Identification of heterozygous p.Y150C and p.V274M mutations in the HJV gene in a Japanese patient with a mild phenotype of juvenile hemochromatosis: A case report.

Juvenile hemochromatosis (JH) is known as a progressive iron-storage disease, and causes severe organ impairments, including cardiomyopathy and liver cirrhosis. However, JH is a rare genetic disorder, and information for genetic mutations and phenotypes is limited. Here, we report a case of JH with heterozygous p.Y150C and p.V274M mutations in the HJV gene. A 39-year-old Japanese man was referred to Kurume University Hospital, Kurume, Japan, for fatigue and liver injury, which first appeared at the age of 25 years. There was no history of alcohol abuse and medication, and viral hepatitis, autoimmune liver diseases, and Wilson's disease were absent. However, transferrin saturation, serum ferritin, and fasting serum hepcidin levels were 98.4%, 6421 ng/mL, and 7.4 ng/mL, respectively. Furthermore, a marked reduction in signal intensity of the liver in T1/T2-weighted magnetic resonance images was seen and the R2* maps showed hepatic iron overload. Family history of hemochromatosis and severe organ impairment, such as cardiac dysfunction and diabetes mellitus, were negative. In addition, the HFE and HAMP genes did not show any mutation. However, we identified novel heterozygous p.Y150C and p.V274M mutations in the HJV gene in the patient. The p.Y150C and p.V274M mutations were seen in his mother and father, respectively. After phlebotomy, fatigue disappeared and serum transaminase levels were normalized. Furthermore, R2* maps showed a reduction of hepatic iron concentration. We first demonstrated heterozygous p.Y150C and p.V274M mutations in the HJV gene of patients with a mild JH phenotype. Thus, genetic testing should be considered even in patients with a mild phenotype of hemochromatosis.

Triclosan sutures for surgical site infection in colorectal cancer.

BACKGROUND: Among all procedures, surgical site infections (SSIs) in colorectal surgery continue to have the highest rate, accounting for 5%-45%. To prevent the bacterial colonization of suture material, which disables local mechanisms of wound decontamination, triclosan-coated sutures were developed. We assessed the effectiveness of triclosan-coated sutures used for skin closure on the rate of SSIs in colorectal cancer surgery. METHODS: Until August 2012, we used conventional methods for skin closure in colorectal cancer surgery at the Department of Gastroenterological Surgery, Fukuoka University Faculty of Medicine. Therefore, for the control group, we retrospectively collected surveillance data over a 1.5-y period. From September 2012, we began using triclosan-coated polydioxanone antimicrobial sutures (PDS plus) for skin and fascia closure. Hence, we collected data for the study group from September 2012 to October 2013. Differences in baseline characteristics and selection bias were adjusted using the propensity score-matching method. RESULTS: A total of 399 patients who underwent colorectal surgery were included in this study. There were 214 patients in the control group and 185 patients in the study group. Baseline patient characteristics were similar between the propensity score-matched groups. The incidence of SSIs was less in the study group. Multivariate logistic regression analysis showed that the site of the procedure, laparoscopic surgery, and using triclosan-coated sutures remained the independent predictors of SSIs. CONCLUSIONS: The use of triclosan-coated sutures was advantageous for decreasing the risk of SSIs after colorectal surgery.

Can grade 2 neutropenia predict the risk of grade 3 neutropenia in metastatic colorectal cancer patients treated with chemotherapy?

