Feasibility and outcomes of robotic sphincter-preserving surgery for rectal cancer after neoadjuvant treatment in patients with preexisting colostomy.

BACKGROUND: Diverting colostomy followed by neoadjuvant treatment is a treatment of choice for obstructive rectal cancer. Such patients may be treated via a robotic approach with several advantages over conventional laparoscopic surgery. Conversely, the existing stoma may interfere with the optimal trocar position and thus affect the quality of robotic surgery. Moreover, the console surgeon does not face the patient, which may endanger the stoma. METHODS: Patients with rectal cancer who underwent sphincter-preserving surgery were retrospectively investigated using a robotic platform after neoadjuvant treatment at our hospital. Based on pretreatment stoma creation, patients were divided into the NS (those without a stoma) and S groups (patients with a stoma). Baseline characteristics, types of neoadjuvant treatment, short-term surgical outcomes, postoperative anorectal manometric data, and survival were compared between the groups. RESULTS: The NS and S groups comprised 65 and 9 patients, respectively. Conversion to laparotomy was required in three patients in the NS group. The S group required a longer console time than the NS group (median: 367 vs. 253 min, respectively, p = 0.038); however, no difference was observed in the total operative time (p = 0.15) and blood loss (p = 0.70). Postoperative complication rates, anorectal function, and oncological outcomes were similar between the groups. CONCLUSIONS: Although console time was longer in patients with a stoma, robotic surgery could be performed safely like in those without a stoma after neoadjuvant treatment.

Stereotactic navigation using registration based on intra-abdominal landmarks in robotic-assisted lateral pelvic lymph node dissection.

BACKGROUND: We carried out robot-assisted lateral pelvic lymph node dissection (LPLND) for rectal cancer with a stereotactic navigation system. The purpose of this study was to evaluate the accuracy and feasibility of the system. METHODS: We constructed a navigation system based on the Polaris Spectra optical tracking device (Northern Digital Inc., Canada) and the open-source software 3D Slicer (version 3.8.1; http://www.slicer.org ). We used the landmark-based registration method for patient-to-image registration. Body surface landmarks and intra-abdominal landmarks were used. We evaluated the time required for registration and target registration error (TRE; the distance between corresponding points after registration) for the root of the superior gluteal artery the root of the obturator or superior vesical artery, and the obturator foramen during minimally invasive LPLND for rectal cancer. Five patients who had LPLND for rectal cancer at the University of Tokyo Hospital between September 2020 and May 2021 were enrolled. RESULTS: The mean time required for registration was 49 s with the body surface landmarks and 88 s with the intra-abdominal landmarks. The mean TRE improved markedly when the registration was performed using intra-abdominal landmarks. The mean TRE of the root of the superior gluteal artery, the root of the obturator or superior vesical artery, and the obturator foramen were 55.8 mm, 53.4 mm, and 55.2 mm with the body surface landmarks and 11.8 mm, 10.0 mm, and 12.6 mm with the intra-abdominal landmarks, respectively. There were no adverse events related to the registration process. CONCLUSIONS: When stereotactic navigation systems are used for minimally invasive LPLND, the use of intra-abdominal landmarks for registration is feasible and may allow simpler and more accurate navigation than the use of body surface landmarks.

A randomized, controlled trial of once-weekly teriparatide injection versus alendronate in patients at high risk of osteoporotic fracture: primary results of the Japanese Osteoporosis Intervention Trial-05.

