Handling unstable analytes: literature review and expert panel survey by the Japan Bioanalysis Forum Discussion Group.

Analyzing unstable small molecule drugs and metabolites in blood continues to be challenging for bioanalysis. Although scientific countermeasures such as immediate cooling, immediate freezing, addition of enzyme inhibitors, pH adjustment, dried blood spot or derivatization have been developed, selecting the best practices has become an issue in the pharmaceutical industry as the number of drugs with such problems is increasing, even for generic drugs. In this study, we conducted a comprehensive literature review and a questionnaire survey to determine a suitable practice for evaluating instability and implementing countermeasures. Three areas of focus, matrix selection, effect of hemolysis and selection of esterase inhibitors, are discussed.

Successful treatment of gastric cancer after complete response of lung cancer by nivolumab: a case report.

BACKGROUND: Nivolumab is effective for gastric cancer and lung cancer, but complete response is rare. We experienced a case of synchronous gastric cancer and lung cancer who was treated by nivolumab and laparoscopic gastrectomy. CASE PRESENTATION: A 63-year-old male consulted our institution and was found to have gastric cancer cT1(SM)N0M0 Stage IA and lung cancer cT2N2M1(PUL) Stage IV. He received eight chemotherapy treatments plus radiation, but the lung disease remained progressive. Finally, he received nivolumab therapy and complete response of both cancers was obtained. The gastric cancer recurred, but was successfully treated by laparoscopic gastrectomy. The resected specimen revealed three lesions, each being pT1aN0M0 Stage IA. The primary gastric cancer seemed to have completely vanished without scarring. CONCLUSIONS: This was thought to be a rare case of gastric cancer recurrence after complete response of gastric cancer and lung cancer to nivolumab.

[A Case of Esophageal Neuroendocrine Carcinoma(NEC)Treated with Collective Treatment].

A 68-year-old man presented to our hospital. An upper gastrointestinal tract endoscopy performed elsewhere revealed an elevated lesion with a circumferential esophageal cancer(identified as small cell carcinoma). Perthe treatment forsmall cell cancer and the standard treatment for esophageal neuroendocrine carcinoma, 7 courses of CBDCA(5mg/m2)plus ETP (100mg/m2)were administered. The lesion shrank and the lymph node swelling disappeared and the patient was deemed to be in partial remission. Nine months later, however, the primary tumor increased in size. A transthoracic subtotal esophagectomy( laparoscope-assisted), 2 area dissection, and gastric tube reconstruction(post-sternal)were performed at 2 years and 10 months afterdiagnosis.

[Three Cases of Lower Advanced Rectal Cancer Involving Pathological Complete Response after Neoadjuvant Chemoradiotherapy].

Neoadjuvant chemoradiotherapy(NACRT)was administered at our hospital to 3 patients with lower advanced rectal cancer; NACRT resulted in pathological complete response(pCR). Case 1: A 65-year-old man was diagnosed with T4aN1M0, cStage Ⅲb disease; after chemoradiotherapy(CRT), the clinical stage improved to T4aN0M0, ycStage Ⅱb. Laparoscopic Hartmann's procedure and D3 lymph node dissection were performed 51 days after CRT. No recurrence was observed 31 months after surgery. Case 2: A 67-year-old man was diagnosed with T4aN2M0, cStage Ⅲb disease; after CRT, the clinical stage improved to T4aN1M0, ycStage Ⅲa. Laparoscopic abdominoperitoneal resection and D3 lymph node dissection were performed 57 days after CRT. No recurrence was observed 21 months after surgery. Case 3: An 83-year-old woman was diagnosed with T4aN2M0, cStage Ⅲb disease; after CRT, the clinical stage improved to T4aN0M0, ycStageⅡb. Laparoscopic abdominoperitoneal resection and D3 lymph node dissection were performed 64 days after CRT. No recurrence was observed 16 months after surgery. Here, we report 3 cases of lower advanced rectal cancer involving curative resection following CRT, and we provide a short literature review.