PURPOSE: Neutropenia is a major factor affecting continuation of chemotherapy for colorectal cancer. In many clinical trials, a neutrophil count of >1500 is targeted for continuation; for a count of <1500, medication is commonly discontinued. However, there is no definitive evidence supporting the need for a neutrophil count of 1500 for continuation of chemotherapy. In the clinical trials that we conducted, we discontinued chemotherapy when the neutrophil count was <1000 (grade 3); for a count of 1000-1500 (grade 2), chemotherapy was continued. Therefore, even practical treatment uses the same setting. Our aim was to examine neutrophil counts during continuation of chemotherapy in colorectal cancer patients with counts of 1000-1500 and to assess the need for discontinuation of medication for neutrophil counts in this range. Moreover, we examined neutrophil counts during the previous course of chemotherapy when they fell below 1000. METHODS: The study included 144 patients who received XELOX + bevacizumab therapy and XELOX therapy for advanced or recurrent colorectal cancer. RESULTS: Thirty (20.8 %) patients had neutrophil counts of 1000-1500. One (3.3 %) of 30 patients had a neutrophil count of <1000 during the following course of chemotherapy. Moreover, among the patients with neutrophil counts of <1000, 27.3 % had counts of 1000-1500 during the previous course of chemotherapy and 72.7 % had counts of >1500. CONCLUSIONS: Based on these results, grade 2 neutropenia cannot predict the risk of grade 3 neutropenia. Continuation of chemotherapy in patients with neutrophil counts of 1000-1500 may be appropriate, and discontinuation of therapy is not always required.

Administration of chemotherapy via the median cubital vein without implantable central venous access ports: port-free chemotherapy for metastatic colorectal cancer patients.

BACKGROUND: Repeated venous punctures are usually required during chemotherapy administration for cancer patients. Central venous catheters and implantable port systems have substantially facilitated vascular access, and safe, easy-to-handle port systems have become an integral part of daily clinical routines in oncology. However, several serious complications are associated with central venous ports (CV-ports), and recent developments of combined oral capecitabine and oxaliplatin (XELOX) therapies allow CV-port-free administration. In this study, the safety and efficacy of CV-port-free chemotherapy administration via the median cubital vein was assessed in metastatic colorectal cancer patients. METHODS: This study included 144 patients who received XELOX + bevacizumab (BV) or XELOX therapy for metastatic colorectal cancer without CV-port implantation. RESULTS: Eighty-five patients experienced transient vascular pain. The drip infusion route was switched to the opposite side following vascular pain in only 1 patient. No patients required CV-port implantation or delayed treatment due to adverse events associated with drug administration via the peripheral vein. Grade 3 or higher hemotoxicity and grade 3 or higher non-hematological toxicity was noted in 12.5 and 17.4 % of patients, respectively. CONCLUSIONS: Port-free-chemotherapy administration via the median cubital vein is appropriate for patients with colorectal cancer, thereby avoiding complications associated with CV-ports.

[A case of unresected gastric cancer that maintained long tumor dormancy by use of paclitaxel+S-1 combination therapy].

Here we report a case of unresected gastric cancer that maintained long tumor dormancy by use of paclitaxel+S-1 combination therapy. A 58-year-old woman was admitted to the hospital for peritoneal dissemination of unresectable gastric cancer. The patient further showed ileus with peritoneal dissemination in computed tomography(CT), and we performed resection of the intestine to release the stenosis. In addition, combination chemotherapy using paclitaxel(60mg/m2, weekly) and S-1(80mg/m2, every 2 weeks)was started after the operation. The patient was discharged from the hospital 7 3 days after the operation, and we continued combination chemotherapy as an outpatient over the following 3 years without serious side effects. Furthermore, tumor makers for gastric cancer were stable, although we could not examine tumor size since the patient rejected examinations such as CT. After 3 years, the patient was admitted to the hospital with cholecystitis, and we were able to evaluate the benefit of the chemotherapy against gastric cancer. The tumor size clearly remained unchanged compared to previous measurements, suggesting that the tumor maintained dormancy in this case.

Pilot study of the early start of chemotherapy after resection of primary colorectal cancer with distant metastases (Pearl Star 01).

