Relationship between perioperative oncological evaluation and recurrence using circulating tumor DNA with KRAS mutation in patients with colorectal cancer.

BACKGROUND: The detection of circulating tumor DNA (ctDNA) in colorectal cancer (CRC) by liquid biopsy may have prognostic information. In this perioperative study, we evaluate if there is a relationship between mutant allele frequency (MAF) of Kirsten rat sarcoma viral oncogene homolog (KRAS) and tumor recurrence and how that could be useful in the early detection of recurrence. METHODS: Among 304 cases of colorectal cancer surgery, ctDNA was sampled from the perioperative blood of 84 patients with CRC with KRAS mutation (exon 4 p.A146T, exon 4 p.A146V, exon 2 p.G12A, exon 2 p.G12C, exon 2 p.G12D, exon 2 p.G12S, exon 2 p.G12V, exon 2 p.G13D, exon 3 p.Q61H) and analyzed using the digital polymerase chain reaction system. The median observation period was 26 months. RESULTS: Although the relationship between the perioperative MAF of KRAS and recurrence was not proved, tumor diameter, tumor depth, and stage were correlated with the preoperative MAF of KRAS (p = 0.034, p = 0.002, p = 0.008). However, tumor diameter, tumor depth, and stage did not correlate with MAF of KRAS at postoperative day 30. CONCLUSIONS: In this study, pathological tumor size, tumor depth, and stage were correlated with preoperative MAF of KRAS, but it was unreliable to predict recurrence by detection of ctDNA with KRAS mutation in the perioperative period of colorectal surgery.

Endoscopic full-thickness resection of an esophageal leiomyoma located in close proximity to the azygos vein.

Third-space endoscopic techniques, such as peroral endoscopic tumor resection (POET) and submucosal tunneling endoscopic resection (STER), enable access to deep organs and tissues that have been previously inaccessible with an endoscope. We present a 29-year-old man with a submucosal tumor (40 × 25 mm) located at 5 o'clock in the upper thoracic esophagus. Histological diagnosis by endoscopic ultrasound-fine needle aspiration was leiomyoma. Computed tomography showed the azygos vein posterior to the tumor. However, because endoscopic ultrasound revealed space between them, POET was performed. Because the tumor originated from the deep layer of the muscularis propria, full-thickness resection was performed to achieve R0 resection. The azygos vein arch was seen through the mediastinal space after tumor enucleation. The final histopathological diagnosis was leiomyoma. POET is a potentially revolutionary endoscopic technique that enables full-thickness resection of nonepithelial lesions. Preoperative computed tomography or endoscopic ultrasound to determine peritumoral anatomy is important to ensure safety. During the procedure, it is important to operate under direct vision, accurately identify the tumor boundary, and dissect along the boundary to avoid damaging the tumor and surrounding structures.

Oncological evaluation in the perioperative period using cfDNA with BRAF V600E mutation in patients with colorectal cancer.

The detection of circulating cell-free DNA (cfDNA) by liquid biopsy is reported to provide prognostic information in colorectal cancer (CRC). Although the frequency of BRAF V600E mutation in CRC is less than 10%, it is associated with poor responses to conventional chemotherapy. We conducted a prospective study to investigate the relationship between the perioperative mutant allele frequency (MAF) of BRAF V600E and tumor recurrence, and to evaluate the possibility of early detection of recurrence. Among 362 patients who underwent radical resection, cfDNA was extracted from the perioperative blood of 11 CRC patients with BRAF V600E mutation and analyzed using the digital polymerase chain reaction (dPCR) system. The median follow-up time was 22 months, and there were four cases of recurrence. Although there was no correlation between recurrence and the perioperative MAF of BRAF V600E, tumor diameter was correlated with the MAF (p = 0.024), and the MAF increased with time in two patients from whom additional samples were obtained prior to recurrence. In this study, we identified a correlation between the pathological tumor diameter and the MAF, but it was difficult to predict recurrence by measuring cfDNA with BRAF V600E mutation in the perioperative period of radical resection of CRC.