[A Case of Long-Term Survival with Far Advanced Gastric Cancer after Multidisciplinary Treatments, including Conversion Surgery].

An 82-year-old man with Stage Ⅳ advanced gastric cancer and multiple liver metastases was referred to our hospital. Chemotherapy using S-1 was administered, resulting in withdrawal from the usual course because of an adverse event of grade 4 anorexia. GIS and EOB-MRI showed a prominent tumor reduction in both lesions; however, despite this, distal gastrectomy, D2 lymph node dissection, liver biopsy for S3 lesion, partial liver resection for S6 lesion, and cholecystectomy were performed to obtain a therapeutic diagnosis. Pathology revealed that the tumor cells remained in the main liver metastatic lesions. Therapeutic effect was assessed as Grade 2. Although weekly paclitaxel followed by reduced S-1 dosage was introduced after surgery, the recurrent mass was observed in the para-aortic region after 2 years. Subsequently, para-aortic lymph node dissection was performed because no new lesion was detected. More than 10 years have passed without any recurrence since the first surgery. As part of a multidisciplinary treatment for far advanced gastric cancer with multiple liver metastases (Stage Ⅳ), conversion surgery might be considered effective.

Upregulation of microRNA-31 is associated with poor prognosis in patients with advanced colorectal cancer.

Colorectal cancer (CRC) manifests after the accumulation of genetic and epigenetic alterations along with tumor microenvironments. MicroRNA (miRNA/miR) molecules have been revealed to serve in critical roles in the progression various types of cancer, and their expression level is often an important diagnostic, predictive or prognostic biomarker. The aim of the present study was to evaluate the potential of miRNAs as prognostic biomarkers for patients with advanced CRC. miRNA arrays were performed on CRC specimens obtained from tumors with various molecular statuses [e.g. KRAS proto-oncogene, GTPase (KRAS)/B-Raf proto-oncogene, serine/threonine kinase (BRAF)/microsatellite instability (MSI)], and their paired normal mucosal specimens. The miRNA array revealed that miR-31-5p (miR-31) was specifically upregulated in CRCs with the BRAF V600E mutation, the results of which were supported by subsequent analysis of a dataset retrieved from The Cancer Genome Atlas (TCGA) database, which contained information regarding 170 patients with CRC including 51 BRAF-mutant CRCs. Of our cohort of 67 patients with stage IV CRC, 15 (22%) and 4 (6%) showed KRAS and BRAF V600E mutations, respectively. Since the median miR-31 expression was 3.45 (range, 0.004-6330.531), the cut-off value was chosen as 3.5, and all tumors were categorized into two groups accordingly (high-/low-miR-31 expression). The high miR-31 expression group (n=33) was significantly associated with a poorer mortality (univariate hazard ratio=2.12; 95% confidence interval, 0.23-0.95; P=0.03) and exhibited a shorter median survival time (MST; 20.1 months) compared with the low miR-31 expression group (n=34) (MST, 38.3 months; P=0.03), indicating that miR-31 is a promising prognostic biomarker for patients with advanced CRC. Thus, performing a functional analysis of miR-31 expression may lead to the development of new targeted therapies for the various genetic subtypes of CRC.

Chiral Higgs Mode in Nematic Superconductors.

Nematic superconductivity with spontaneously broken rotation symmetry has recently been reported in doped topological insulators, M_{x}Bi_{2}Se_{3} (M=Cu, Sr, Nb). Here we show that the electromagnetic (EM) response of these compounds provides a spectroscopy for bosonic excitations that reflect the pairing channel and the broken symmetries of the ground state. Using quasiclassical Keldysh theory, we find two characteristic bosonic modes in nematic superconductors: the nematicity mode and the chiral Higgs mode. The former corresponds to the vibrations of the nematic order parameter associated with broken crystal symmetry, while the latter represents the excitation of chiral Cooper pairs. The chiral Higgs mode softens at a critical doping, signaling a dynamical instability of the nematic state towards a new chiral ground state with broken time reversal and mirror symmetry. Evolution of the bosonic spectrum is directly captured by EM power absorption spectra. We also discuss contributions to the bosonic spectrum from subdominant pairing channels to the EM response.