In this randomized, controlled trial, treatment with once-weekly subcutaneous injection of teriparatide for 72 weeks was found to be associated with a significant reduction in the incidence of morphometric vertebral fractures compared with alendronate in women with primary osteoporosis who were at high risk of fracture. INTRODUCTION: To determine whether the anti-fracture efficacy of teriparatide is superior to that of alendronate, a prospective, randomized, open-label, blinded-endpoint trial was performed. METHODS: Japanese women aged at least 75 years were eligible for the study if they had primary osteoporosis and were at high risk of fracture. Patients were randomly assigned in a 1:1 ratio to receive sequential therapy (once-weekly subcutaneous injection of teriparatide 56.5 µg for 72 weeks followed by alendronate for 48 weeks) or monotherapy with alendronate for 120 weeks. The primary endpoint was the incidence of morphometric vertebral fractures at 72 weeks (at the end of teriparatide treatment). RESULTS: Between October 2014 and December 2017, 1011 patients (505 in the teriparatide group and 506 in the alendronate group) were enrolled. Of these, 778 patients (351 and 427, respectively) were included in the primary analysis. The incidence of morphometric vertebral fractures was significantly lower in the teriparatide group (56 per 419.9 person-years, annual incidence rate 0.1334) than in the alendronate group (96 per 553.6 person-years, annual incidence rate 0.1734), with a rate ratio of 0.78 (95% confidence interval 0.61 to 0.99, P = 0.04). In both groups, adverse events were most frequently reported in the following system organ classes: infections and infestations, gastrointestinal disorders, and musculoskeletal and connective tissue disorders. CONCLUSION: Once-weekly subcutaneous injection of teriparatide significantly reduced the incidence of morphometric vertebral fractures compared with alendronate in women with primary osteoporosis who were at high risk of fracture. TRIAL REGISTRATION: jRCTs031180235 and UMIN000015573, March 12, 2019.

Hepatocellular carcinoma tumour burden score to stratify prognosis after resection.

BACKGROUND: Although the Barcelona Clinic Liver Cancer (BCLC) staging system has been largely adopted in clinical practice, recent studies have emphasized the need for further refinement and subclassification of this system. METHODS: Patients who underwent hepatectomy with curative intent for BCLC-0, -A or -B hepatocellular carcinoma (HCC) between 2000 and 2017 were identified using a multi-institutional database. The tumour burden score (TBS) was calculated, and overall survival (OS) was examined in relation to TBS and BCLC stage. RESULTS: Among 1053 patients, 63 (6·0 per cent) had BCLC-0, 826 (78·4 per cent) BCLC-A and 164 (15·6 per cent) had BCLC-B HCC. OS worsened incrementally with higher TBS (5-year OS 77·9, 61 and 39 per cent for low, medium and high TBS respectively; P < 0·001). No differences in OS were noted among patients with similar TBS, irrespective of BCLC stage (61·6 versus 58·9 per cent for BCLC-A/medium TBS versus BCLC-B/medium TBS, P = 0·930; 45 versus 13 per cent for BCLC-A/high TBS versus BCLC-B/high TBS, P = 0·175). Patients with BCLC-B HCC and a medium TBS had better OS than those with BCLC-A disease and a high TBS (58·9 versus 45 per cent; P = 0·005). On multivariable analysis, TBS remained associated with OS among patients with BCLC-A (medium TBS: hazard ratio (HR) 2·07, 95 per cent c.i. 1·42 to 3·02, P < 0·001; high TBS: HR 4·05, 2·40 to 6·82, P < 0·001) and BCLC-B (high TBS: HR 3·85, 2·03 to 7·30; P < 0·001) HCC. TBS could also stratify prognosis among patients in an external validation cohort (5-year OS 79, 51·2 and 28 per cent for low, medium and high TBS respectively; P = 0·010). CONCLUSION: The prognosis of patients with HCC varied according to the BCLC stage but was largely dependent on the TBS.