Two case of bilateral approach in laparoscopic pancreas-sparing distal duodenectomy for duodenal neoplasms arising from the distal duodenum.

INTRODUCTION: Laparoscopic pancreas-sparing distal duodenectomy is a less invasive surgical therapy; however, the anatomical complexity of the duodenum increases the difficulty of laparoscopic procedures. We introduce our technique for laparoscopic pancreas-sparing distal duodenectomy for distal duodenal tumors. PRESENTATION OF CASES: A first patient was 47-year-old woman who had 30 mm of duodenal tumor which located in third portion of duodenum. A second patient was 66-year-old man who had 35 mm of submucosal tumor which located in the third portion of duodenum. Laparoscopic pancreas-sparing duodenectomy was performed using bilateral approach for both cases. We began by dissecting an avascular area on the right side of the transverse mesocolon to mobilize the second and third portions of the duodenum with the uncinate process of the pancreas. Next, from the left side, the jejunum and the fourth portion of the duodenum were fully mobilized orally from the surrounding tissue, connecting the dissection plane with the right-side area. The jejunum and duodenum were cut with a linear stapler. Intracorporeal reconstruction was performed in an overlapped manner. We performed this procedure in two patients. Operative time was 326 and 370 min, respectively. Patients were discharged on postoperative days 9-12 without postoperative complications. DISCUSSION: Duodenal tumors are found increasingly often because of developments in endoscopic technology and techniques; therefore, establishing safe surgical procedures for duodenal tumor excision is imperative. Our surgical approach was simple and safe procedure. CONCLUSION: Laparoscopic pancreas-sparing distal duodenectomy with a bilateral approach is a useful approach without wide mobilization of duodenum.

5-Nitrouracil stabilizes the plasma concentration values of 5-FU in colorectal cancer patients receiving capecitabine.

Capecitabine is selectively converted from 5'-DFUR to 5-fluorouracil (5-FU) in tumours by thymidine phosphorylase (TP). We investigated the addition of 5-nitrouracil (5-NU), a TP inhibitor, into blood samples for precise measurements of plasma 5-FU concentrations. The plasma concentration of 5-FU was measured after capecitabine administration. Two samples were obtained at 1 or 2 h after capecitabine administration and 5-NU was added to one of each pair. Samples were stored at room temperature or 4 °C and 5-FU concentrations were measured immediately or 1.5 or 3 h later. The mean plasma 5-FU concentration was significantly higher at room temperature than at 4 °C (p < 0.001). The 5-FU concentration was significantly increased in the absence of 5-NU than in the presence of 5-NU (p < 0.001). The 5-FU change in concentration was greater in the absence of 5-NU, and reached 190% of the maximum compared with baseline. A significant interaction was found between temperature and 5-NU conditions (p < 0.001). Differences between the presence or absence of 5-NU were greater at room temperature than under refrigerated conditions. 5-FU plasma concentrations after capecitabine administration varied with time, temperature, and the presence or absence of 5-NU. This indicates that plasma concentrations of 5-FU change dependent on storage conditions after blood collection.

Geriatric Nutritional Risk Index as a prognostic factor in patients with esophageal squamous cell carcinoma -retrospective cohort study.

PURPOSE: The Geriatric Nutritional Risk Index (GNRI) is a new index recently introduced to predict the risk of nutrition-related complications and mortality. Our aim is to examine the association between the GNRI and long-term prognosis in patients with esophageal squamous cell carcinoma (ESCC) who underwent esophagectomy. METHODS: The present study enrolled consecutive 216 patients with ESCC who underwent esophagectomy. The GNRI at admission to the hospital was calculated as follows: (1.489 × albumin, g/l) + (41.7 × present/ideal body weight). The characteristics and long-term prognosis were compared between four groups: the severe risk (GNRI: <82), moderate risk (GNRI: 82 to <92), low risk (GNRI: 92 to <98) and no risk (GNRI: >98) groups. The 5-year overall survival and independent prognostic factors were investigated, respectively. RESULTS: A decreased GNRI significantly correlated with unfavorable overall survival (p < 0.001). In all patients, a multivariate analysis demonstrated that the severe and moderate risk groups (GNRI: <92) (hazard ratio 0.50; p = 0.002), T factor (≥T2) (hazard ratio 0.52; p = 0.026), and N positive factor (hazard ratio 0.47; p = 0.004) were independent prognostic factors. In the subgroup analysis, which excluded patients with preoperative chemoradiotherapy, the severe and moderate risk groups (GNRI: <92) (hazard ratio 0.48; p = 0.0057), and T factor (≥T2) (hazard ratio; p = 0.021) were independent prognostic factors. CONCLUSIONS: GNRI is considered to be a useful prognostic factor in patients with ESCC undergoing esophagectomy.

