Signaling adaptor protein Crk is involved in malignant feature of pancreatic cancer associated with phosphorylation of c-Met.

Signaling adaptor protein Crk has been shown to play an important role in various human cancers. Crk links tyrosine kinases and guanine nucleotide exchange factors (GEFs) such as C3G and Dock180 to activate small G-proteins Rap and Rac, respectively. In pancreatic cancer, various molecular targeted therapies have provided no significant therapeutic benefit for the patients so far due to constitutive activation of KRAS by frequent KRAS mutation. Therefore, the establishment of novel molecular targeted therapy in KRAS-independent manner is required. Here, we investigated a potential of Crk as a therapeutic target in pancreatic cancer. Immunohistochemistry on human pancreatic cancer specimens revealed that the patients with high expression of Crk had a worse prognosis than those with low expression. We established Crk-knockdown pancreatic cancer cells by siRNA using PANC-1, AsPC-1, and MIA PaCa-2 cells, which showed decreased cell proliferation, invasion, and adhesion. In Crk-knockdown pancreatic cancer cells, the decrease of c-Met phosphorylation was observed. In the orthotopic xenograft model, Crk depletion prolonged survival of mice significantly. Thus, signaling adaptor protein Crk is involved in malignant potential of pancreatic cancer associated with decrease of c-Met phosphorylation, and Crk can be considered to be a potential therapeutic molecular target.

[Subcutaneous myeloid sarcoma in a patient with essential thrombocythemia that transformed into acute myeloid leukemia].

Since November 2008, an 80-year-old man had been administered hydroxyurea and aspirin for the treatment of essential thrombocythemia (ET). In January 2012, his white blood cell count was markedly elevated, and he was treated with busulfan and cytarabine. In October 2012, he was hospitalized because of fever and general malaise, and a central venous port was placed in the right anterior chest owing to difficulty obtaining peripheral vascular access. Approximately 2 weeks after port placement, a subcutaneous mass was observed near the port. The patient died in November 2012 owing to exacerbation of the original disease. Autopsy revealed transformation to acute myeloid leukemia( AML; M2 subtype) and myeloid sarcoma (MS) in lymph nodes and the right anterior chest. The incidence of transformation of ET to AML is low, and MS as a comorbidity is rare. However, the risk of MS complications should be considered in patients with hematological malignancies due to recent increases in the use of central venous ports in such cases.

Actions of a novel water-soluble benzodiazepine-receptor agonist JM-1232(-) on synaptic transmission in adult rat spinal substantia gelatinosa neurons.

Although the intrathecal administration of JM-1232(-) reportedly produces antinociception, this action has not yet been examined at the cellular level. We examined the action of JM-1232(-) on synaptic transmission in spinal substantia gelatinosa (SG) neurons which play an important role in regulating nociceptive transmission from the periphery. The whole-cell patch-clamp technique was applied to the SG neurons of adult rat spinal cord slices. Bath-applied JM-1232(-) prolonged the decay phase of GABA(A)-receptor mediated spontaneous inhibitory postsynaptic current (sIPSC) and increased its frequency without a change in amplitude. The former but not latter action was sensitive to a benzodiazepine-receptor antagonist flumazenil. JM-1232(-) also increased glycinergic sIPSC frequency with no change in amplitude and decay phase. On the other hand, glutamatergic spontaneous excitatory transmission was unaffected by JM-1232(-). These results indicate that JM-1232(-) enhances inhibitory transmission by (1) prolonging the decay phase of GABAergic sIPSC through benzodiazepine-receptor activation and by (2) increasing the spontaneous release of GABA and glycine from nerve terminals without its activation. This enhancement could contribute to at least a part of the antinociceptive effect of intrathecally-administered JM-1232(-).

[Difficulty in left-sided double-lumen tube placement in patients undergoing surgical graft replacement of the descending aorta is predicted from tracheobronchial compression].

BACKGROUND: In surgical graft replacement of the descending aorta graft, one-lung ventilation (OLV) is required to provide adequate surgical view and to allow removal of blood from the left lung. It is best to use a double-lumen tube (DLT) to assure OLV but it is sometimes difficult to place the left-sided DLT due to thoracic aneurysm or the dissection lumen. We retrospectively investigated tracheobronchial anatomy by chest X-ray and chest computed tomography (CT) in 29 cases of descending aorta replacement to determine how best to manage difficult placement of the left-sided DLT. METHODS: From our database of 29 patients who had undergone descending aorta replacement between February 1, 2005, and December 31, 2009, we investigated the association between difficulty in placing the left-sided DLT and tracheobronchial anatomy by chest X-ray and CT. RESULTS: We could not place a left-sided DLT in 3 of 29 cases. Two of these cases were planned surgery for aortic aneurysm and the other was an emergency operation for acute aortic dissection. We could manage the two cases safely using a right-sided DLT. We compared chest X-ray and chest CT images of these 3 cases with the other 26 cases and found that compression of the tracheobronchial tree was prevalent in the cases of difficult placement of the left-sided DLT. CONCLUSIONS: We experienced difficulty in placement of the left-sided DLT in 3 of 29 cases of descending aorta replacement. We can predict difficulty of left-sided DLT placement by the presence of compression of the tracheobronchial tree on chest CT.

Validation study of postoperative liver failure and mortality risk scores after liver resection for perihilar cholangiocarcinoma.

Background: Surgery for perihilar cholangiocarcinoma (PHCC) remains a challenging procedure with high morbidity and mortality. The Academic Medical Center (Amsterdam UMC) and Memorial Sloan Kettering Cancer Center proposed a postoperative mortality risk score (POMRS) and post-hepatectomy liver failure score (PHLFS) to predict patient outcomes. This study aimed to validate the POMRS and PHLFS for PHCC patients at Hokkaido University. Methods: Medical records of 260 consecutive PHCC patients who had undergone major hepatectomy with extrahepatic bile duct resection without pancreaticoduodenectomy at Hokkaido University between March 2001 and November 2018 were evaluated to validate the PHLFS and POMRS. Results: The observed risks for PHLF were 13.7%, 24.5%, and 39.8% for the low-risk, intermediate-risk, and high-risk groups, respectively, in the study cohort. A receiver-operator characteristic (ROC) analysis revealed that the PHLFS had moderate predictive value, with an analysis under the curve (AUC) value of 0.62. Mortality rates based on the POMRS were 1.7%, 5%, and 5.1% for the low-risk, intermediate-risk, and high-risk groups, respectively. The ROC analysis demonstrated an AUC value of 0.58. Conclusions: This external validation study showed that for PHLFS the threshold for discrimination in an Eastern cohort was reached (AUC >0.6), but it would require optimization of the model before use in clinical practice is acceptable. The POMRS were not applicable in the eastern cohort. Further external validation is recommended.

Effects of cardiologist experience on outcomes of patients with ST-elevated myocardial infarction treated with primary PCI in a local area in Japan.

Primary percutaneous coronary intervention (PCI) for ST-elevated myocardial infarction (STEMI) results in dramatically improved clinical outcomes when performed in a timely manner. Although guidelines for STEMI patients recommend PCI should be performed by experienced operators with acceptable PCI volume, cardiologists in a local area must perform primary PCI at their own hospitals. This study evaluated the effects of cardiologist experience on outcomes for STEMI patients in a local area in Japan.Between April 2007 and March 2010, 140 consecutive STEMI patients were admitted to our hospital and 121 of these patients received primary PCI. STEMI patients undergoing primary PCI were divided into two groups according to the operator's experience as a cardiologist. We retrospectively analyzed their clinical backgrounds, PCI findings, in-hospital outcomes, and drug administration at discharge.There were no significant differences in any clinical characteristics, angiographic findings, or PCI procedures between the two groups. Clinical outcomes of the two groups were similar, except for the length of hospital stay (21.1 ± 5.8 versus 15.5 ± 9.7; P = 0.0255). The frequency of administration of drugs such as ß-blockers (59.1% versus 34.0%; P = 0.0086), aldosterone blockade (10.4% versus 25.5%; P = 0.0334), and nicorandil (76.1% versus 25.5%; P = < 0.0001) was different between the two groups.The clinical outcomes of STEMI patients in this study were satisfactory and almost equivalent when compared according to the experience of the attending cardiologist. The present findings suggest the important clinical implication that younger cardiologists who have experienced PCI procedures to a certain extent can safely perform primary PCI and contribute to better prognoses of STEMI patients.

Identification of physiological and toxic conformations in Abeta42 aggregates.

Aggregation of the 42-residue amyloid beta-protein (Abeta42) plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Despite numerous structural studies on Abeta aggregates, the relationship between tertiary structure and toxicity remains unclear. Our proline scanning and solid-state NMR studies suggested that aggregates both of wild-type Abeta42 and of E22K-Abeta42 (one of the mutants related to cerebral amyloid angiopathy) contain two conformers: a major one with a turn at positions 25 and 26, and a minor one with a turn at positions 22 and 23. To identify the toxic conformer, the derivative Abeta42-lactam(22K-23E), in which the side chains at positions 22 and 23 were covalently linked, was synthesized as a minor conformer surrogate, along with Abeta42-lactam(25K-26E) as a major conformer surrogate. The Abeta42-lactam(22K-23E) showed stronger aggregation, neurotoxicity, radical generation, and oligomerization than wild-type Abeta42, whereas in Abeta42-lactam(25K-26E) were weak. The transition from the physiological conformation with a turn at positions 25 and 26 to the toxic conformation with a turn at positions 22 and 23 might be a key event in the pathogenesis of AD.

Verification of the C-terminal intramolecular beta-sheet in Abeta42 aggregates using solid-state NMR: implications for potent neurotoxicity through the formation of radicals.

Structural analysis of 42-residue amyloid beta (Abeta42) aggregates using rotational resonance in solid-state NMR verified that C(beta) and/or C(gamma) of Met-35 and the carboxyl carbon of Ala-42 are proximal enough to form an intramolecular antiparallel beta-sheet in the C-terminus. The S-oxidized radical cation at Met-35, an ultimate radical species responsible for neurotoxicity, could be stabilized by the carboxylate anion at the C-terminus, resulting in aggregation to cause long-term oxidative stress.

Lusutrombopag (Mulpleta®) treatment in a patient with thrombocytopenia complicated by cirrhosis prior to continuous epidural anesthesia during renal artery embolization: a case report.

BACKGROUND: The oral thrombopoietin (TPO) receptor agonist lusutrombopag (Mulpleta®) was developed to improve thrombocytopenia in patients with chronic liver disease prior to elective invasive medical procedures. Mulpleta® was first approved for use in Japan in 2015 and in the USA in 2018. In the present report, we discuss a case in which pain management was performed during left renal artery embolization via continuous epidural anesthesia following oral administration of lusutrombopag. To our knowledge, this is the first report to discuss the use of lusutrombopag prior to epidural anesthesia. CASE PRESENTATION: The patient was a 78-year-old woman scheduled to undergo renal artery embolization to address a 3-cm aneurysm of the left renal artery. Fourteen days prior to the scheduled embolization procedure, the urologist was asked to insert an epidural catheter for perioperative and postoperative analgesia. Type C chronic cirrhosis was observed, and platelet count was 5.6 × 104/µL. Eleven days prior to embolization, oral lusutrombopag was initiated at a dosage of 3 mg/day (day 1). Oral lusutrombopag therapy was continued for 5 days, and platelet count on day 11 (i.e., the day prior to surgery) was 12.6 × 104/µL. An epidural catheter was inserted on day 12, following which embolization was performed. Platelet count on day 13 was 11.0 × 104/µL, and the catheter was removed on day 14. No symptoms of epidural hematoma or thrombosis were observed during the patient's disease course. CONCLUSIONS: As lusutrombopag is a relatively safe platelet-increasing agent, we believe that this drug can serve as a potential treatment option when performing elective epidural anesthesia in patients with chronic liver disease complicated by thrombocytopenia.

Blood stasis may cause thrombosis in the left superior pulmonary vein stump after left upper lobectomy.

BACKGROUND: We previously reported that arterial infarction of vital organs after lobectomy might occur only after left upper lobectomy and be caused by thrombosis in the left superior pulmonary vein stump. We hypothesized that changes in blood flow, such as blood stasis and disturbed stagnant flow, in the left superior pulmonary vein stump cause thrombosis, and this was evaluated by intraoperative ultrasonography. METHODS: From July 2013 to April 2014, 24 patients underwent lobectomy in the Steel Memorial Muroran Hospital. During the procedure, an ultrasound probe was placed at the pulmonary vein stump and the velocity in the stump was recorded with pulse Doppler mode. The peak velocity and the presence of spontaneous echo contrast in the stump were evaluated. After the operation, the patients underwent contrast-enhanced CT within 3 months. RESULTS: The operative procedures were seven left upper lobectomies, four left lower lobectomies, seven right upper lobectomies, and six right lower lobectomies. Blood flow was significantly slower in the left superior pulmonary vein stump than in the right pulmonary vein stumps. However, that was not significantly slower than that in the left inferior pulmonary vein stump. Spontaneous echo contrast in the pulmonary vein stump was seen in three patients who underwent left upper lobectomy. Of the three patients with spontaneous echo contrast, two patients developed thrombosis in the left superior vein stump within 3 months after the operation. There was no patient who developed arterial infarction. CONCLUSIONS: In patients who underwent left upper lobectomy, intraoperative ultrasonography to evaluate blood flow and the presence of spontaneous echo contrast in the left superior pulmonary vein stump may be useful to predict thrombosis that may cause arterial infarction.

Effective surgical treatment for controlling the acute heart failure induced by acutely progressed mitral regurgitation with nonbacterial thrombotic endocarditis.

A 45-year-old woman complaining of consciousness disturbance demonstrated multiple brain infarctions. Echocardiogram showed vegetation on the posterior mitral leaflet. Infectious endocarditis was initially suspected and we started empirical antibiotics. However, mitral vegetation grew rapidly and caused severe mitral regurgitation. Acute heart failure was so poorly controlled by conservative treatment that we concluded cardiac surgery was indicated. Mitral valve replacement was safely performed, and there was no sign of heart failure or recurrent thromboembolism during the postoperative course. Thereafter, multiple hepatic masses and a solid lesion in the pancreatic head were detected by computed tomography. The patient finally died of multiple organ failure that presumably resulted from malignancy in the terminal stage. The clinical course of this case can be explained by the pathology of nonbacterial thrombotic endocarditis (NBTE). The standard treatment for NBTE consists of systemic anticoagulation as well as controlling the underlying malignancy. However, we could not diagnose this case as NBTE before surgery. Although mitral valve replacement was finally effective to control acute heart failure in this case, NBTE should be exactly diagnosed as quickly as possible and the treatment policy should be deliberated.

Clinical manifestations and effects of primary percutaneous coronary intervention for patients with delayed pre-hospital time in acute myocardial infarction.

BACKGROUND: Prolonged pre-hospital time for acute myocardial infarction (AMI) is associated with decreased indication for primary percutaneous coronary intervention (PCI). However, the efficacy of primary PCI in AMI patients with prolonged pre-hospital time has not been fully investigated in Japan. METHODS AND RESULTS: A total of 3010 consecutive AMI patients admitted to AMI-Kyoto Multi-Center Risk Study Group hospitals were retrospectively analyzed, and the clinical characteristics and in-hospital prognosis of these patients were reviewed. Patients with pre-hospital delay [elapsed time (ET)>12 h] had a lower frequency of Killip≥3 (9.3%) and less frequently received primary PCI (77.7%) compared with patients with ET≤12 h. In the ET>12 h group, older patients or patients with MI history tended to be complicated by heart failure. Primary PCI was performed for patients with ET>12 h, irrespective of the severity of heart failure [Killip 1 (78.7%) vs Killip≥2 (74.0%); p=0.3827]. On multivariate logistic regression analysis, age [odds ratio (OR) 1.053], MI history (OR 2.860), Killip≥2 (OR 10.235), and multi-vessels or left main coronary artery as culprit (OR 11.712) were significant independent positive predictors of in-hospital mortality for patients with ET>12 h. Practice of primary PCI was not a significant negative predictor for patients with ET>12 h (OR 0.812), but it was for patients with ET≤12 h (OR 0.425). CONCLUSIONS: These findings indicate that patients with ET>12 h have a less severe condition and less frequently receive primary PCI compared with patients with ET≤12 h. Although primary PCI is often performed for these patients irrespective of the severity of heart failure, no preferable effect of primary PCI on the in-hospital mortality is demonstrated. In contrary, practice of primary PCI is a significant negative predictor of in-hospital mortality for patients with ET≤12 h.