Class B1 GPCR activation by an intracellular agonist.

G protein-coupled receptors (GPCRs) generally accommodate specific ligands in the orthosteric-binding pockets. Ligand binding triggers a receptor allosteric conformational change that leads to the activation of intracellular transducers, G proteins and ß-arrestins. Because these signals often induce adverse effects, the selective activation mechanism for each transducer must be elucidated. Thus, many orthosteric-biased agonists have been developed, and intracellular-biased agonists have recently attracted broad interest. These agonists bind within the receptor intracellular cavity and preferentially tune the specific signalling pathway over other signalling pathways, without allosteric rearrangement of the receptor from the extracellular side1-3. However, only antagonist-bound structures are currently available1,4-6, and there is no evidence to support that biased agonist binding occurs within the intracellular cavity. This limits the comprehension of intracellular-biased agonism and potential drug development. Here we report the cryogenic electron microscopy structure of a complex of Gs and the human parathyroid hormone type 1 receptor (PTH1R) bound to a PTH1R agonist, PCO371. PCO371 binds within an intracellular pocket of PTH1R and directly interacts with Gs. The PCO371-binding mode rearranges the intracellular region towards the active conformation without extracellularly induced allosteric signal propagation. PCO371 stabilizes the significantly outward-bent conformation of transmembrane helix 6, which facilitates binding to G proteins rather than ß-arrestins. Furthermore, PCO371 binds within the highly conserved intracellular pocket, activating 7 out of the 15 class B1 GPCRs. Our study identifies a new and conserved intracellular agonist-binding pocket and provides evidence of a biased signalling mechanism that targets the receptor-transducer interface.

Intraspecific divergence in a coastal plant, Euphorbia jolkinii, at a major biogeographic boundary in East Asia.

PREMISE: Quaternary climatic fluctuations and long-distance seed dispersal across the sea are critical factors affecting the distribution of coastal plants, but the spatiotemporal nature of population expansion and distribution change of East Asian coastal plants during this period are rarely examined. To explore this process, we investigated the genome-wide phylogenetic patterns of Euphorbia jolkinii Boiss. (Euphorbiaceae), which grows widely on littoral areas of Japan, Korea, and Taiwan. METHODS: We used plastome sequences and genome-wide single nucleotide polymorphisms in samples across the species range to reveal phylogeographic patterns and spatiotemporal distributional changes. We conducted ecological niche modeling for the present and the last glacial maximum (LGM). RESULTS: Genetic differentiation was observed between the northern and southern populations of E. jolkinii, separated by the major biogeographic boundary, the Tokara Gap. These two groups of populations differentiated during the glacial period and subsequently intermingled in the intermorainic areas of the central Ryukyu Islands after the LGM. Ecological niche models suggested that the potential range of E. jolkinii was restricted to southern Kyushu; however, it was widespread in the southern Ryukyu Islands and Taiwan during the LGM. CONCLUSIONS: This study provides evidence of genetic differentiation among coastal plant populations separated by the prominent biogeographical boundary. Although coastal plants are typically expected to maintain population connectivity through sea-drifted seed dispersal, our findings suggest that genetic differences may arise because of a combination of limited gene flow and changes in climate during the glacial period.

Thick mesopancreas is a novel predictor of surgical outcomes of patients who undergo pancreaticoduodenectomy.

