution of the lung metastases and complete recovery was diagnosed. Following this, a treatment with S-1 alone was continued until the appearance of bone metastases at which time radiotherapy was performed. The treatment is currently ongoing and no recurrence of the lung metastases has been shown. CONCLUSION: There have been numerous reports of the combination of S-1 + CDDP in esophageal cancer for NAC or in inoperable cases. However, our report suggests that this method may be effective in cases of recurrence or distal metastases.

Chemosensitivity prediction in esophageal squamous cell carcinoma: novel marker genes and efficacy-prediction formulae using their expression data.

Esophageal cancer is a highly lethal disease and the optimal therapy remains unclear. Since adjuvant chemotherapy gives a better chance of survival, we attempted to develop a chemosensitivity prediction model to improve individual responses to therapy. Comprehensive gene expression analyses (cDNA and oligonucleotide microarrays) and MTT assay of 8 drugs in 20 KYSE squamous cell carcinoma cell lines were performed to distinguish candidate marker genes whose expression levels reproducibly correlated with cellular drug sensitivities. After confirmation with real-time RT-PCR, we performed multiple regression analyses to develop drug-sensitivity prediction formulae using the quantified expression data of selected marker genes. Using the same sets of genes, we also constructed prediction models for individual clinical responses to 5-FU-based chemotherapy using 18 cases. We selected 5 better marker genes, known as drug sensitivity determinants, identified 9 novel predictive genes for 4 of 8 anticancer drugs [5-FU, CDDP, DOX, and CPT-11 (SN-38)], and developed highly predictive formulae of in vitro sensitivities to the 4 drugs and clinical responses to 5-FU-based adjuvant chemotherapies in terms of overall and disease-free survivals. Our selected genes are likely to be effective drug-sensitivity markers and formulae using the 9 novel genes would provide advantages in prediction.

Activator protein accelerates dihydropyrimidine dehydrogenase gene transcription in cancer cells.

Dihydropyrimidine dehydrogenase is the most extensively investigated predictive marker for individual response to 5-fluorouracil. Clinical responses to the anticancer agent, along with various reports, have clearly shown that dihydropyrimidine dehydrogenase activity is closely correlated to its mRNA levels, but the regulatory mechanisms of its expression have remained unclear. We attempted to clarify the mechanisms and found that activator protein (AP-1) is probably one of the key factors in the transcriptional regulation of DPYD in cancer cells, and that phorbol 12-myristate 13-acetate (PMA) plus ionomycin treatment enhances transcription of DPYD via AP-1 activation. In this study, we characterized our previously subcloned 5' region of human DPYD, an approximately 3.0-kb fragment (accession no. AB162145). Luciferase reporter assay showed that the clone showed strong promoter activities in 293T and HSC42 cells, and comparative analysis using 5' deletion mutants suggested the existence of several positive and negative regulatory regions, including putative binding sites for AP-1, SP-1, and nuclear factor-kappaB. PMA/ionomycin treatment increased the mRNA level of DPYD in HSC42 cells, and electrophoretic gel mobility shift assay showed that the complex on the putative AP-1 binding site was drastically induced by PMA/ionomycin treatment. The complexes formed were competed out by preincubation with the cold-consensus AP-1 binding site, and the DNA binding complex formed on the site contained c-Jun and c-Fos, which are components of AP-1 transcription factor. We further identified the functional AP-1 binding site (nucleotide positions from -290 to -280), whose nucleotide mutations abolished PMA/ionomycin-induced DPYD promoter activation.

Aberrant methylation of DPYD promoter, DPYD expression, and cellular sensitivity to 5-fluorouracil in cancer cells.

PURPOSE: Dihydropyrimidine dehydrogenase (DPD), the initial rate-limiting enzyme in the degradation of 5-fluorouracil (5-FU), is known to be a principal factor in clinical responses to the anticancer agent 5-FU, and various reports have clearly demonstrated that DPD activity is closely correlated to mRNA levels. However, the regulatory mechanisms of DPD gene (DPYD) expression remain unclear. In this study, the regulatory mechanisms have been intensively studied. EXPERIMENTAL DESIGN AND RESULTS: A subcloned 3.0-kb fragment of the 5' region of DPYD contains a total of 60 CpG sites, suggesting that methylation status may affect the repression of DPYD. The clone showed various promoter activities that were largely correlated with mRNA levels in most cell lines, except HSC3 and HepG2. Bisulfite sequencing analysis revealed that various CpG sites around the transcription start site were abnormally methylated in cells with low DPYD expression: Reversal of hypermethylation by 5-azacytidine treatment significantly increased DPYD expression in HSC3 and HepG2 cells that showed strong promoter activity. In HepG2, in vitro methylation of the DPYD promoter directly decreased promoter activity, and 5-azacytidine treatment restored higher DPYD expression in a dose- and time-dependent manner, along with decreased sensitivity to 5-FU. CONCLUSIONS: We found that DPD activity was controlled, at least in part, at the transcription level of DPYD and that aberrant methylation of the DPYD promoter region acted as one of the repressors of DPYD expression and affected sensitivity to 5-FU in cancer cells. Our new results could lead to a more precise understanding of the molecular basis of 5-FU response.

[Neoadjuvant chemoradiotherapy for advanced squamous cell carcinoma of thoracic esophagus].

Advanced thoracic esophageal cancer has a poor prognosis despite advances in surgery, such as three-field lymph node dissection. Multimodal therapy is needed to improve local control, resectability and survival rate. Fifteen patients with advanced squamous cell carcinoma of the thoracic esophagus were treated with neoadjuvant chemoradiotherapy (NAC) combined with concurrent radiation (30 Gy/12 f) and 3 courses of 5-FU and CDDP (CDDP 5 mg/m2/day + 5-FU 250 mg/m2/day: day 1-5: div). In the absence of unresectable disease and surgical risk, 12 patients underwent esophagectomy (Group 1) and 3 patients underwent additional chemoradiotherapy because of high surgical risk (Group 2). Side effects consisted of nausea, vomiting and myelo-suppression in 8 patients, but all patients tolerated and completed a full course of NAC. The effective rate (CR + PR) of NAC was 58.3% in Group 1 and 66.7% in Group 2. No patients showed pathological CR. Two-year survival rate was 28.1% in Group 1 (PR: 33.3%, NC: 20.0%) and 33.5% in Group 2. This protocol had acceptable toxicities but did not show survival benefit. Further trials are necessary to improve survival rate.