Clinical significance of preoperative chemoradiotherapy for advanced esophageal cancer, evaluated by propensity score matching and weighting of inverse probability of treatment.

The present study used inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) to compare survival benefits among 112 patients with resectable, stage II-IV esophageal squamous cell carcinoma (SCC) treated between 1996 and 2016 with neoadjuvant chemoradiotherapy (NAC) plus surgery (Group A, n=55) or with surgery alone (Group B, n=57). Their propensity scores (PS) were calculated using a multivariable logistic regression model in which age, sex, cancer site, primary tumor length, cTNM stage, lymph node metastasis and depth of tumor invasion were the independent variables, and used to match Groups A and B according to the IPTW and matching method. After IPTW and PSM, univariate analysis was used to assess overall survival (OS) and disease-free survival (DFS), followed by Cox proportional hazard models for OS using IPTW between the two groups and the subgroups. After PSM, 5-year OS and DFS were significantly higher in Group A (OS: 65.2%, DFS: 65.2%) compared with Group B (OS: 31.2%, DFS: 20.87%). Similarly, after IPTW, OS and DFS were significantly higher in Group A compared with Group B patients. Five-year OS was 73.18% for Group A and 37.69% for Group B (hazard ratio: 0.2899, 95% confidence interval: 0.1167-0.7205). To conclude, treatment was more effective in Group A patients with clinical stage II, N0 and T3 disease involving the mid-esophagus. It was concluded that for patients with esophageal SCC, NAC plus esophagectomy exhibited improved survival compared with surgery alone, as demonstrated by use of IPTW and PSM methods.

[Three Cases of Decompression Failure in Colon Stent Placement for Obstructive Colorectal Cancer].

Forty-four patients underwent decompression using a self-expandable metallic stent for obstructive colorectal cancer as a bridge to surgery in our department. Three failure cases were examined. Case 1: A Rs, Ra type 2 cancer was treated with WallflexTM 60 mm. Enough decompression could not be obtained, and an additional stent was placed. Consequently, the patient underwent a transverse colostomy. Case 2: A Ra type 2 cancer was treated with Niti-S 60 mm. The patient's chief complaint was not improved due to the tumor ingrowth. Consequently, he underwent a transverse colostomy. Case 3: A sigmoid type 2 cancer was treated with Niti-S 80 mm. Decompression was successful. However, CT scan revealed another tumor in the descending colon. He underwent a transverse colostomy for further examination. The causes of the failure differed in each case. We gained many learning points from these cases that are useful for future treatment.

[A Resected Case of Rectal Metastasis from Gastric Cancer].

An 82-year-oldwoman previously underwent total gastrectomy for gastric cancer at the age of 75 years. After 7 years of follow-up, a colonoscopy was performedto investigate the cause of constipation, which revealedan irregularity in the rectal submucosa. A colonoscopy-guidedbiopsy showedpoorly differentiatedad enocarcinoma, andthe immunohistochemical staining pattern showedMUC2(-), MUC5AC(+), CDX2(+), andCA1 25(-). FDG-PET showedintense uptake only at the rectum. Thus, laparoscopic high anterior resection was performed. Pathological findings showed that poorly differentiated adenocarcinoma and signet-ring cell carcinoma hadd evelopedmainly in the submucosa. In comparison with the immunohistological features of the previous gastric cancer, the rectal tumor hadsimilar morphological characteristics. The definitive diagnosis was rectal metastasis from gastric cancer. She has remained recurrence-free in the 20 months since this operation.

[HER2-Positive Advanced Gastric Cancer with Para-Aortic Lymph Node Metastases Treated with Conversion Surgery after Chemotherapy-A Case Report].