ANTECEDENTES: Aunque el sistema de estadificación del Barcelona Clinic Liver Cancer (BCLC) ha sido adoptado en gran medida en la práctica clínica, estudios recientes han enfatizado la necesidad de un mayor refinamiento y subclasificación del sistema BCLC. MÉTODOS: Los pacientes con carcinoma hepatocelular (hepatocellular cancer, HCC) BCLC-0, A y B que se sometieron a una hepatectomía con intención curativa entre 2000 y 2017 fueron identificados utilizando una base de datos multi-institucional. Se calculó la puntuación de carga tumoral (tumour burden score, TBS) y se examinó la supervivencia global (overall survival, OS) en relación con la TBS y los estadios BCLC. RESULTADOS: En la serie de 1.053 pacientes, 63 (6%) tenían HCC BCLC-0, 826 (78,4%) HCC BCLC-A y 164 (15,6%) HCC BCLC-B. La OS disminuyó de forma incremental en función de la mayor TBS (OS a 5 años; TBS baja: 77,9% versus TBS media: 61% versus TBS alta: 39%, P < 0,001). No se observaron diferencias en la OS entre pacientes con una puntuación TBS similar, independientemente del estadio BCLC (BCLC-A/TBS media: 61,6% versus BCLC-B/TBS media: 58,9%, P = 0,93; BCLC-A/TBS alta: 45,1% versus BCLC-B/TBS alta: 12,8%, P = 0,175). Los pacientes con BCLC-B/TBS media tuvieron una mejor OS que los pacientes con BCLC-A/TBS alta (58,9% versus 45,1%, P = 0,005). En el análisis multivariable, la TBS se mantuvo asociada a la OS en el caso de BCLC-A (TBS media: cociente de riesgos instantáneos, hazard ratio, HR = 2,07, i.c. del 95%: 1,42-3,02, P < 0,001; TBS alta: HR = 4,05, i.c. del 95%: 2,40-6,82, P < 0,001) y BCLC-B pacientes (TBS alta: HR = 3,85, i.c. del 95%: 2,03-7,30, P < 0,001). La TBS también pudo estratificar el pronóstico entre pacientes en una cohorte de validación externa (OS a 5 años; TBS baja: 78,7% versus TBS media: 51,2% versus TBS alta: 27,6%, P = 0,01). CONCLUSIÓN: El pronóstico de los pacientes con HCC varió según el estadio BCLC, pero dependió en gran medida de la TBS.

Possible Lightest Ξ Hypernucleus with Modern ΞN Interactions.

Experimental evidence exists that the Ξ-nucleus interaction is attractive. We search for NNΞ and NNNΞ bound systems on the basis of the AV8 NN potential combined with either a phenomenological Nijmegen ΞN potential or a first principles HAL QCD ΞN potential. The binding energies of the three-body and four-body systems (below the d+Ξ and ^{3}H/^{3}He+Ξ thresholds, respectively) are calculated by a high precision variational approach, the Gaussian expansion method. Although the two ΞN potentials have significantly different isospin (T) and spin (S) dependence, the NNNΞ system with quantum numbers (T=0, J^{π}=1^{+}) appears to be bound (one deep for Nijmegen and one shallow for HAL QCD) below the ^{3}H/^{3}He+Ξ threshold. Experimental implications for such a state are discussed.

Incidence of and risk factors for lymphocele formation after lateral pelvic lymph node dissection for rectal cancer: a retrospective study.

AIM: Pelvic lymphocele is a common complication that develops after pelvic lymph node dissection. The incidence of pelvic lymphocele formation has been reported to be 10.5-51% after gynaecological or urological procedures. However, no evidence has been reported thus far with regard to the development of pelvic lymphocele following lateral pelvic lymph node dissection (LPND) for low rectal cancer. The aim of this study was to investigate the incidence of and risk factors for lymphocele formation after LPND for low rectal cancer and to examine its clinical management. METHOD: We retrospectively analysed the incidence of and risk factors for pelvic lymphocele formation after LPND for rectal cancer in our hospital between January 2012 and December 2017. We also compared the size of the lymphocele between asymptomatic and symptomatic patients by using CT volumetry and examined its clinical management. RESULTS: A total of 30 out of 98 patients (30.8%) developed pelvic lymphocele after rectal LPND. The number of resected nodes was significantly higher in patients with a pelvic lymphocele (P < 0.01). The median volume was significantly higher in patients with symptomatic pelvic lymphocele (P = 0.011). Among the nine symptomatic patients, two underwent CT-guided drainage, one underwent transurethral ureteral stent placement and one underwent laparoscopic marsupialization. CONCLUSION: It is essential to keep in mind the possibility of pelvic lymphocele formation during follow-up of patients who undergo LPND, and to consider an appropriate treatment when these patients are symptomatic.