Cardiac arrest caused by rapidly increasing ascites in a patient with TAFRO syndrome: a case report.

Case: Thrombocytopenia, anasarca, fever, renal insufficiency, and organomegaly (TAFRO) syndrome is a newly defined systemic inflammatory disorder with gradual progression of symptoms. A 59-year-old man with fever and ascites of unknown cause developed sudden-onset shock and respiratory failure in the general ward. Cardiac arrest immediately followed. Although he was resuscitated, frequent administration of adrenaline was required to maintain his blood pressure. His circulation was most effectively stabilized by drainage of fluid from his distended abdomen. The volume of discharged ascites reached 4,000 mL at that time, and several liters continued to be discharged for >1 month. The diagnosis of TAFRO syndrome was based on the clinical features and laboratory and histological findings. Outcome: The ascites volume and concentrations of inflammatory parameters decreased with treatment using several immunosuppressive agents. Conclusion: The newly defined TAFRO syndrome may be life-threatening. Patients should be monitored for progression to shock and cardiac arrest, especially those with rapidly increasing ascites.

A cytokine signal inhibitor for rheumatoid arthritis enhances cancer metastasis via depletion of NK cells in an experimental lung metastasis mouse model of colon cancer.

Current therapy for rheumatoid arthritis (RA) relies on global suppression of the immune response or specific blockade of inflammatory cytokines. However, it is unclear how immunosuppressants affect patients with cancer. Therefore, in the present study, the effect of three biological agents, tofacitinib, anti-mouse IL-6 receptor antibody (MR16-1) and etanercept, which are used for the treatment of RA diseases, on a tumor-bearing mouse model was investigated. The effect of the three agents was examined using a mouse lung-metastasis model with the murine colon 26 cancer cell line. Lymphocyte subsets and natural killer (NK) cells in peripheral blood and spleen were analyzed using fluorescence-activated cell sorting, and the number of lung surface nodules was examined. In the continuous tofacitinib administration (15 mg/kg/day) group, the number of lung surface nodules was significantly increased compared with that of the vehicle-treated group (vehicle, 1.20±0.58; tofacitinib, 35.6±10.81; P<0.01). NK cell number in the blood and spleen of tofacitinib-treated mice was decreased 10-fold, and the percentage of cluster of differentiation (CD)11+CD27- NK cells was significantly reduced. MR16-1 [8 mg/mouse; once a week; intraperitoneal (i.p.)] or etanercept (1 mg/mouse; 3 times a week; i.p.) treatment did not affect the number of NK cells or lung metastasis. In the present study, immunosuppressants that target cytokines, including tofacitinib, were demonstrated to inhibit the proliferation and differentiation of NK cells, and exhibit the potential to promote cancer metastasis using a mouse model of lung metastasis.

[A Case of Remnant Gastric Cancer That Completely Responded to Neoadjuvant S-1 and Cisplatin Therapy].

A 69-year-old man, who had undergone distal gastrectomy for duodenal ulcer, was diagnosed with remnant gastric cancer and jejunal mesenteric lymph node metastasis. To improve curability, we planned 2 courses of S-1 and cisplatin therapy. After chemotherapy, primary lesion and lymph node metastases reduced in size drastically. Completion gastrectomy and lymph node dissection were performed with curative intent. The tumor was found to have a pathological complete response(pCR) to chemotherapy on histological examination.