A 56-year-old woman diagnosed with type 2 gastric cancer and multiple lymph node metastases(T3N3M1[lym], cStage Ⅳ)was treated with chemotherapy using trastuzumab with S-1 plus cisplatin for 6 cycles. The primary lesion showed PR, and lymph node metastases disappeared after the chemotherapy. Because of adverse events, she was administered with 2 additional cycles of trastuzumab with S-1 plus cisplatin and 6 cycles of trastuzumab with capecitabine plus oxaliplatin. However, the primary lesion increased in size. Therefore, she underwent distal gastrectomy and D1+ lymphadenectomy with para-aortic lymph node sampling as a conversion surgery. The pathological diagnosis was T2N0M0, pStage ⅠB, and the primary cancer was Grade 1a owing to the chemotherapeutic effect. She survives without recurrence or postoperative adjuvant therapies 3 years after the surgery.

[A Case of Far-Advanced Esophageal Cancer with Multiple Metastases Showing Long-Term Survival after Chemotherapy].

A 71-year-oldman with voice hoarseness was referredto our hospital for further examination. He was diagnosedwith unresectable Stage Ⅳb esophageal cancer, with direct invasion to the aorta andtrachea andmultiple metastases to the lymph nodes, lungs, and adrenal gland. Because his performance status(PS)was deemedto be favorable, he receivedchemotherapy with docetaxel(DOC), cisplatin, and5 -FU(DCF therapy). After 2 cycles of DCF therapy, the primary lesion was scarred. No malignant lesions were detected in the biopsy performed. No distant metastases were identified on PET-CT. As a subsequent treatment, S-1 plus DOC therapy was administered. Finally, single S-1 administration was continued. The treatment periodwas 14 months. Treatment was concludedbecause a complete response(CR)was maintained. Three years after the conclusion of treatment, CR remains maintained. The overall survival in cases of unresectable advanced esophageal cancer is saidto be 3-10 months, but there are remarkable cases such as this one. If a goodPS is maintained, treatment shouldbe actively considered because CR is possible.

Negative Thermal Magnetoresistivity as a Signature of a Chiral Anomaly in Weyl Superconductors.

We propose that the chiral anomaly of Weyl superconductors gives rise to negative thermal magnetoresistivity induced by emergent magnetic fields, which are generated by vortex textures of order parameters or lattice strain. We establish this scenario by combining the argument based on Berry curvatures and the quasiclassical theory of the Eilenberger equation with quantum corrections arising from inhomogeneous structures. It is found that the chiral anomaly contribution of the thermal conductivity exhibits characteristic temperature dependence, which can be a smoking-gun signature of this effect.

Laparoscopic treatment of median arcuate ligament syndrome in a 16-year-old male.

INTRODUCTION: MALS(Median Arcuate Ligament Syndrome) is rare disease. We experienced the case of MALS and successfully treated by laparoscopic approach. PRESENTATION OF CASE: A 16-year-old male was admitted to our hospital with postprandial epigastric pain that had been present for 3 years. Abdominal three-dimensional computed tomographic angiography showed stenosis of the celiac trunk, and abdominal Doppler ultrasonography showed that the blood flow in the celiac trunk varied between inspiration and expiration. Hence, the patient was diagnosed with median arcuate ligament syndrome. Laparoscopic decompression of the celiac trunk was performed by division of the ligament and partial excision of the celiac plexus. Intraoperative Doppler ultrasonography showed markedly improved flow in the celiac artery. The patient was discharged from hospital on postoperative day 7, and has no recurrent symptoms at 12 months postoperatively. DISCUSSION: This case was most youngest male MALS treated by laparoscopic approach. CONCLUSION: Laparoscopic division of the median arcuate ligament is a minimally invasive, safe, and effective method for decompression of the celiac artery.

[The Implications of Conversion Surgery for Stage â £ Gastric Cancer].