Vascular anatomy of the splenic flexure, focusing on the accessory middle colic artery and vein.

AIM: Recently, the accessory middle colic artery (AMCA) has been recognized as the vessel that supplies blood to the splenic flexure. However, the positional relationship between the AMCA and inferior mesenteric vein (IMV) has not been evaluated. Herein, we aimed to evaluate the anatomy of the AMCA and the splenic flexure vein (SFV). METHOD: Two hundred and five patients with colorectal cancer who underwent enhanced CT preoperatively were enrolled in the present study. The locations of the AMCA and IMV were evaluated, focusing on the positional relationship between the vessels and pancreas - below the pancreas or to the dorsal side of the pancreas. RESULTS: The AMCA was observed in 74 (36.1%) patients whereas the SFV was found in 177 (86.3%) patients. The left colic artery (LCA) was the major artery accompanying the SFV in 87 (42.4%) of patients. The AMCA accompanied the SFV in 65 (32.7%) patients. In 15 (7.8%) patients, no artery accompanied the SFV. The origin of the AMCA was located on the dorsal side of the pancreas in 15 (20.3%) of these 74 patients. Similarly, the destination of the IMV was located on the dorsal side of the pancreas in 65 (31.7%) of patients. CONCLUSION: The SFV was observed in most patients, and the LCA or AMCA was the common accompanying artery. In some patients these vessels were located on the dorsal side of the pancreas and not below it. Preoperative evaluation of this anatomy may be beneficial for lymph node dissection during left-sided hemicolectomy.

Effects of preceding endoscopic treatment on laparoscopic surgery for early rectal cancer.

AIM: Endoscopic treatment for rectal cancer, such as endoscopic mucosal resection and endoscopic submucosal dissection, causes inflammation, oedema and fibrosis in the surrounding tissue. However, little is known about the effect of these endoscopic therapies on salvage laparoscopic rectal surgery. The objective of this retrospective cohort study was to analyse the effect of preceding endoscopic treatment on the outcomes of laparoscopic surgery for rectal cancer. METHOD: We analysed 53 patients who underwent laparoscopic surgery for rectal cancer with clinical Tis or T1 at our department between May 2011 and June 2019. Data from 30 patients who underwent laparoscopic surgery after preceding endoscopic treatment (Group E + S) were compared with those of 23 patients who underwent laparoscopic surgery alone (Group S). RESULTS: There was no significant difference between the groups with respect to preoperative details. The mean operative time tended to be longer in Group E + S, and the volume of intra-operative blood loss was greater in Group E + S than in Group S (median 63 ml vs 10 ml, P = 0.049). There were no significant differences between the groups in other surgical parameters or oncological outcomes. CONCLUSION: Laparoscopic surgery after endoscopic treatment for rectal cancer may be difficult due to an increased risk of intra-operative bleeding. Long-term prognosis after surgery was not affected by preceding endoscopic treatment in rectal cancer.

Utility of computed tomography and 18 F-fluorodeoxyglucose with positron emission tomography/computed tomography for distinguishing appendiceal mucocele caused by mucinous adenocarcinoma from other pathologies.

AIM: Differentiating appendiceal mucocele with mucinous adenocarcinoma from other pathologies before surgery is difficult. The objective of this study was to evaluate the utility of CT and 18 F-fluorodeoxyglucose (FDG) with positron emission tomography (PET)/CT for differentiating mucinous adenocarcinoma of appendiceal mucocele from other pathologies. METHOD: The study included 25 patients who underwent surgery for clinically diagnosed appendiceal mucoceles detected on CT at the University of Tokyo Hospital. Among these patients, 19 underwent FDG-PET/CT preoperatively. We compared features of the CT imaging findings and maximum standard uptake values (SUVmax ) detected by FDG-PET/CT between mucocele with mucinous adenocarcinoma and other pathologies. RESULTS: A total of 13 men (52%) and 12 women (48%) were included in this study, with a median age of 65 years (range 34-83). There were six patients (24%) with pathologically confirmed mucinous adenocarcinoma, 15 patients (60%) with appendiceal mucinous neoplasm and four patients (16%) with simple mucocele caused by chronic inflammation. On the CT findings, wall irregularity was the only significant feature for the two groups in this study (83.3% vs 0.0%, P < 0.01). There was a significant difference in the SUVmax levels on PET/CT between the two groups (100.0% vs 20.0%, P < 0.01). CONCLUSION: Distinguishing between mucocele with mucinous adenocarcinoma and other pathologies using imaging modalities is challenging. Our results suggest that wall irregularity on CT and elevated SUVmax on PET/CT are useful factors that can be employed for such discrimination.