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.

Impact of mobilisation therapy on the haemodynamic and respiratory status of elderly intubated patients in an intensive care unit: A retrospective analysis.

OBJECTIVES: This study identified respiratory and haemodynamic parameters affected by limited mobilisation therapy in elderly, critically ill, intubated patients in an intensive care unit. METHODS: Over 18 months, we retrospectively assessed physiological changes during 43 mobilisation therapy sessions in 23 patients requiring mechanical ventilation for >48h. We compared heart rate, mean arterial blood pressure, respiratory rate, partial pressure of oxygen in arterial blood/inspired fraction of oxygen and lactate before and after mobilisation therapy, which entailed sitting on the edge of a hospital bed without back support. We analysed baseline characteristics and therapy duration. RESULTS: Patients' median age was 75 (interquartile range: 65-79) years, and the median Acute Physiology and Chronic Health Evaluation II score was 27 (26-31). Average therapy duration was 1h (0.5-2h). Therapy did not significantly modify heart rate or arterial blood pressure but increased the partial pressure of oxygen in arterial blood/inspired fraction of oxygen ratio significantly, from 218.8 (135.4-271.7) to 237.3 (167.2-284.9; p=0.007), indicating improved lung function. CONCLUSION: In this retrospective review, mobilisation therapy had no adverse effect on elderly, critically ill, intubated patients' haemodynamic status and appeared to improve the PaO2/FIO2 ratio; further research is required to confirm this finding.

Spontaneous Pneumoperitoneum due to Constipation.

We report a rare case of spontaneous pneumoperitoneum. An 82-year-old Japanese male patient was referred to our hospital because of constipation and abdominal pain. Abdominal computed tomography revealed a large amount of feces in the colon and rectum, and free air in the abdomen. Based on these findings, the patient was diagnosed with gastrointestinal perforation. Emergency exploratory laparotomy was performed. Neither perforation nor ischemic changes were recognized in the digestive tract. The patient's defecation was managed postoperatively until discharge on the 13th postoperative day. The authors assumed that free air, which was released after a mucosal injury due to the internal pressure caused by the presence of a large amount of feces in the colon and rectum, had penetrated the bowel wall through the bowel mucosa. We herein report the present case while also reviewing the pertinent literature.

Randomized Controlled Study to Evaluate the Efficacy of a Preoperative Respiratory Rehabilitation Program to Prevent Postoperative Pulmonary Complications after Esophagectomy.

BACKGROUND/AIMS: Patients with postoperative pulmonary complications after esophagectomy often have increased mortality. The purpose of the study was to examine the efficacy of preventing postoperative pulmonary complications by an intensive preoperative respiratory rehabilitation (PR) program for esophageal cancer patients. METHODS: This study was a prospective randomized controlled study. Thirty patients in the PR group and 30 patients in the no preoperative respiratory rehabilitation (NPR) group were included. The PR group received preoperative rehabilitation for more than 7 days, while the NPR group did not receive any preoperative rehabilitation. All patients underwent postoperative rehabilitation from the first postoperative day. The postoperative pulmonary complications were evaluated using the Clavien-Dindo classification (CDC) and the Utrecht Pneumonia Scoring System (UPSS). RESULTS: The CDC grade in the PR group was significantly lower than that in the NPR group (p = 0.014). The UPSS score in the PR group was significantly lower than that in the NPR group at postoperative day 1 (p = 0.031). In the multivariate analysis, NPR was an independent risk factor for postoperative pulmonary complications greater than CDC grade II (OR: 3.99, 95% CI: 1.28-12.4, p = 0.017). CONCLUSIONS: This study showed that the intensive PR program was capable of reducing the postoperative pulmonary complications in esophageal cancer patients.

Prone Position Is Useful in Thoracoscopic Enucleation of Esophageal Leiomyoma.