BACKGROUND: The median survival time(MST)of Stage Ⅳ advanced gastric cancer is reportedly 6-13 months. The standard treatment for Stage Ⅳ gastric cancer is systemic chemotherapy. With advancements in chemotherapy, the number of conversion surgery(CS)is increasing. AIM: We evaluated the clinical significance of CS for Stage Ⅳ gastric cancer. METHOD: We retrospectively examined the clinicopathological variables and oncologic outcomes of 11 patients with Stage Ⅳ gastric cancer who received CS after induction chemotherapy. RESULTS: The MST was 86.4 months in all patients. No significant difference was detected in non-curative clinical factors, pathological type, residual tumor, or Ef-Grade. A longer prognosis could be achieved when an R0 resection was obtained, with excellent histopathologial response, without peritoneal dissemination, and with negative peritoneal lavage cytology. CONCLUSION: This study provides positive evidence that CS for Stage Ⅳ gastric cancer could be performed safely and could possibly provide longer survival in selected patients.

Prediction of Anastomotic Leakage After Laparoscopic Low Anterior Resection in Male Rectal Cancer by Pelvic Measurement in Magnetic Resonance Imaging.

OBJECTIVE: Anastomotic leakage after laparoscopic low anterior resection in male rectal cancer patients with a narrow pelvis cannot be easily resolved. The objective of this study is to assess numerical information of narrow pelvis and to determine whether prediction of morbidity can be possible. METHODS: Retrospective medical record review was performed. From July 2007 to January 2013, 43 consecutive male patients with low rectal cancer who underwent laparoscopic low anterior resection were divided into the anastomotic leakage-negative group and anastomotic leakage-positive group. Eleven anatomic parameters were measured from preoperative magnetic resonance imaging of pelvis and a new index called "pelvic index" was calculated. RESULTS: The pelvic index (difference between the interspinous distance and the diameter of the mesorectum divided by the depth of the cavity of the lesser pelvis) in the leakage-positive group was significantly smaller than that in the negative group (P=0.038). Comparison between those 2 groups at the border of the cut-off value of the pelvic index (13.0) showed a significant difference. CONCLUSIONS: Preoperative assessment by the pelvic index can predict the narrow pelvis and risk of anastomotic leakage.

Local control of sphincter-preserving procedures and abdominoperineal resection for locally advanced low rectal cancer: Propensity score matched analysis.

Sphincter-preserving procedures (SPPs) for surgical treatment of low-lying rectal tumors have advanced considerably. However, their oncological safety for locally advanced low rectal cancer compared with abdominoperineal resection (APR) is contentious. We retrospectively analyzed cohort data of 1500 consecutive patients who underwent elective resection for stage II-III rectal cancer between 2010 and 2011. Patients with tumors 2-5 cm from the anal verge and clinical stage T3-4 were eligible. Primary outcome was 3-year local recurrence rate, and confounding effects were minimized by propensity score matching. The study involved 794 patients (456 SPPs and 338 APR). Before matching, candidates for APR were more likely to have lower and advanced lesions, whereas SPPs were carried out more often following preoperative treatment, by laparoscopic approach, and at institutions with higher case volume. After matching, 398 patients (199 each for SPPs and APR) were included in the analysis sample. Postoperative morbidity was similar between the SPPs and APR groups (38% vs 39%; RR 0.98, 95% CI 0.77-1.27). Margin involvement was present in eight patients in the SPPs group (one and seven at the distal and radial margins, respectively) and in 12 patients in the APR group. No difference in 3-year local recurrence rate was noted between the two groups (11% vs 14%; HR 0.77, 95% CI 0.42-1.41). In this observational study, comparability was ensured by adjusting for possible confounding factors. Our results suggest that SPPs and APR for locally advanced low rectal cancer have demonstrably equivalent oncological local control.

Feasibility of sequential adjuvant chemotherapy with a 3-month oxaliplatin-based regimen followed by 3 months of capecitabine in patients with stage III and high-risk stage II colorectal cancer: JSWOG-C2 study.