Obstruction is associated with perineural invasion in T3/T4 colon cancer.

AIM: Perineural invasion (PNI) is a risk factor for recurrence and metastasis and consequently leads to decreased survival in patients with various malignancies. Recent studies showed that stent placement in obstructive colon cancer increases the frequency of PNI. We hypothesized that mechanical stress including obstruction itself may be associated with PNI. METHOD: We retrospectively reviewed 496 patients with pathological T3 or T4 colon cancer who did not receive preoperative treatment. Data were collected from medical charts and pathological findings. The relationships between PNI and other clinicopathological factors were analysed using univariate and multivariate analyses. RESULTS: PNI was observed in 239 (48%) patients. Obstruction was markedly more frequent in PNI-positive cancer (39%) than in PNI-negative cancer (24%, P = 0.0003). Multivariate analyses identified obstruction as one of the significant factors associated with PNI (OR 1.68, P = 0.028). Moreover, in 414 patients without distant metastasis who underwent complete resection, PNI was an independent factor associated with poor recurrence-free survival (hazard ratio 2.35, P = 0.003). The coexistence of PNI and obstruction resulted in greater decreases in recurrence-free survival than PNI-negative and/or non-obstructive cases. CONCLUSION: Our results suggest that obstruction is associated with PNI and consequently contributes to an increased postoperative recurrence in colon cancer.

Genetic And Morphological Evaluation (GAME) score for patients with colorectal liver metastases.

BACKGROUND: This study sought to develop a clinical risk score for resectable colorectal liver metastasis (CRLM) by combining clinicopathological and clinically available biological indicators, including KRAS. METHODS: A cohort of patients who underwent resection for CRLM at the Johns Hopkins Hospital (JHH) was analysed to identify independent predictors of overall survival (OS) that can be assessed before operation; these factors were combined into the Genetic And Morphological Evaluation (GAME) score. The score was compared with the current standard (Fong score) and validated in an external cohort of patients from the Memorial Sloan Kettering Cancer Center (MSKCC). RESULTS: Six preoperative predictors of worse OS were identified on multivariable Cox regression analysis in the JHH cohort (502 patients). The GAME score was calculated by allocating points to each patient according to the presence of these predictive factors: KRAS-mutated tumours (1 point); carcinoembryonic antigen level 20 ng/ml or more (1 point), primary tumour lymph node metastasis (1 point); Tumour Burden Score between 3 and 8 (1 point) or 9 and over (2 points); and extrahepatic disease (2 points). The high-risk group in the JHH cohort (GAME score at least 4 points) had a 5-year OS rate of 11 per cent, compared with 73·4 per cent for those in the low-risk group (score 0-1 point). Importantly, in cohorts from both the JHH and MSKCC (747 patients), the discriminatory capacity of the GAME score was superior to that of the Fong score, as demonstrated by the C-index and the Akaike information criterion. CONCLUSION: The GAME score is a preoperative prognostic tool that can be used to inform treatment selection.

Silent KEL alleles identified from Japanese individuals with the Ko phenotype.