PURPOSE: Mesopancreas resection is a crucial but difficult procedure when performing pancreaticoduodenectomy. This study evaluated the influence of mesopancreas thickness on surgical outcomes in patients undergoing pancreaticoduodenectomy. METHODS: We measured the thickness of the fat tissue on the right side of the superior mesenteric artery from the dorsal margin of the confluence of the superior mesenteric vein and portal vein to the ventral margin of the left renal vein on preoperative contrast-enhanced computed tomography and defined it as the mesopancreas thickness. We evaluated the correlation between mesopancreas thickness and intraoperative and postoperative variables in 357 patients who underwent pancreaticoduodenectomy. RESULTS: Multivariate analysis revealed that a thick mesopancreas was significantly associated with a long operative time (ß = 10.361; 95% confidence interval, 0.370-20.353, p = 0.042), high estimated blood loss (ß = 36.038; 95% confidence interval, -27.192-99.268, p = 0.013), and a low number of resected lymph nodes (ß = -1.551; 95% confidence interval, -2.662--0.439, p = 0.006). This analysis further revealed that thick mesopancreas was a significant risk factor for overall morbidity (odds ratio 2.170; 95% confidence interval 1.340-3.520, p = 0.002), major morbidity (odds ratio 2.430; 95% confidence interval 1.360-4.340, p = 0.003), and a longer hospital stay (ß = 2.386; 95% confidence interval 0.299-4.474, p = 0.025). CONCLUSION: A thick mesopancreas could predict a longer operation time, higher estimated blood loss, fewer resected lymph nodes, more frequent overall and major morbidities, and a longer hospital stay in patients who underwent pancreaticoduodenectomy more precisely than the body mass index.

Aqueous Povidone-Iodine Versus Normal Saline For Intraoperative Wound Irrigation on The Incidence of Surgical Site Infection in Clean-Contaminated Wounds After Gastroenterological Surgery: A Single-Institute, Prospective, Blinded-Endpoint, Randomized Controlled Trial.

OBJECTIVE: This trial evaluated the superiority of intraoperative wound irrigation (IOWI) with aqueous povidone-iodine (PVP-I) compared with that with saline for reducing the incidence of surgical site infection (SSI). BACKGROUND: IOWI with aqueous PVP-I is recommended for the prevention of SSI by the World Health Organization and the Centers for Disease Control and Prevention, although the evidence level is low. METHODS: This single institute in Japan, prospective, randomized, blinded-endpoint trial was conducted to assess the superiority of IOWI with aqueous PVP-I in comparison with IOWI with saline for reducing the incidence of SSI in clean-contaminated wounds after gastroenterological surgery. Patients 20 years or older were assessed for eligibility, and the eligible participants were randomized at a 1:1 ratio using a computer-generated block randomization. In the study group, IOWI was performed for 1 minute with 40 mL of aqueous 10% PVP-I before skin closure. In the control group, the procedure was performed with 100 mL of saline. Participants, assessors, and analysts were masked to the treatment allocation. The primary outcome was the incidence of incisional SSI in the intention-to-treat set. RESULTS: Between June 2019 and March 2022, 941 patients were randomized to the study group (473 patients) or the control group (468 patients). The incidence of incisional SSI was 7.6% in the study group and 5.1% in the control group (risk difference 0.025, 95% CI -0.006 to 0.056; risk ratio 1.484, 95% CI 0.9 to 2.448; P =0.154). CONCLUSION: The current recommendation of IOWI with aqueous PVP-I should be reconsidered.

Molecular aggregation in liquid-crystalline layers crucially affects their physics: smectic A (SmA)-nematic (N) phase transition.

Recently, two molecular packing modes of the alkyl chain in smectic A (SmA) liquid crystal phases were revealed: normal and tilted types, which are named by the orientation relative to the layer normal. This study reveals the relationship between the packing mode and thermodynamic order of the SmA-nematic (N) phase transition. Two normal type and three tilted type mesogens were subject to thermodynamic and structural experiments. The DSC results showed that the SmA-N phase transitions of the normal and tilted types are of the second and first order, respectively. The analysis of the intensities of reflections in wide-angle X-ray diffraction related to the periodicity of the SmA layer yielded the distribution of the mass centers of molecules along the normal to the SmA layers. The resultant distribution offered a rationale for the correlation of the thermodynamic order of the SmA-N phase transition and molecular packing modes in the SmA phases based on the Meyer-Lubensky theory.

A postoperative body weight increase is a novel risk factor for incisional hernia of midline abdominal incision after elective gastroenterological surgery.