A 36-year-old man was admitted to our institute due to the diagnosis of esophageal submucosal tumor detected by a periodical upper gastrointestinal endoscopic examination without any complaint. Thoracoscopic enucleation of the lesion with the preoperative clinical diagnosis of esophageal leiomyoma was performed under general anesthesia in the prone position. After immunohistochemical examination, the pathological diagnosis was leiomyoma. There was no remarkable event during the postoperative hospital stay, and the patient was discharged on the 12th day after surgery. This case report suggests that the prone position might be superior to the left lateral decubitus position in thoracoscopic enucleation of esophageal leiomyoma.

Evaluating the fundamental critical care support course in critical care education in Japan: a survey of Japanese fundamental critical care support course experience.

BACKGROUND: The Fundamental Critical Care Support (FCCS) course has been introduced after minimal adaptation according to Japanese clinical settings. The original course in the USA is often used to prepare residents for rotations in the intensive care unit (ICU). Therefore, the FCCS program can be appropriate for the basic training of critical care in Japan to standardize critical care management. The purpose of this study is to evaluate whether Japanese FCCS course is useful and has a possibility to deserve a basis of critical care management in Japan. METHODS: The course program was provided with the form of lecture and skills stations. Pre- and post-training knowledge was assessed. After completion of the 2-day course, a questionnaire survey was administered to all course participants. Participants were asked to fill out the questions regarding socio-demographic characteristics. Participants were also asked to identify which lectures or skill stations they thought to be useful for clinical practice. Then, they were asked to rate their performance of each field: 'Assessment,' 'Diagnosis,' 'Recognition,' 'Response,' and 'Transfer'. RESULTS: The number of participants increased year after year and reached 1,804 during the past 4 years. Nearly 70% of the participants were physicians. Most of the others were nurses. In the established year, the percentage of physicians who had clinical experience more than 5 years exceeded 50%, however, this percentage gradually decreased. On the contrary, the percentages of residents and nurses increased. Regarding useful sessions, nearly half of the participants thought that mechanical ventilation was the most useful. With regard to the results of pre- and post-tests, the participants had already shown a high average mark (78.8 ± 14.1) at the pre-test. Furthermore, the score at the post-test was significantly improved (82.0 ± 6.6, p < 0.01). The participants' confidence in any field regarding critical care management was almost 4 points (5-point scale). CONCLUSIONS: It is considered that Japanese FCCS course is useful and has a promising basis of critical care management in Japan. Therefore, it is reasonable to think that Japanese FCCS mission has been successfully achieved.

Perioperative management of a neonate with Cantrell syndrome.

Cantrell syndrome is a congenital malformation with a pentalogy characterized by defects involving the abdominal wall, lower sternum, anterior diaphragm, and diaphragmatic pericardium, as well as congenital cardiac anomalies. We recently managed anesthesia in a patient with this syndrome and herein report our experience. The patient was a 14-day-old male neonate, who had been diagnosed with Cantrell syndrome, including ventricular septal defect, left ventricular diverticulum, abdominal wall defect, omphalocele, and sternal hypoplasia. Surgical interventions to close the ventricular septal defect, resect the left ventricular diverticulum, and close the omphalocele were scheduled. After cardiac surgery, the hernial contents were returned to their original compartment and, subsequently, an attempt was made to suture the abdominal wall. However, blood pressure fell markedly and the attempt was discontinued. The chest was left open postoperatively and the patient was transferred to the intensive care unit (ICU), during which time circulatory and respiratory management was very complex. Issues requiring particular attention in the management of anesthesia for patients with this syndrome include complications of diverse cardiac malformations, pulmonary hypertension, pulmonary hypoplasia, and respiratory and circulatory failure associated with increased intraabdominal pressure due to primary closure of the omphalocele. Accordingly, extreme caution must be taken to restore respiratory and circulatory control.

Dexmedetomidine sedation for pediatric post-Fontan procedure patients.