BACKGROUND: The start of chemotherapy usually requires a delay of about 4 weeks after surgical resection of colorectal cancer. However, there is no evidence for the required length of this delay interval. In addition, there is a chance that a patient may die because postoperative chemotherapy was not started soon enough and a metastatic tumor was able to develop rapidly. We therefore conducted a pilot study to determine the safety and feasibility of an early start of chemotherapy after the resection of colorectal cancer with distant metastases. METHODS: Five patients were enrolled. They received XELOX therapy (130 mg/m2 of oxaliplatin on day 1 plus 1,000 mg/m2 of capecitabine twice daily on days 1 to 14) on the 7th postoperative day and XELOX + bevacizumab (7.5 mg/kg of bevacizumab on day 1) after the 2nd cycle of chemotherapy. RESULTS: Five patients underwent open surgery. The procedures included right hemicolectomy in 1 patient, sigmoidectomy in 2 patients, high anterior resection in 1 patient, and Hartmann procedure in 1 patient. All patients started chemotherapy on postoperative day 7. The median number of cycles of chemotherapy was 11 (8 to 22). No postoperative complications were observed. The tumor reduction rate was 44.3% (32.0 to 66.6%). Progression-free survival was 10.3 months. CONCLUSIONS: An early start of chemotherapy after surgery is feasible and safe. These findings suggest possible changes in the start time of chemotherapy after surgery in the future. We have already started a new phase II trial to confirm the effects of the early start of chemotherapy after surgery. TRIAL REGISTRATION: UMIN000004361.

Long-term outcome of laparoscopic surgery for T1 cancer patients of the colorectum.

BACKGROUND/AIMS: Many reports of laparoscopic colorectal surgery (LCS) for advanced cancer have been published indicating that LCS is an optimal and less invasive surgical treatment. On the other hand, there are few reports that address the early stages of cancer, especially with regard to the long-term outcome. This study analyzed the short- and long-term outcomes after LCS in patients with T1 cancer. METHODOLOGY: Between 1994 and 2005, a total of 135 LCS, including 129 laparoscopic colectomies and 6 laparoscopic anterior resections were performed in patients with T1 cancer that was diagnosed after the operation. The median follow-up was 83.5 months (range, 33-165). RESULTS: Postoperative complications included 6 wound infections (4%), 3 bowel obstructions (2%), 2 anastomotic leakage (1.3%), 1 atelectasis (0.67%). None of the patients required a re-operation. Oral intake was started after a mean of 2.9 postoperative days and the mean postoperative hospital stay was 14.4 days. There was no mortality and the overall survival was 100% in long-term follow up. CONCLUSIONS: LCS for T1 cancer is technically and oncologically safe based on the long-term outcomes when performed by surgeons with sufficient experience in laparoscopic techniques.

Single orifice vein reconstruction in left liver plus caudate lobe graft.

BACKGROUND/AIMS: We describe the innovative techniques with single orifice vein reconstruction for the complete venous drainage in the left liver plus caudate lobe graft. METHODOLOGY: Eight left liver plus caudate lobe grafts used for living donor adult liver transplantation were reviewed. A wide and single venous orifice was created by gathering the left, middle or its tributaries, and/or short hepatic vein using a patch vein graft or a conduit vein graft. This single, newly-created orifice was then anastomosed to the common trunk created in the recipient's hepatic veins. RESULTS: Of 8 liver grafts, six included the middle hepatic vein trunk. Another two included only the middle hepatic vein tributaries. Significantly-sized short hepatic veins were preserved in 4 grafts and were connected with the major hepatic veins or tributaries of the middle hepatic vein to make a single orifice using a conduit vein graft. For remaining 4 grafts without significantly-sized short hepatic veins, two adjacent hepatic vein trunks (left and middle hepatic veins) were simply connected together. To enlarge the common orifice of the hepatic veins, the patch vein grafts were further attached. Hepatic vein waveforms of all grafts showed the biphasic or triphasic pattern and the graft congestion was not observed immediately after venoplasty. No graft was lost due to hepatic venous outflow block with the mean follow-up of 15 months. CONCLUSIONS: The short-term results of our technique were satisfactory. The present technique can simplify graft-to-recipient hepatic vein reconstruction without unfavorable tension on the anastomosis.

Prospective randomized trial of a closed-suction drain versus a Penrose drain after a colectomy.

BACKGROUND/AIMS: Prospective studies in the gastroenterological surgery literature have shown fewer wound related complications with a closed-suction drainage than with an open passive drainage. This study compared the SSI and cost of closed-suction drainage and open passive drainage in a randomized trial. METHODOLOGY: This study involved 112 patients undergoing colectomy from December, 2003 through April, 2007. A closed-suction or an open (Penrose) drainage was used based on the surgeon's preference. The cost and the incidence of complications including SSI was compared in the two drain types. RESULTS: The SSI rate was 13/112 cases 11.6%, but there was no significant difference between the drain groups. In addition, 18 laparoscopic surgery cases did not show any wound infection or drain infections. The closed-suction drain was not expensive regarding personnel expenses and the cost of changing the dressings. CONCLUSIONS: No statistically significant postoperative differences were observed between a closed-suction drain or an open drain after a colectomy. However, a closed-suction drain management is useful for the reduction of a cost, labor saving, and the decrease of medical waste.