PURPOSE: Midline abdominal incisions (MAIs) are widely used in both open and minimally invasive surgery. Incisional hernia (IH) accounts for most long-term postoperative wound complications. This study explored the risk factors for IH due to MAI in patients with clean-contaminated wounds after elective gastroenterological surgery. METHODS: The present study targeted patients enrolled in 2 randomized controlled trials to evaluate the efficacy of intraoperative interventions for incisional SSI prevention after gastroenterological surgery for clean-contaminated wounds. The patients were reassessed, and pre- and intraoperative variables and postoperative outcomes were collected. IH was defined as any abdominal wall gap, regardless of bulge, in the area of a postoperative scar that was perceptible or palpable on clinical examination or computed tomography according to the European Hernia Society guidelines. The risk factors for IH were identified using univariate and multivariate analyses. RESULTS: The study population included 1,281 patients, of whom 273 (21.3%) developed IH. Seventy-four (5.8%) patients developed incisional SSI. Multivariate logistic regression analysis revealed that female sex (odds ratio [OR], 1.39; 95% confidence interval [CI] 1.03-1.86, p = 0.031), high preoperative body mass index (OR, 1.81; 95% CI 1.19-2.77, p = 0.006), incisional SSI (OR, 2.29; 95% CI 1.34-3.93, p = 0.003), and postoperative body weight increase (OR, 1.49; 95% CI 1.09-2.04, p = 0.012) were independent risk factors for IH due to MAI in patients who underwent elective gastroenterological surgery. CONCLUSION: We identified postoperative body weight increase at one year as a novel risk factor for IH in patients with MAI after elective gastroenterological surgery.

Multiple origins of two Ochrosia (Apocynaceae) species endemic to the Bonin (Ogasawara) Islands.

The genus, Ochrosia, is widely distributed from the West Indian Ocean throughout tropical Asia to the Middle Southern Pacific region. Ochrosia comprises many island-endemic species, suggesting that long-distance dispersal and isolation after migration are key factors for clarifying the diversification process. However, the phylogeny and biogeography of endemic Ochrosia species have not been evaluated well due to the difficulty of adequate sampling from the entire distribution range of the genus. In this study, we focused on two Ochrosia species endemic to the Bonin (Ogasawara) Islands in the northwest Pacific. The Bonin Islands are of volcanic origins and consist of two islands groups, the Ogasawara and Volcano Islands groups, approximately 300 km apart. Ochrosia nakaiana is endemic to the Ogasawara Islands group, whereas O. hexandra is endemic to the Volcano Islands group. To elucidate the phylogenetic positions of these two endemic Ochrosia species, we conducted molecular phylogenetic studies with dating and biogeographic analyses including other Ochrosia species. The phylogenetic trees showed that the two endemic species had distinct origins; O. nakaiana was closely related to O. oppositifolia and O. iwasakiana, whereas O. hexandra was related to O. mariannensis. Based on the chloroplast DNA phylogeny, the genus, Ochrosia, divided into two major lineages 36.6 million years ago. Further, the two endemic species of the Bonin Islands were independently derived approximately 1-2 million years ago. Ochrosia nakaiana originated from the Southeast Asia, New Caledonia, or other Pacific Islands, while O. hexandra derived from O. mariannensis in Micronesia. We demonstrated different origins of the two endemic Ochrosia species on the Bonin Islands. This study provided an excellent example of the complex origins and speciation of flora in the oceanic islands.

Molecular dynamics and kinetics of isothermal cold crystallization with tunable dimensionality in a molecular glass former, 5'-(2,3-difluorophenyl)-2'-ethoxy-4-pentyloxy-2,3-difluorotolane.