OBJECTIVE: The hemodynamic, respiratory, and sedative effects of dexmedetomidine (DEX) for pediatric patients post-Fontan surgery. DESIGN: Retrospective. SETTING: Single institutional intensive care unit. PARTICIPANTS: Fourteen patients undergoing Fontan-type surgery. RESULT: A retrospective review was conducted on 14 pediatric patients who had undergone a Fontan procedure for congenital heart disease. A vital component of postoperative management of these patients is to prevent an increase in pulmonary vascular resistance (PVR) that may lead to a serious reduction in cardiac output. DEX an alpha-2 adrenergic receptor agonist might offer an advantage over current sedation methods in preventing a rise in PVR. Nine patients received sedation with DEX and five patients in a control group were administered standard regimens of sedation and analgesia. The DEX group exhibited no evidence of an increased partial pressure of arterial carbon dioxide postoperatively as opposed to the control group. This lack of respiratory depression made the DEX group less likely to increase their PVR. However, the DEX group did experience a significant incidence of bradycardia that required the use of a cardiac pacemaker. CONCLUSIONS: The results of this retrospective review of the role of DEX in the management of the post-Fontan surgical pediatric patient indicate some potential advantages.

Influence of the porosity of hydroxyapatite ceramics on in vitro and in vivo bone formation by cultured rat bone marrow stromal cells.

The in vitro and in vivo osteoblastic differentiation of rat bone marrow stromal cells (MSCs) was assessed on hydroxyapatite disks with 3 different porosities: 30%, 50%, and 70% (HA30, HA50, and HA70, respectively). MSCs obtained by 10-day culture of fresh bone marrow cells were subcultured for 2 weeks on 3 kinds of porous HA disks in the presence and absence of dexamethasone (Dex). After 2 weeks of subculture, alkaline phosphatase (ALP) activity and osteocalcin production of MSCs/HA composites with Dex were higher than those without, and increased with increasing porosity. The resultant bone tissue grafts "cultured-bone/HA constructs" were implanted subcutaneously into the backs of syngeneic rats, and harvested 1, 2, and 4 weeks after implantation. At 1 week, only cultured-bone/HA70 constructs exhibited expanded bone formation. At 2 and 4 weeks, active osteoblasts and progressive bone formation were observed morphologically in both cultured-bone/HA50 and HA70 constructs. At 4 weeks, bone tissue was observed even in cultured-bone/HA30 constructs. ALP activity and osteocalcin production also increased with increasing porosity and time after implantation. In this in vivo model, different scaffold porosity with similar crystal morphology of the apatite phase demonstrated marked differences in ability to support osteogenesis by implanted rat MSCs.

Osteogenic differentiation of human dental papilla mesenchymal cells.

We isolated dental papilla from impacted human molar and proliferated adherent fibroblastic cells after collagenase treatment of the papilla. The cells were negative for hematopoietic markers but positive for CD29, CD44, CD90, CD105, and CD166. When the cells were further cultured in the presence of beta-glycerophosphate, ascorbic acid, and dexamethasone for 14 days, mineralized areas together with osteogenic differentiation evidenced by high alkaline phosphatase activity and osteocalcin contents were observed. The differentiation was confirmed at both protein and gene expression levels. The cells can also be cryopreserved and, after thawing, could show in vivo bone-forming capability. These results indicate that mesenchymal type cells localize in dental papilla and that the cells can be culture expanded/utilized for bone tissue engineering.

Role of metallothionein isoforms in bone formation processes in rat marrow mesenchymal stem cells in culture.

Temporal changes in mRNAs for metallothionein (MT) isoforms in subcultures of rat marrow mesenchymal stem cells (MSCs) after treatment with dexamethasone were investigated. Both MT-1 and MT-2 mRNA expression in the cultured MSCs with dexamethasone showed maximum levels at d 1, whereas ALP and osteocalcin mRNAs peaked at d 12. MT-3 mRNA was not detected in the cultured MSCs at any time. The expression level of MT-2 mRNA at d 1 was 9.4-fold higher than that of MT-1 mRNA. Finally, osteoblast differentiation and mineralization of MSCs at d 14 was inhibited by the addition of a common antisense oligonucleotide for both MT-1 and MT-2 in the culture medium during the first 4 d. The results suggest that the large amounts of MT-2 are produced in the early stage of subculture of MSCs, and this might regulate their differentiation.