BACKGROUND: Six months of oxaliplatin-based chemotherapy is the standard adjuvant chemotherapy for completely resected stage III colorectal cancer (CRC). Also, patients with stage II CRC who are considered to be at high risk of disease recurrence often receive the same adjuvant chemotherapy treatment. We prospectively investigated the extent and degree of neuropathy suffered by stage III and high-risk stage II resectable CRC patients who underwent sequential approach involving 3 months of an oxaliplatin-based regimen followed by 3 months of capecitabine. PATIENTS AND METHODS: Patients with completely resected stage III and high-risk stage II CRC aged ≥20 years were eligible. Patients were treated with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) for 3 months followed by capecitabine (2,500 mg/m2 on days 1-14 every 3 weeks) for 3 months. Primary end points were frequency and the grade of oxaliplatin-induced neurotoxicity as evaluated using the physician-based Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) grading and the patient-based scale, self-reported Patient Neurotoxicity Questionnaire. RESULTS: Ninety-one patients were enrolled and 86 patients assessed. Eighty-four percent of patients completed the planned oxaliplatin-based therapy for 3 months, and 63% of patients completed all treatments for the full 6 months. Overall incidences of grade 3 or 4 peripheral sensory or motor neuropathy according to the CTCAE were 3.5% and 1.2%, respectively. Regarding the peripheral sensory neuropathy, the proportion of Patient Neurotoxicity Questionnaire (grade C-E) and CTCAE (grade 2-4) at months 1.5/3/6 were 11.3/22.1/29.4% and 5.3/4.4/11.3%, respectively (Spearman correlation coefficient: 0.47). CONCLUSION: A sequential approach to adjuvant chemotherapy with 3 months of an oxaliplatin-based regimen followed by 3 months of capecitabine was tolerated by patients and associated with a low incidence of neuropathy.

Fluctuation in Plasma 5-Fluorouracil Concentration During Continuous 5-Fluorouracil Infusion for Colorectal Cancer.

BACKGROUND/AIM: It is generally believed that the plasma concentration of 5-fluorouracil (5-FU) is constant when 5-FU is continually administered for chemotherapy. The aim of the present study was to verify whether this is true. PATIENTS AND METHODS: Nine patients with colorectal cancer were enrolled in this study. All patients received chemotherapy; four patients received FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) and five received FOLFOX (leucovorin, 5-fluorouracil, oxaliplatin). 5-FU was administered continuously (2400 mg/m(2)) for 46 h. Serum was collected at 12 points after the start of administration. The concentration of 5-FU was evaluated using a new immunoassay method and gas chromatography-mass spectrometric (GC/MS) method. RESULTS: The concentrations of 5-FU fluctuated dramatically over time, with greater than 3-fold changes in each individual, and the pattern was not constant. CONCLUSION: Because the serum concentration of 5-FU fluctuates and displays various patterns, the dosage should not be based on body surface area. A new individualized method for determining the 5-FU dosage should be developed.

Multi-layered intra-abdominal adhesion prophylaxis following laparoscopic colorectal surgery.

BACKGROUND: Small bowel obstruction secondary to intra-abdominal adhesions is a frequent postoperative complication. Less invasive surgery carries a lower risk of postoperative adhesions, but adhesions may still occur after laparoscopic colorectal surgery. We present here some of our methods of adhesion prophylaxis for laparoscopic colorectal surgery. METHODS: The 167 patients who underwent laparoscopic colorectal surgery at our center from 2007 to 2012 were retrospectively reviewed. To prevent postoperative intra-abdominal adhesions, anti-adhesion barriers were placed using the half-overlap method. The rate of postoperative small bowel obstruction was compared among three groups: patients who received no adhesion prophylaxis (Group NP), patients who received single-layered adhesion prophylaxis adjacent to the incision (Group SP), and patients who received three layers of adhesion prophylaxis at different depths (Group MLP). RESULTS: The rate of postoperative ileus was significantly different among the three groups, at 9.7 % (6/62) in Group NP, 5.0 % (1/19) in Group SP, and 0 % (0/86) in Group MLP). CONCLUSIONS: This retrospective analysis found that placement of multi-layered anti-adhesion barriers using the half-overlap method provided the most effective prophylaxis. Prospective clinical trials are needed to further evaluate these methods of anti-adhesion prophylaxis.