This paper characterizes the molecular mobility that triggers the cold crystallization abilities in 5'-(2,3-difluorophenyl)-2'-ethoxy-4-pentyloxy-2,3-difluorotolane (short name DFP25DFT) material by broadband dielectric spectroscopy (BDS). We analyze the properties of identified molecular motions by referring to the Vogel-Fulcher-Tammann (VFT) model for the structural α-process associated with molecular rotation in isotropic liquid and the Eyring and Starkweather approach for the thermally activated processes, ß-process related to intramolecular movement in liquid and glassy state and emerging during cold crystallization α'-process ascribed to confined movements of molecules located adjacent to crystalline surfaces. To characterize the material, we employ single-crystal X-ray diffraction, differential scanning calorimetry (DSC), adiabatic calorimetry, and polarizing optical microscopy (POM), while we utilize molecular mechanics simulations (MM2) to explore molecular flexibility. Our study focuses on inter- and intramolecular interactions that determine the cold-crystallization tendency. We demonstrate that the solidification path is controlled by the fragility of the system, the dipole-dipole attraction, and the intramolecular dynamics. The study of cold crystallization kinetics under isothermal conditions reveals the complexity of the process: the formation of two crystalline phases, Cr2 and Cr3, proceeding in different modes. This feature discloses the possibility of switching the crystal growth between three- and two-dimensional in the cold-crystallization process driven by different mechanisms.

Drain output volume after pancreaticoduodenectomy is a useful warning sign for postoperative complications.

INTRODUCTION: The drain output volume (DOV) after pancreaticoduodenectomy (PD) is an easily assessable indicator in clinical settings. We explored the utility of the DOV as a possible warning sign of complications after PD. METHODS: A total of 404 patients undergoing PD were considered for inclusion. The predictability of the DOV for overall morbidity, major complications, intraabdominal infection (IAI), clinically relevant (CR) postoperative pancreatic fistula (POPF), CR delayed gastric emptying (DGE), CR chyle leak (CL), and CR post-pancreatectomy hemorrhaging (PPH) was evaluated. RESULTS: One hundred (24.8%) patients developed major complications, and 131 (32.4%) developed IAI. Regarding CR post-pancreatectomy complications, 75 (18.6%) patients developed CR-POPF, 23 (5.7%) developed CR-DGE, 20 (5.0%) developed CR-CL, and 28 (6.9%) developed CR-PPH. The median DOV on postoperative day (POD) 1 and POD 3 was 266 and 234.5 ml, respectively. A low DOV on POD 1 was an independent predictor of CR-POPF, and a high DOV on POD 3 was an independent predictor of CR-CL. A receiver operating characteristics (ROC) analysis revealed that the DOV on POD 1 had a negative predictive value (area under the curve [AUC] 0.655, sensitivity 65.0%, specificity 65.3%, 95% confidence interval [CI]: 0.587-0.724), with a calculated optimal cut-off value of 227 ml. An ROC analysis also revealed that the DOV on POD 3 had a positive predictive value (AUC 0.753, sensitivity 70.1%, specificity 75.0%, 95% CI: 0.651-0.856), with a calculated optimal cut-off value of 332 ml. CONCLUSION: A low DOV on POD 1 might be a postoperative warning sign for CR-POPF, similar to high drain amylase (DA) on POD 1, high DA on POD 3, and high CRP on POD 3. When the DOV on POD 1 after PD was low, surgeons should evaluate the reasons of a low DOV. A high DOV on POD 3 was a postoperative warning sign CR-CL, and might require an appropriate management of protein loss.

RELATIONSHIP BETWEEN PREOPERATIVE FOVEAL MICROSTRUCTURE AND VISUAL ACUITY IN MACULA-OFF RHEGMATOGENOUS RETINAL DETACHMENT: Imaging Analysis by Swept Source Optical Coherence Tomography.