BACKGROUND AND OBJECTIVE: The rare Ko phenotype lacks all 36 antigens in the Kell blood system. The molecular basis of the Ko phenotype has been investigated, and more than 40 silent KEL alleles are reported by many investigators. The majority of silent alleles are the KEL*02 background. Here, we report molecular genetic analysis of the KEL gene in Japanese individuals with the Ko phenotype. MATERIALS AND METHODS: The Ko phenotype was screened from Japanese blood donors for several years using monoclonal anti-Ku or anti-K14 by an automated blood grouping system PK7300. Kell-related antigens were typed by standard tube tests. Genomic DNA was extracted from the blood samples, and KEL gene was analysed by polymerase chain reaction (PCR) and Sanger sequencing. RESULTS: We collected 35 Ko blood samples with K-k-, Kp(a-b-), Js(a-b-) and K14-. PCR and sequence analysis revealed that 11 individuals were homozygous for a mutant KEL allele with a c.299G>C (p.Cys100Ser) mutation (rs. 200268316). Three individuals were homozygous for the KEL*02N.24 allele that is c.715G>T (p.Glu239*), and one individual was homozygous for the KEL*02N.40 allele that is c.1474C>T (p.Arg492*). Five individuals were homozygous for novel KEL alleles with single-nucleotide mutations, four individuals had a c.2175delC (p.Pro725 fs*43), and one individual had a c.328delA (p.Arg110 fs*79). The remaining 15 individuals were compound heterozygous, and eight new alleles were identified from them. CONCLUSIONS: We identified three known and ten new silent KEL alleles from Japanese individuals with the Ko phenotype. The KEL allele with the c.299G>C (p.Cys100Ser) mutation was the most frequent.

Evaluation of the vascular anatomy of the left-sided colon focused on the accessory middle colic artery: a single-centre study of 734 patients.

AIM: Surgery for colorectal cancer located in the splenic flexure is difficult to perform because of the complex anatomy. Recently, in addition to the middle colic artery and left colic artery (LCA), the accessory middle colic artery (AMCA) has been recognized as a feeding artery for the left-sided colon. This study aimed to evaluate the vascular anatomy of the splenic flexure focusing on the AMCA in a large number of patients. METHOD: A total of 734 patients who underwent CT before surgery for colorectal cancer were enrolled. We retrospectively evaluated the vascular anatomy using both two- and three-dimensional CT angiography. RESULTS: The AMCA existed in 36.4% of the cases (n = 267). In many cases, it originated from the superior mesenteric artery (n = 228, 85.4%). The AMCA had a common trunk with the transverse pancreatic artery in 54 patients (20.2%). The frequency of the presence of the AMCA was associated with the branching pattern of the LCA, and was more frequent when the LCA was absent (P < 0.001). CONCLUSION: The presence of the AMCA is not rare and the AMCA has some branching patterns; therefore, recognizing it preoperatively and intra-operatively is important, being especially careful when the LCA is absent.

Evaluation of the molecular lipid organization in millimeter-sized stratum corneum by synchrotron X-ray diffraction.

BACKGROUND: The aim of this study was to investigate whether the lamellar and lateral structure of intercellular lipid of stratum corneum (SC) can be evaluated from millimeter-sized SC (MSC) by X-ray diffraction. MATERIALS AND METHODS: A 12 mm × 12 mm SC sheet from hairless mouse was divided into 16 pieces measuring 3 mm × 3 mm square. From another sheet, 4 pieces of ultramillimeter-sized SC (USC:1.5 mm × 1.5 mm square) were prepared. Small and wide-angle X-ray diffraction (SAXD and WAXD) measurements were performed on each piece. For MSC and USC, changes in the lamellar and lateral structure after the application of d-limonene were measured. RESULTS: The intensity of SAXD peaks due to the lamellar phase of long periodicity phase (LPP) and WAXD peaks due to the lateral hydrocarbon chain-packing structures varied in MSC and USC pieces, although over the 12 mm × 12 mm SC sheet. These results indicated that the intercellular lipid components and their proportion appeared nearly uniform. Application of d-limonene on MSC and USC piece with strong peaks in SAXD and the WAXD resulted in the disappearance of peaks due to the lamellar phase of LPP and decrease in peak intensity for the lateral hydrocarbon chain-packing structures. These changes are consistent with normal-sized sample results. CONCLUSION: We found that the selection of a sample piece with strong diffraction peaks due to the lamellar and lateral structure enabled evaluation of the SC structure in small-sized samples by X-ray diffraction.