Predictive factors of early recurrent death after a curative resection of gastric cancer.

Although several prognostic factors for gastric cancer have been shown, the predictive factors of early recurrent death remain to be elucidated. This study included 402 patients who underwent a curative resection for gastric cancer. Fifty-six patients died of recurrence. A multivariate analysis was performed to determine the independent factors correlated with survival time. The patients with an elevation of tumor markers, tumors in the upper one third of the stomach, deep wall invasion (T3, T4), extended lymph node metastases (N2, N3), an advanced stage (stages III and IV), and operation (total gastrectomy) showed a significantly different survival time. According to a multivariate analysis, the survival time was independently associated with tumor location, tumor markers, and lymph node metastases. The patients with tumors in the upper one third of the stomach, elevated tumor markers, and extended lymph node metastases can not be controlled by surgery alone.

Modification of the endoscopic management of congenital duodenal stenosis.

This report documents a new endoscopic management modality for congenital membranous stenosis in the third portion of the duodenum. Standard approaches to duodenal stenosis in newborns include a laparotomy with an enteroenterostomy, bypassing the obstruction, or a duodenoduodenostomy with excision. We successfully developed a modification of the endoscopic treatment modality for congenital duodenal diaphragm.

Efficacy and safety of endoscopic submucosal dissection under general anesthesia.

AIM: To evaluate the efficacy and safety of endoscopic submucosal dissection (ESD) under general anesthesia. METHODS: From January 2011 to July 2014, 206 consecutive patients had undergone ESD under general anesthesia for neoplasms of the stomach, esophagus, and colorectum were enrolled in this retrospective study. The efficacy and safety of ESD under general anesthesia were assessed. RESULTS: The en bloc resection rate of esophageal, gastric, and colorectal lesions was 100.0%, 98.3%, and 96.1%, respectively. The complication rate of perforation and bleeding were 0.0% and 0.0% in esophageal ESD, 1.7% and 1.7% in gastric ESD, and 3.9% and 2.0% in colorectal ESD, respectively. No cases of aspiration pneumonia were observed. All complications were managed by conservative treatment, with no surgical intervention required. CONCLUSION: With the cooperation of an anesthesiologist, ESD under general anesthesia appears to be a useful method, decreasing the risk of complications.

CD4+ T-lymphocytes are activated by surgical stress following colorectal resection in cancer patients.

The aim of the present study was to measure adenosine triphosphate (ATP) levels in CD4+ T cells as a marker of T-cell activity following surgery for colorectal cancer using the ImmuKnow assay kit. A total of 16 consecutive patients who underwent surgical resection for colorectal cancer between August and December, 2012 were enrolled in this study, of whom 7 underwent laparoscopic resection and 9 underwent open abdominal surgery. The intracellular ATP levels in CD4+ T-lymphocytes were measured using the ImmuKnow assay kit preoperatively and on the 1st, 4th and 8th postoperative days, as were the white blood cell (WBC) count, lymphocyte count and C-reactive protein (CRP) levels. The ATP level of the CD4+ T-cells was significantly elevated on the 1st day following surgery compared to the preoperative level (P<0.01) and gradually returned to preoperative levels; the lymphocyte count was significantly decreased on the 1st postoperative day (P<0.001). In addition, the ImmuKnow assay demonstrated that only the ATP level, but not the WBC count, lymphocyte count or CRP level, exhibited a significant difference on the 1st (P=0.080) and 8th (P=0.042) postoperative days between the laparoscopic and open abdominal surgery groups. In conclusion, the ATP level of CD4+ T-lymphocytes was increased in response to surgical stress, in tandem with a decrease in the lymphocyte count. Therefore, the ImmuKnow assay kit may be clinically applicable for monitoring the immune response following surgery, as it exhibits a higher sensitivity compared to other assays.

Impact of perioperative probiotic treatment for surgical site infections in patients with colorectal cancer.

The aim of the present study was to estimate the effect of the perioperative administration of probiotics in patients undergoing colorectal cancer (CRC) surgery. The study focused on a total of 156 consecutive surgeries carried out from among all the elective CRC surgeries performed between April 2009 and March 2013. The patients involved in surgeries undertaken between April 2009 and October 2011 were placed in the non-probiotic group (group A, 81 patients) and those involved in surgeries between November 2011 and March 2013 were placed in the probiotic group (group B, 75 patients). Postoperative infectious complications were recorded, and the immune responses and fecal microbiota were determined. A breakdown of infectious complications showed that 21 (13.5%) patients experienced superficial incisional surgical site infections (SSIs), of which 16 patients were from group A (19.8%), and five patients from group B (6.7%) (P=0.016). The ImmuKnow® adenosine triphosphate values peaked on the first postoperative day (POD) in both groups. In group A, the ImmuKnow value of the first POD was increased significantly compared with the preoperative value (P=0.022). In group B, the value of the first POD did not increase compared with the preoperative value (P=0.28). In conclusion, probiotic treatment can reduce superficial incisional SSIs in patients undergoing CRC surgery. Perioperative probiotic treatment can enhance immune responses and improve the intestinal microbial environment.

A single-arm Phase II validation study of preventing oxaliplatin-induced hypersensitivity reactions by dexamethasone: the AVOID trial.

BACKGROUND: Patients with colorectal cancer treated with oxaliplatin are at risk of hypersensitivity reactions, with the incidence estimated to be 12%-20%. Coinfusion of dexamethasone and oxaliplatin could potentially reduce the incidence of these reactions, but oxaliplatin is reported to be incompatible with alkaline compounds in solution. However, in a previous retrospective study we found that the pH of a solution of dexamethasone and oxaliplatin was less than 7.4, and that hypersensitivity to oxaliplatin could have been prevented by coinfusion of dexamethasone. We aimed to evaluate the effectiveness of coinfusion of dexamethasone and oxaliplatin to prevent oxaliplatin-induced hypersensitivity reactions. PATIENTS AND METHODS: The AVOID trial was a prospective, multicenter, open-label, single-arm Phase II trial conducted from January to September 2013. The study included 73 patients who received capecitabine plus oxaliplatin (XELOX) or XELOX plus bevacizumab therapy for colorectal cancer. In all patients, oxaliplatin was administered in combination with dexamethasone. The primary outcome measure was the presence of hypersensitivity reactions. RESULTS: Hypersensitivity reactions occurred in three patients (4.1%); all three experienced a cutaneous reaction (grade 1 erythema). None of the 73 patients developed respiratory symptoms, ocular symptoms, or anaphylaxis. Grade 3 or higher hemotoxicity occurred in 13.7% of the patients and grade 3 or higher nonhematological toxicity occurred in 13.7%. The response rate to treatment was 64.4%. CONCLUSION: The coinfusion of dexamethasone and oxaliplatin effectively reduced oxaliplatin-induced hypersensitivity reactions in patients with colorectal cancer. This approach should be considered for all patients treated with oxaliplatin, allowing treatment to be completed as planned.

Efficacy of XELOX plus Bevacizumab in Brain Metastasis from Rectal Cancer.

Brain metastasis (BM) is rare in colorectal cancer (CRC) patients. Although BM from CRC is a late-stage phenomenon with an extremely poor prognosis, some subsets of patients would benefit from a multidisciplinary management strategy. The prognosis of patients with BM from CRC was associated with the curability of the therapy for BM and the number of metastatic organs. Metastatic brain tumors are generally treated with radiotherapy because many anticancer drugs cannot cross the blood-brain barrier. Here, we present a case treated with XELOX (capecitabine and oxaliplatin) plus bevacizumab for BM from rectal cancer. To our knowledge, this is the first report of a patient who was successfully treated for BM from CRC without radiotherapy. The findings could lead to a paradigm shift in the use of chemotherapy for BM from CRC.