PURPOSE: To visualize foveal microstructures in macula-off rhegmatogenous retinal detachment using swept source optical coherence tomography preoperatively and postoperatively and to investigate the relationship between foveal microstructures and postoperative visual acuity. METHODS: We retrospectively analyzed 42 eyes of 42 consecutive patients diagnosed with macula-off rhegmatogenous retinal detachment who underwent anatomically successful repair surgery and were followed up for 6 months. We used swept source optical coherence tomography to investigate the relationship between preoperative and postoperative continuity of both the external limiting membrane (ELM) and ellipsoid zone (Ez) and preoperative and postoperative best-corrected visual acuity. RESULTS: Both preoperative ELM and Ez were continuous in 9 eyes (21%; ELM+/Ez+ eyes), only the ELM was continuous in 25 eyes (60%; ELM+/Ez- eyes), and neither was continuous in 8 eyes (19%; ELM-/Ez- eyes). Postoperative best-corrected visual acuity in ELM+/Ez+ eyes (-0.05 ± 0.04 logarithm of the minimum angle of resolution units, Snellen equivalent 20/18) was significantly better than that in both ELM+/Ez- (0.16 ± 0.16, 20/29; P = 0.03) and ELM-/Ez- (0.86 ± 0.37, 20/145; P < 0.001) eyes. Postoperative best-corrected visual acuity was significantly better in ELM+/Ez- than in ELM-/Ez- eyes (P < 0.001). CONCLUSION: In macula-off rhegmatogenous retinal detachment, preoperative continuity of the ELM and Ez may be a predictor of postoperative best-corrected visual acuity.

O-GlcNAc Engineering of GPCR Peptide-Agonists Improves Their Stability and in Vivo Activity.

Peptide agonists of GPCRs and other receptors are powerful signaling molecules with high potential as biological tools and therapeutics, but they are typically plagued by instability and short half-lives in vivo. Nature uses protein glycosylation to increase the serum stability of secreted proteins. However, these extracellular modifications are complex and heterogeneous in structure, making them an impractical solution. In contrast, intracellular proteins are subjected to a simple version of glycosylation termed O-GlcNAc modification. In our studies of this modification, we found that O-GlcNAcylation inhibits proteolysis, and strikingly, this stabilization occurs despite large distances in primary sequence (10-15 amino acids) between the O-GlcNAc and the site of cleavage. We therefore hypothesized that this "remote stabilization" concept could be useful to engineer the stability and potentially additional properties of peptide or protein therapeutics. Here, we describe the application of O-GlcNAcylation to two clinically important peptides: glucagon-like peptide-1 (GLP-1) and the parathyroid hormone (PTH), which respectively help control glucose and calcium levels in the blood. For both peptides, we found O-GlcNAcylated analogs that are equipotent to unmodified peptide in cell-based activation assays, while several GLP-1 analogs were biased agonists relative to GLP-1. As we predicted, O-GlcNAcylation can improve the stability of both GLP-1 and PTH in serum despite the fact that the O-GlcNAc can be quite remote from characterized sites of peptide cleavage. The O-GlcNAcylated GLP-1 and PTH also displayed significantly improved in vivo activity. Finally, we employed structure-based molecular modeling and receptor mutagenesis to predict how O-GlcNAcylation can be accommodated by the receptors and the potential interactions that contribute to peptide activity. This approach demonstrates the potential of O-GlcNAcylation for generating analogs of therapeutic peptides with enhanced proteolytic stability.

A lack of postoperative complications after pancreatectomy contributes to the long-term survival of patients with pancreatic cancer.

BACKGROUND: /Objectives: The objectives of this study were to identify the factors affecting patients' survival and the characteristics of five-year survivors of pancreatic ductal adenocarcinoma (PDAC) after pancreatectomy as well as to clarify the correlation between the development of postoperative complications and a five-year survival. METHODS: A total of 104 patients underwent pancreatectomy for PDAC between April 2005 and March 2013 with curative intent. Patients who survived for more than five years after pancreatectomy were classified as long-term survivors. Sixteen demographic and clinical variables and 10 pathological variables were comprehensively assessed for their associations with the patients' survival time and long-term survival. RESULTS: The presence of preoperative comorbidity (OR: 1.65, 95% CI 1.02-2.67, p = 0.042), postoperative overall complications (OR: 1.78, 95% CI 1.03-3.10, p = 0.041), a lymph node positivity ratio of ≥0.2 (OR: 3.04, 95% CI 1.51-6.11, p = 0.002), and portal invasion (OR: 2.58, 95% CI 1.48-4.49, p = 0.001) were identified as independent factors affecting the patients' survival. The absence of postoperative overall complications was identified as an independent factor related to long-term survival in the multivariate analysis (OR: 0.08, 95% CI 0.01-0.82, p = 0.034). CONCLUSIONS: The presence of preoperative comorbidity, postoperative overall complications, LNR ≥0.2, and portal invasion were prognostic factors affecting the patients' survival, and avoiding postoperative complications after pancreatectomy might contribute to the long-term survival of PDAC patients after pancreatectomy. The further improvement of surgical procedures and perioperative care in order to reduce the rate of postoperative complications should be attempted.

Bridge of preoperative biliary drainage is a useful management for patients undergoing pancreaticoduodenectomy.

BACKGROUND/OBJECTIVES: The aims of this study were to clarify the effect of preoperative biliary drainage (PBD) on postoperative outcomes and the role of preoperative intentional exchange from endoscopic nasobiliary drainage (ENBD) to endoscopic retrograde biliary drainage (ERBD) for patients waiting to undergo pancreaticoduodenectomy (PD). METHODS: We evaluated the effect of PBD and intentional exchange of PBD on the perioperative variables in 292 patients. RESULTS: A total of 179 (61.3%) of 292 patients received PBD. There was no marked difference in the postoperative outcomes between the patients who did and did not receive PBD. Among the 160 patients who initially received endoscopic PBD, 10 (6.3%) underwent stent exchange for stent dysfunction, 59 (36.9%) who did not develop stent dysfunction underwent intentional stent exchange from ENBD to ERBD (bridge PBD group), and 91 (56.9%) did not receive any stent exchange (unchanged PBD group). The bridge PBD group had a longer duration of PBD (37 days) (p < 0.001) and a shorter preoperative hospital stay after PBD (32 days) (p < 0.001) than the unchanged PBD group (25 and 46 days, respectively); however, there were no significant differences in the postoperative variables. The incidence of stent exchange due to stent dysfunction in the bridge PBD group (11.9%) was lower than that in patients who initially received ERBD (36.0%) (p = 0.015). CONCLUSIONS: Bridge PBD worked well for extending the duration of PBD without worsening the postoperative outcomes after PD.

Preoperative intravascular ultrasonographic evaluation of leiomyosarcoma of the inferior vena cava: A case report.

Leiomyosarcoma of the inferior vena cava is a rare malignant tumor originating from smooth muscle cells of the vascular media. Its preoperative diagnosis by conventional noninvasive examinations such as abdominal ultrasonography, X-ray computed tomography, and magnetic resonance imaging, may be difficult because of their nonspecific findings. We present the case of a 72-year-old woman with leiomyosarcoma of the inferior vena cava diagnosed by intravascular ultrasonography.

A High Abdominal Aortic Calcification Score on CT is a Risk Factor for Postoperative Pancreatic Fistula in Elderly Patients Undergoing Pancreaticoduodenectomy.

BACKGROUND: To evaluate the clinical significance of a CT-based evaluation of abdominal aortic calcification (AAC) in the postoperative outcomes after pancreaticoduodenectomy (PD) in elderly patients. METHODS: Patients 70 years of age and older who were randomly assigned to Group A were compared with those younger than 70 who were assigned to Group B in terms of preoperative and intraoperative variables and postoperative outcomes. We compared the patients with clinically relevant postoperative pancreatic fistula (CR-POPF) (Group C) to those without CR-POPF (Group D), and especially Group A. We also compared the patients with CR-POPF (Group E) to those without CR-POPF (Group E) to clarify the risk factors for POPF, in each of the analyses. The AAC score was determined using the methods of Agatston et al. RESULTS: Group A more often had frequent atherosclerosis-related comorbidities (62.2%), low serum albumin (55.9%), and a high AAC score (66.1%). There were no significant differences in the postoperative variables. The comparisons between Groups C and D identified four independent risk factors for CR-POPF: BMI ≥ 25 (OR 8.54, 95% CI 3.15-23.1), male gender (OR 3.17, 95% CI 1.28-7.85), soft pancreatic parenchyma (OR 3.43, 95% CI 1.34-8.81), and the absence of MPD dilatation (OR 5.70, 95% CI 2.13-15.3). Comparisons between Groups E and F identified two independent risk factors for CR-POPF: BMI ≥ 25 (OR 29.4, 95% CI 5.77-150) and a high ACC score (OR 10.8, 95% CI 2.08-56.6). CONCLUSIONS: We demonstrated, for the first time, that a high AAC score is a risk factor of CR-POPF in elderly patients who underwent PD.

The Optimal Duration of PTH(1-34) Infusion Is One Hour per Day to Increase Bone Mass in Rats.

Parathyroid hormone (PTH) is a potential medicine for osteoporosis, and subcutaneous (s.c.) PTH treatment enhances bone mass; however, continuous infusion of PTH elicits bone resorption and induces bone loss. To clarify this contradictory phenomenon, we examined bone markers and bone mass in rats to assess the optimal duration of PTH(1-34) infusion. Continuous infusion of PTH at 1 µg/kg/h (Css, steady-state concentration ca. 300 pg/mL) for 1-4 h clearly stimulated the expression both of bone formation-related genes (c-fos, Wnt4, EphrinB2) and of bone resorption-related genes (tnfsf11, tnfsf11b, encoding receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG)), but s.c. treatment stimulated these genes only 1-h after the injection. Rats were treated with 1-, 2-, or 4-h infusions of PTH daily using a totally implanted catheter system, and the femoral bone mineral density (BMD) was measured at 4 weeks. The 1-h infusion of PTH significantly stimulated serum bone formation markers (procollagen I N-terminal propeptide (PINP) and osteocalcin) on day 14 and femoral BMD at 2 and 4 weeks, but the 4-h infusion of PTH did not enhance BMD. Since the 4-h infusion increased the levels of both the bone formation markers and a bone resorption marker (urinary C-terminal telopeptide of type 1 collagen (CTx)), the increased bone resorption may predominate over bone formation. The intermittent elevation of plasma PTH to 300 pg/mL for 1-h each day is optimal for increasing bone mass in rats. In osteoporosis therapy in human, using the optimal duration for the clinical dose of PTH may selectively stimulate bone formation.

Clinical characteristics of synchronous colorectal cancers in Japan.

BACKGROUND: Incidence and clinical characteristics of synchronous colorectal cancer (sCRC) patients significantly vary among studies, likely due to differences in surveillance methodology. If remain undetected, sCRC can progress to more advanced stages seriously aggravating patient prognosis. We studied the incidence and clinicopathological characteristics of Japanese patients with sCRCs who underwent surgery for primary CRC and received exhaustive perioperative surveillance. METHODS: We recruited 1005 patients with surgically resected CRCs between January 2007 and December 2011. The associations of clinical and pathological factors with sCRC development were assessed by univariate and multivariate logistic regression. RESULTS: Eighty-four patients (8.4 %) developed sCRCs, 16 of them (19.0 %) harboring three or more cancers. Companion sCRCs were smaller and earlier stage than the index lesion (P < 0.0001). In multivariate analysis, advanced age (odds ratio (OR) 1.03 per year; P = 0.009) and left colon tumor location (OR 1.78; P = 0.013) are associated with higher risk of sCRCs, particularly in females. Overall survival did not differ between solitary CRC and sCRC (P = 0.62). CONCLUSIONS: Our results highlight the importance of perioperative colonoscopy examination to ensure the absence of sCRCs that, being small and early staged, are more difficult to detect. The incidence of sCRC, and notably of triple or more sCRCs, was higher than previously recognized. Because they are also significantly higher than expected by merely stochastic accumulation of individual cancerous lesions, we suggest that the occurrence of many sCRC reflects a hitherto uncharacterized predisposition condition.

Multiple primary malignancies involving primary sporadic colorectal cancer in Japan: incidence of gastric cancer with colorectal cancer patients may be higher than previously recognized.

BACKGROUND: Improvement in the prognosis of colorectal cancer (CRC) patients has led to increasing occurrences of multiple primary malignancies (MPMs) alongside CRC but little is known about their characteristics. This study was undertaken to clarify the clinical and pathological features of MPMs, especially those at extra colonic sites, in patients with CRC. METHODS: We reviewed 1,111 patients who underwent operations for primary sporadic CRC in Saitama Medical Center, Jichi Medical University between April 2007 and March 2012. Two patients with familial adenomatous polyposis, one with hereditary non-polyposis colorectal cancer, two with colitic cancer, and any patients with metastasis from CRC were excluded. We compared the clinicopathological features of CRC patients with and without MPMs. As a control, we used a database compiled of patients with gastric cancer (GC) detected by mass screening performed in the Saitama Prefecture in Japan 2010 and compared these with CRC patients with synchronous GC. RESULTS: Multiple primary malignancies at extracolonic sites were identified in 117 of 1,111 CRC patients (10.5%). The median age was 68 (range, 29 to 96) versus 71 (50 to 92) (P < 0.001). The incidence of GC (44.4% (52 of 117)) was the highest of all MPMs. All CRC patients with GC were older than 57 years. Synchronous GC was detected in 26 patients. By contrast, out of 200,007 screened people, 225 people were diagnosed as having GC in the Saitama Prefecture. The age-standardized incidence of synchronous GC in CRC patients was significantly higher (0.53%) than in the control group (0.03%) (odds ratio, 18.8; 95% confidence interval, 18.6 to 19.0; P < 0.001). CONCLUSION: Patients with CRC who were older than 50 years preferentially developed GC synchronously and metachronously. Thus, this patient group should undergo careful perioperative screening for GC.

Instruction of expert surgeon secures favorable outcomes after standard pancreaticoduodenectomy performed by less experienced surgeons.

BACKGROUND/AIMS: We investigated the factors associated with a favorable outcome after standard pancreaticoduodenectomy (PD) performed by the less experienced surgeon under expert supervision in a high-volume hospital of PD. METHODOLOGY: Between April 2009 and March 2013, 139 PDs were performed in our hospital, and among them 99 PDs were standard fashion. Two expert surgeons performed 57 of 99 PDs, and the cases were assigned as Group A. Forty-two of 99 PDs were performed by 5 less experienced surgeons under the instruction of expert surgeons, and the cases were assigned as Group B. We compared the intraoperative outcomes and postoperative major complications and mortality between two groups. RESULTS: There was no hospital death in Group B, but one in Group A (1.8%), and the overall mortality rate of 99 patients in this series was 1.0%. In comparison of postoperative major complications, there was no significant difference in the frequencies of patients with all postoperative major complications (Group A; 43.9% vs. Group B 33.3%). CONCLUSIONS: Outcomes after standard PD performed by less experienced surgeons were favorable. The instruction of expert surgeon in a high volume hospital may secure a favorable outcome after standard PD.

[Systemic chemotherapy and surgery for recurrent metachronous liver metastases with peritoneal dissemination from triple colon cancers-a case report].

Although the first-line treatment for liver metastases arising from colorectal cancer is surgery, it is unknown whether this treatment is equally effective for liver metastases with peritoneal dissemination. We report a case of long-term survival after oxaliplatin-based chemotherapy and surgery for metachronous liver metastases with peritoneal dissemination from triple colon cancer. A 76-year-old man with a history of stage III descending colon cancer developed recurrent localized peritoneal dissemination and multiple liver metastases 30 months after surgery. He underwent partial liver resection, partial peritoneal resection, and 8 courses of capecitabine plus oxalitlatin (XELOX). There has been no disease recurrence 75 months after the initial surgery. While though there is no consensus for treatment of liver metastasis with peritoneal dissemination, surgery combined with systemic chemotherapy may be beneficial.