Prognostic impact of margin status in liver resections for colorectal metastases after bevacizumab.

BACKGROUND: Margin status with resection of colorectal liver metastasis (CRLM) was an important prognostic factor in the years before the introduction of biological chemotherapy. This study examined outcomes following CRLM resection in patients who received neoadjuvant chemotherapy with or without the monoclonal antiangiogenic antibody bevacizumab. METHODS: Patients who underwent surgery for CRLM at the Johns Hopkins Hospital between 2000 and 2015 were identified from an institutional database. Data regarding surgical margin status, preoperative bevacizumab administration and overall survival (OS) were assessed using multivariable analyses. RESULTS: Of 630 patients who underwent CRLM resection, 417 (66·2 per cent) received neoadjuvant chemotherapy with (214, 34·0 per cent) or without (203, 32·2 per cent) bevacizumab. The remaining 213 (33·8 per cent) did not receive neoadjuvant chemotherapy. Univariable analysis found that positive margins were associated with worse 5-year OS than R0 resection (36·2 versus 54·9 per cent; P = 0·005). After dichotomizing by the receipt of preoperative bevacizumab versus chemotherapy alone, the prognostic value of pathological margin persisted among patients who did not receive preoperative bevacizumab (5-year OS 53·0 versus 37 per cent after R0 versus R1 resection; P = 0·010). OS was not significantly associated with margin status in bevacizumab-treated patients (5-year OS 46·8 versus 33 per cent after R0 versus R1 resection; P = 0·081), in whom 5-year survival was slightly worse (presumably reflecting more advanced disease) than among patients treated with cytotoxic agents alone. Pathological margin status was not significantly associated with 5-year OS in patients with a complete or near-complete response to chemotherapy and bevacizumab (43 versus 30 per cent after R0 versus R1 resection; P = 0·917), but this may be due to a type II error. CONCLUSION: The impact of margin status varied according to the receipt of bevacizumab. Bevacizumab may have a role to play in improving outcomes among patients with more advanced disease.

High-Resolution Quantum Sensing with Shaped Control Pulses.

We investigate the application of amplitude-shaped control pulses for enhancing the time and frequency resolution of multipulse quantum sensing sequences. Using the electronic spin of a single nitrogen-vacancy center in diamond and up to 10 000 coherent microwave pulses with a cosine square envelope, we demonstrate 0.6-ps timing resolution for the interpulse delay. This represents a refinement by over 3 orders of magnitude compared to the 2-ns hardware sampling. We apply the method for the detection of external ac magnetic fields and nuclear magnetic resonance signals of ^{13}C spins with high spectral resolution. Our method is simple to implement and especially useful for quantum applications that require fast phase gates, many control pulses, and high fidelity.

Efficacy and safety of rebamipide liquid for chemoradiotherapy-induced oral mucositis in patients with head and neck cancer: a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II study.

BACKGROUND: Recent preclinical and phase I studies have reported that rebamipide decreased the severity of chemoradiotherapy-induced oral mucositis in patients with oral cancer. This placebo-controlled randomized phase II study assessed the clinical benefit of rebamipide in reducing the incidence of severe chemoradiotherapy-induced oral mucositis in patients with head and neck cancer (HNC). METHODS: Patients aged 20-75 years with HNC who were scheduled to receive chemoradiotherapy were enrolled. Patients were randomized to receive rebamipide 2% liquid, rebamipide 4% liquid, or placebo. The primary endpoint was the incidence of grade ≥ 3 oral mucositis determined by clinical examination and assessed by central review according to the Common Terminology Criteria of Adverse Events version 3.0. Secondary endpoints were the time to onset of grade ≥ 3 oral mucositis and the incidence of functional impairment (grade ≥ 3) based on the evaluation by the Oral Mucositis Evaluation Committee. RESULTS: From April 2014 to August 2015, 97 patients with HNC were enrolled, of whom 94 received treatment. The incidence of grade ≥ 3 oral mucositis was 29% and 25% in the rebamipide 2% and 4% groups, respectively, compared with 39% in the placebo group. The proportion of patients who did not develop grade ≥ 3 oral mucositis by day 50 of treatment was 57.9% in the placebo group, whereas the proportion was 68.0% in the rebamipide 2% group and 71.3% in the rebamipide 4% group. The incidences of adverse events potentially related to the study drug were 16%, 26%, and 13% in the placebo, rebamipide 2%, and rebamipide 4% groups, respectively. There was no significant difference in treatment compliance among the groups. CONCLUSIONS: The present phase II study suggests that mouth washing with rebamipide may be effective and safe for patients with HNC receiving chemoradiotherapy, and 4% liquid is the optimal dose of rebamipide. TRIAL REGISTRATION: ClinicalTrials.gov under the identifier NCT02085460 (the date of trial registration: March 11, 2014).