Free jejunal graft repair after pharyngolaryngo-esophagectomy-risk factor analysis for postoperative dysphagia.

PURPOSE: Reconstruction with free jejunal graft (FJG) has been widely accepted for patients undergone pharyngo-cervical esophageal resection. Those patients often suffer variety of complications regarding postoperative peros function. We investigated risk factors especially focused on the development of dysphagia after FJG reconstruction. METHODS: A retrospective analysis was conducted using clinical chart review of 30 consecutive patients who underwent reconstruction with a FJG after pharyngo-laryngoesophagectomy from 1995 to 2010. Mortality, morbidity, and postoperative dysphagia were investigated. Dysphagia was defined when the patients required enteral nutrition until later than 1 month postoperatively without any other complications, including anastomotic leakage, anastomotic stricture, FJG ischemic necrosis, and hospital death. Data on potential clinical factors were extracted and the relation of these variables to postoperative dysphagia was examined by univariate and multivariate analysis. RESULTS: There was one patient with hospital death over total 30 patients who deceased due to fatal postoperative bleeding from arterial anastomosis of FJG. Postoperative complications occurred in 14 patients (46.7%) those included respiratory complication in 5, anastomotic leakage 3, FJG ischemic necrosis 2, paralytic ileus 2, ischemic change of tracheostomy 2, anastomotic stricture 1 and dysphagia 9. Dysphagia was the most frequent in this series. Multivariate analysis demonstrated induction radiation (≥60 Gy) was independently significant factors for postoperative dysphagia. CONCLUSION: FJG reconstruction may be safe and functionally satisfactory surgical option after pharyngo-laryngo-esophagectomy. Postoperative dysphagia may be induced prior radiation therapy.

Expression of human epidermal growth factor receptor 2 in primary and paired parenchymal recurrent and/or metastatic sites of gastric cancer.

Human epidermal growth factor receptor 2 (HER2) status has been evaluated at the primary site of gastric cancer when planning trastuzumab therapy against recurrent or metastatic lesions, since tissue sampling is uncommon in recurrent or metastatic lesions. This study retrospectively investigated the concordance of HER2 expression between primary and metastatic/recurrent lesions in order to confirm sensitivity to trastuzumab. The subjects comprised 37 patients with gastric adenocarcinoma who underwent tissue biopsy or surgical resection of the primary sites and 49 paired synchronous or metachronous metastatic sites (excluding lymph nodes) at the Fukuoka University Hospital between January, 1998 and September, 2012. All the samples were evaluated for HER2 status at the invasive front by immunohistochemistry (IHC). The HER2 positivity rate of the primary sites was ~16% and the concordance ratio of the IHC results between primary and paired metastatic sites was ~97%. No discordant cases regarding HER2 status were found among metachronous interventions for metastatic lesions. Only one patient exhibited conversion from a HER2-negative status in all the portions of the primary site to a positive status in a metastatic site. In conclusion, a high concordance ratio for HER2 status was observed between primary and paired metastatic lesions. Thus, employing trastuzumab therapy against metastatic or recurrent gastric cancer based on the HER2 status of the primary lesion appears to be an acceptable approach.

A Report of Disseminated Carcinomatosis of the Bone Marrow Originating from Transverse Colon Cancer Successfully Treated with Chemotherapy Using XELOX plus Bevacizumab.

A 61-year-old male, who had been admitted to another hospital due to disseminated intravascular coagulation (DIC), was referred to our hospital. Total colonoscopy, abdominal dynamic CT and positron-emission tomography revealed bone metastasis and multiple lymphocytic metastases from transverse colon cancer in addition to disseminated carcinomatosis of the bone marrow (DCBM). We immediately performed chemotherapy with XELOX + bevacizumab and denosumab against DCBM from transverse colon cancer in order to avoid radical surgery. In addition, we initiated the administration of recombinant human soluble thrombomodulin for 1 week to treat DIC. The patient was able to tolerate and receive 4 cycles of chemotherapy without any severe side effects. After receiving the 4 cycles of treatment, he recovered from DIC, and the bone and multiple lymphocytic metastases disappeared.