Prospective study of dietary energy density and weight gain in a Japanese adult population.

High dietary energy density (ED) has been associated with weight gain. However, little is known about the long-term effects of ED on weight changes among free-living subjects, particularly in Japanese and other Asian populations. In this study, we assessed dietary habits and weight changes in participants (5778 males and 7440 females, 35-69 years old) of the Takayama study. ED was estimated using a validated FFQ at baseline only. Information on body weight (BW) was obtained by self-administered questionnaires at baseline and follow-up. Mean BW difference in 9·8 years was 17 (se 4221) g for men and -210 (se 3889) g for women. In men, ED was positively associated with BW at follow-up after controlling for age, BW, height, physical activity score, alcohol consumption, energy intake, years of education at the baseline and change of smoking status during the follow-up. On average, men in the highest quartile of ED (>5·322 kJ/g (>1·272 kcal/g)) gained 138 (se 111) g, whereas men in the lowest ED (<1·057) lost 22 (se 111) g (P for trend=0·01). The association between ED and BW gain was stronger in men with normal weight. In women, the association between ED and weight change was not statistically significant. In conclusion, contrary to some studies that report an association between ED and weight gain in the overweight only, our data suggest that high-ED diets may be associated with weight gain in the lean population as well, at least in male subjects.

TNF-α-induced IL-6 and MMP-9 expression in immortalized ameloblastoma cell line established by hTERT.

OBJECTIVE: Ameloblastoma (AM) shows locally invasive behaviour. However, biological investigations regarding regulation of gene expression associated with AM pathological features are difficult to perform, because AM cells can be passaged for a few generations due to senescence. We report a newly established immortalized AM cell line, AMB cells, by transfection with human telomerase reverse transcriptase (hTERT). Furthermore, we examined whether TNF-α modulates bone resorption-related genes, IL-6 and MMP-9 in cooperation with TGF-ß or IFN-γ. MATERIALS AND METHODS: Following transfection of an hTERT expression vector into AM cells using a non-viral method, the effects of cytokines on the expressions of IL-6 and MMP-9 mRNA were examined using real-time PCR. TNF-α-induced NF-κB activity was examined by western blotting and transcription factor assays. RESULTS: AMB cells continued to grow for more than 100 population doublings. Stimulation with TNF-α increased IL-6 and MMP-9 mRNA expressions, as well as NF-κB activation. Furthermore, TGF-ß and IFN-γ dramatically increased TNF-α-mediated expressions of MMP-9 and IL-6 mRNA, respectively, while those responses were suppressed by NF-κB inhibitor. CONCLUSION: We established an immortalized AM cell line by hTERT transfection. TNF-α-mediated regulation of MMP-9 and IL-6 via NF-κB may play an important role in the pathological behaviour of AMs, such as bone resorption.

A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC).

BACKGROUNDS: Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur-uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer. PATIENTS AND METHODS: The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20-80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500-600 mg/day on days 1-5, followed by 2 days rest) or S-1 (80-120 mg/day on days 1-28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events. RESULTS: In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63-0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm. CONCLUSION: One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection.